2 Early Arthritis Diagnosis and Management

Eular On-line Course on Rheumatic Diseases – module n°2 Bernard Combe, Jackie Nam, Paul Emery

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EARLY ARTHRITIS: DIAGNOSIS AND MANAGEMENT

Jackie Nam, Bernard Combe, Paul Emery

LEARNING OUTCOMES At the end of the module participants should be able to:

• Discuss the term Early Arthritis and its significance

• Describe and evaluate the diagnostic measures used in the diagnosis of Early Arthritis

(clinical, radiological & laboratory)

• Describe and discuss the prognostic factors in Early Arthritis

• Outline and evaluate the treatment modalities (pharmacological and non-pharmacological)

available for the management of Early Arthritis

• Discuss the aims of treatment and the outcome measures used to evaluate the treatment of

the disease

I INTRODUCTION

Rheumatoid arthritis (RA) is the most common and most serious inflammatory arthritis. Untreated it

results in joint destruction, functional impairment and increased mortality. The outcome of the

disease, however, has improved considerably in recent years with early diagnosis, the availability of

effective therapies and the recognition that early intensive treatment strategies result in better

outcomes.

In practice, patients with inflammatory arthritis should be seen early and treated at the earliest

opportunity. Clinicians must differentiate between the early features of RA (an inflammatory arthritis

that has the potential to become progressive and destructive) from those that will remit

spontaneously, and from diseases that may present with similar clinical features, e.g. systemic lupus

erythematosus (SLE) or the spondarthropathies. Decisions with regard to optimal therapeutic

strategies are also required. The goal of treatment is early suppression of inflammation and ideally

establishing remission in order to prevent joint damage, disability, and the long-term complications of

the disease.

This module will provide some background and an approach to the diagnosis and treatment of EARLY

ARTHRITIS.

Other recent reviews on the topic can be found in the reference section (1-7).


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II BACKGROUND

II-1 The Clinical Rationale for Early Management

Although definitions vary, remission implies a low disease activity state that if sustained is neither

damaging nor disabling. Spontaneous remission in true RA is rare. In a cohort of 458 patient with RA

followed up for 1131 patient years, 14% achieved remission without treatment (8). In another study of

183 RA patients with a follow-up of 5 years, a remission rate of 20% was described; 11% were in

spontaneous remission and 9% was drug-induced(9). In the majority of patients, untreated, the

disease persistents and results in joint damage, functional decline and premature mortality.

The joint damage and loss of function in RA occur early in the disease process. Radiographic

outcome studies have shown that 70% of patients with recent onset RA develop bony erosions within

the first 3 years (10). Furthermore, within 3 months of disease onset 25% of patients have erosions

evident on X-ray(11). Newer imaging techniques such as magnetic resonance imaging (MRI) and

ultrasound (US) have confirmed evidence of damage within weeks on onset of symptoms (12, 13).

Early radiographic erosions also predict the future development of further lesions. Those seen on US

& MRI also correlate reliably with later radiographic erosions (14).

Studies have also shown that a delay in treatment is associated with poorer outcomes. In a meta-

analysis of 12 studies with 1133 RA patients, disease duration less than 2 years, an average delay of

9 months in starting DMARDs significantly increased subsequent radiographic progression (15).

Similarly in an early arthritis cohort assessment of patients with symptom onset ≥12 weeks was

associated with a hazard ratio of 1.87 for not achieving DMARD-free remission and a 1.3 times higher

rate of joint destruction over 6 years, as compared with assessment in <12 weeks (16).

As the majority of patients with RA will have persistent disease and there is evidence that joint

damage occurs early and that delayed treatment results in worse outcomes, inflammatory arthritis

should be diagnosed and treated early. The question remains how early is early?

II-2 Window of opportunity The concept of a ‘window-of-opportunity’ suggests that there is a period early in the course of the

disease when the disease process can be altered or maybe even reversed with a complete return to

normality. Therapy during this period may have a much greater effect than treatment at a later stage

in terms of halting disease progression and achieving remission (17).

Previously, studies used a cut-off of less than 5 years to define early disease. By the 1990s, symptom

duration of less than 12 to 24 months was considered early. This duration was chosen because at the


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end of this period, most patients have incurred significant damage when treated conventionally. It is

now recognised that this period may be limited to weeks or months. There is also increasing evidence

that very early RA, i.e. within the first 12 weeks, may be an immunopathologically distinct phase

compared to later disease (18).

Studies have tested this very early window of opportunity. An unblinded study of a single dose of

corticosteroid in 63 patients with mild early inflammatory arthritis (median duration 20 weeks) found

the strongest predictor of disease remission at 6 months to be disease duration less than 12 weeks at

time of therapy(19). Clinical and radiographic outcomes were significantly better at 3 years among a

cohort of 20 patients who started DMARD therapy 3 months after disease onset (very early)

compared to 20 with a median 12 months disease duration at treatment start (early)(11). Remission

was achieved in 50% in the very early group compared to only 15% in the early group. The major

differences between the two groups occurred within the first year and especially during the first 3

months of treatment. Further evidence for the importance of early treatment comes from a post hoc

analysis of a randomised controlled trial of 417 early RA patients in which the use of a biological

DMARD + methotrexate (MTX) in patients with disease duration less than 4 months provided

significantly better disease control with better remission (rate increased by 40%) and low disease

activity scores than treatment later (20). Interestingly this increased remission rate with very early

treatment was not seen in the monotherapy MTX group.

Inflammatory arthritis may even be identified at an earlier stage. It is now recognised that the steps

towards the development of RA occur along a disease continuum from patients who may have a

genetic predisposition for the disease, to those presenting with non-specific symptoms to early

undifferentiated arthritis and RA. Rheumatoid factor (RF) and antibodies to citrullinated peptide

(ACPA) have been detected in patients with RA years before the onset of symptoms - evidence that

the disease process begins in the preclinical phase i.e. before the onset of symptoms. Elevated levels

of high sensitivity C-reactive protein (CRP) have also been shown before onset of clinical disease

(21). Complementary to the serologic changes, imaging with ultrasound and MRI, and arthroscopy

detect synovitis in clinically normal joints of patients with early RA (22).

II-3 The Challenges Of Early Disease

The first few weeks or months of symptoms, therefore, represent a potentially important therapeutic

window in patients with very early synovitis destined to develop RA. However, treating patients within

this phase presents several challenges:

1. Assessing patients with inflammatory arthritis early

2. Predicting which patients with early synovitis will develop RA and thus require treatment

3. Determining how such patients should be treated


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As there is no single diagnostic test, a combination of clinical features and laboratory tests are used to

make the diagnosis of RA. The American College of Rheumatology (ACR) classification criteria have

often been used to define RA. However, as they were developed in populations with long-standing

definite disease, they do not perform as well for the diagnosis of recent-onset RA. In a recent

systematic analysis of literature published between 1988 and December 2006, the sensitivity and

specificity of the 1987 American College of Rheumatology (ACR) criteria in early RA was 77% (68%

to 84%) and 77% (68% to 84%) respectively using the list format (23).

Due to the poor sensitivity early in the disease course, patients with RA may not fulfil these

classification criteria and may therefore be misdiagnosed. The relatively low specificity means that

other conditions such as postviral arthropathies, early spondyloarthropathy, and other self-limiting

arthritides may satisfy the ACR criteria.

As rheumatologists continue to see patients earlier in the course of disease, it has also become clear

that a sizable proportion of patients, who present with an inflammatory arthritis, may have an

undifferentiated arthritis (UA) – a form of arthritis that does not fulfil the 1987 classification criteria for

a more definitive diagnosis. The outcome of these patients varies and the diagnosis may change in

the first years of follow-up. Some patients will progress to RA, and some to other rheumatic diseases

such as spondyloarthropathy. Others will remain undifferentiated or enter into remission. Estimates

from the Leiden early arthritis clinic suggest that of the patients that present with UA, 30% will remit,

30% develop into RA (based on the 1987 ACR criteria) and up to 20% remain undifferentiated. (24).

The key issue facing clinicians seeing patients with UA or early arthritis, therefore, is the prognosis of

early arthritis. Differentiating patients with self-limiting disease from those at risk of developing

persistent inflammatory and erosive arthritis will allow the initiation of appropriate therapeutic

measures for those that will progress and prevent unnecessary treatment for those that will resolve.

Inflammatory Arthritis

Self-limiting

Persistent

Erosive

Non-erosive

Figure 1


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III AN APPROACH TO EARLY ARTHRITIS

There is currently no single best way to manage patients with early arthritis. Rather, the use of the

following principles may guide management strategies:

• Early recognition and treatment of patients with persistent erosive arthritis result in better long-

term clinical outcomes.

• Furthermore, regular monitoring of disease activity and treating to target(25), aiming for remission,

improves outcomes.

The following steps have been suggested as an approach to for the evaluation and treatment of

patients with early arthritis (26):

• Recognise the presence of inflammatory arthritis.

• Exclude diseases other than RA or UA that present as an early inflammatory arthritis (e.g.

systemic lupus erythematosus (SLE), psoriatic arthritis or a spondyloarthropathy).

• Estimate the risk of developing persistent or erosive irreversible arthritis in patients with RA or UA

using a combination of clinical features, laboratory tests and imaging techniques.

• Institute therapy and monitor disease activity, escalating treatment as required in order to achieve

a favourable outcome.

The clinical evaluation remains the cornerstone for evaluating early arthritis; determining whether

arthritis is present or not, differentiating between inflammatory or non-inflammatory disease and

deciding aetiology of the arthropathy. Articular symptoms may be the presenting manifestation of

many infectious, inflammatory or malignant conditions. The clinical feature may also provide clues to

identify those at risk of developing persistent erosive disease (see table 1).

A thorough history should be documented, detailing the distribution of the symptomatic joints, duration

of symptoms and early morning stiffness, response to non-steroidal anti-inflammatories, any

prodromal illness and associated symptoms. Family, personal and past medical histories including

smoking history should also be noted. A comprehensive examination of all systems should be

performed.

Laboratory investigations and imaging are ancillary measures for the diagnosis and prognosis of

patients presenting with early arthritis and should be tailored to the individual. It is important, to be

aware of their limitations when interpreting the results (e.g. avoid false reassurance that pathology is

absent when test results are normal). Imaging techniques are potentially helpful in this setting.


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IV IDENTIFICATION OF INFLAMMATORY JOINT DISEASE The clinical finding of joint swelling not caused by trauma or bony swelling should suggest a diagnosis

of early arthritis, especially if it includes involvement of at least two joints and/or early morning

stiffness lasting 30 minutes or more. Hand or foot involvement is common in inflammatory

arthropathies and is suggested by a positive metacarpophalangeal (MCP) or metatarsophalangeal

(MTP) ‘squeeze test’.

Figure 2: Metacarpophalangeal squeeze test

All new patients with symptoms of an inflammatory arthritis should be referred to a rheumatologist

during the early more treatable phase of the disease, ideally within 6 weeks of symptom onset(27). As

a proportion of patients that will develop severe persistent inflammatory arthritis will have normal/

negative results at disease onset, they should be referred regardless of blood test results or

radiographic findings. If tests are done in primary care referral should not be delayed while waiting for

results.

V IDENTIFICATION OF A DEFINITIVE CAUSE OF AN INFLAMMATORY ARTHROPATHY

V-1 Clinical Features

While joint symptoms predominate early in RA, extra-articular manifestations of RA (nodules,

keratoconjunctivitis sicca etc.) are seldom present early in disease. In other forms of polyarthritis,

extra-articular manifestations may be present early and may precede the onset of synovitis, providing

clinical clues to the diagnosis. This is particularly true with systemic lupus erythematosus (malar rash,


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serositis), reactive arthritis (urethritis, conjunctivitis), psoriatic arthritis (psoriasis, nail pitting) and

sarcoidosis (lung involvement, fever)(28). See table 1.

Figure 3: Malar rash in a patient with systemic

lupus erythematosus

Figure 4: Psoriatic plaques

V-2 Investigations Most cases of suspected inflammatory arthritis will warrant a complete blood count, inflammatory

markers, basic serology including RF, ACPA and antinuclear antibodies, renal and liver function tests

and a urine analysis.

More specific tests may be directed by the clinical presentation including tests for uric acid, cultures

where infection may be suspected, serology for atypical infections e.g. Lyme disease, virology e.g.

hepatitis B, C or parvovirus, serum angiotensin-converting enzyme, specific autoantibodies and

genetic markers. In cases of suspected crystal arthropathy or infection, an aspirate of a joint effusion

will be of value in making a definitive diagnosis. Findings on X-rays may further assist in making the

diagnosis of a specific arthropathy e.g. the presence of cartilage calcification in calcium

pyrophosphate dihydrate deposition disease (CPPD).

Figure 5: Calcification of the triangular fibrocartilage of the wrist in calcium pyrophosphate dihydrate

deposition disease


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Table 1: Differentiating diseases that present as an early arthritis

Arthritis Personal history Typical pattern of joint involvement

Joints affected Associated Features

Laboratory tests

Undifferentiated Arthritis (nonprogressive)

F>M Insidious Oligoarthritis

PIP,MCP, wrist, MTP, knee, ankle

↑CRP/ESR

Rheumatoid Arthritis F>M; 35-50 years

Insidious, progressive symmetrical

PIP,MCP, wrist, MTP, knee, ankle

EMS ↑CRP/ESR, RF+,CCP+

Spondyloarthropathy Psoriasis Urethritis or cervicitis, IBD Family history of psoriasis or IBD

Persistent asymmetric oligoarticular

DIP, PIP, knee, feet, spine

Psoriasis Nail pitting Uveitis, Enthesitis, dactylitis

ESR/ CRP may be normal More severe course in HLA B27 +

Systemic lupus erythematosus

F > M, young

Polyarticular, symmetric, usually nonerosive

PIP, knee

Rash, serositis

Anaemia, ↑ESR/CRP, proteinuria, ANA+, dsDNA+

Viral (HBV, HCV)

Hepatitis risk factors

Acute polyarthritis

PIP, MCP, wrist, knee, ankles

Jaundice ↑ESR/CRP, ↑ LFTs Hepatitis B and C serology

Septic Arthritis (nongonococcal)

Peak incidence in elderly Reduced host immunity Joint prostheses

Acute Monoarticular Often extremely painful (Beware may be polyarticular)

Knee – most common Hip, shoulder, ankle, wrist

Systemic symptoms common

Commonest cause Staphylococcus aureus Synovial fluid is gram stain positive in 50% and culture positive in 90%

Gonococcal

F > M, young, sexually active

Acute oligo- or polyarthritis

Wrist, knee

Fever Rash Skin blisters/pustules, Tenosynovitis

↑ESR/CRP, ↑WBC Synovial fluid gram stain positive in 25% and culture positive in 50% of cases

Osteoarthritis

F > M, Men with knee or hip involvement ↑age

Progressive oligo- or polyarticular asymmetric or symmetric, bony swelling

DIP, PIP, first CMC1, knee, hip, MTP, spine

Normal laboratory tests

Gout

Men, Postmenopausal women, Diuretic use (especially in elderly)

Sudden onset, severe pain with attacks oligoarticular early, polyarticular later

MTP, toes, ankle, knees

Tophi Synovial fluid – urate crystals ↑uric acid level – (normal levels in 40% of acute attacks)

Pseudogout

M=F, ↑age

Chronic Oligo- or polyarticular Acute monoarticular (25%)

Knee, wrist, finger, MTP

Associated conditions include: Hypomagnesaemia Hypophosphataemia Haemochromatosis Wilson’s disease Hyperparathyroidism

↑CRP, ↑WBC

Polymyalgia rheumatica

M = F, older Caucasian

Prolonged morning stiffness

Hip and shoulder girdle PIP, wrist, knee occasionally

RS3PE

Anaemia, ↑ESR/CRP

Sarcoidosis

F>M

Acute symmetrical Chronic uncommon

Knees, ankles Fever, Erythema nodosum & hilar lymphadenopathy with acute sarcoid

↑ESR/CRP Serum ACE

Scleroderma F>M Acute or occasionally. insidious symmetric or asymmetric

MCP, PIP Tendon friction rubs (diffuse disease)

↑CRP/ESR ANA +, Scl-70+, ACA+

RA, rheumatoid arthritis; UA, undifferentiated arthritis; F, female; M, male; PIP, proximal interphalangeal joint; MCP, metacarpophalangeal joint; CMC1, first carpometacarpal joint; MTP, metatarsophalangeal joint; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; RF, rheumatoid factor; CCP, cyclic citrullinated peptide; HBV, hepatitis B virus; HCV, hepatitis C virus, WBC, white blood cells; ANA, antinuclear antibody; ACA, anticentromere antibody; LFT, liver function test; IBD, inflammatory bowel disease


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VI PREDICTION OF OUTCOME OF UNDIFFERENTIATED AND EARLY RHEUMATOID ARTHRITIS 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(29).

VI-1 Assessment of Disease Persistence The frequent spontaneous remission of synovitis in patients with early arthritis (especially those with

symptoms of less than 3 months duration) means that a therapeutic approach, which targets all

patients with very early synovitis, will needlessly expose many patients to potentially toxic therapies.

The ability to distinguish resolving disease from synovitis that persists and develops into RA is thus

essential. Female gender, cigarette smoking, duration of symptoms, the tender and swollen joint

count, hand involvement, the level of acute phase response, presence of RF and ACPA, and the

fulfilment of 1987 ACR diagnostic criteria for RA are factors associated with disease persistence. See

table 2.

An alternative approach is to look at patients more likely to enter spontaneous early remission.

Seronegativity for rheumatoid factor (RF) and fewer active joints at baseline in early RA have been

cited as markers of a favourable outcome(9). Other studies have shown a relationship with male

gender and absence of erosions with higher remission rates (8).

Table 2: Candidate predictors of disease persistence in early arthritis

• Female gender

• Duration of symptoms (more than 12 weeks)

• High tender and swollen joint count

• Hand involvement

• Cigarette smoking

• Acute phase response

• Rheumatoid factor

• ACPA

• Erosions on Xray

• Fulfilment of 1987 ACR diagnostic criteria for RA (sensitivity 88%; specificity

73%)


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VI-2 Assessment of Disease Severity In clinical practice, treatment of early RA is often commenced and increased according to the disease

activity. An alternative approach would be to initiate the most appropriate treatment based on

prognostic stratification, differentiating between those with a more benign disease from those at risk of

developing severe erosive disease who would benefit from more aggressive, and more expensive,

treatment early on to prevent severe outcomes.

Many of the factors predicting disease persistence are also markers of disease severity. Joint damage

and functional disability are the two most common outcome measures of disease severity.

The most reliable prognostic factors of radiological damage are a high acute phase response, the

presence and titre of RF and ACPA at baseline, the HLA-DRB1*0401 allele subtype, and early

erosions or radiological score at disease onset. Factors that have been found to predict future

disability include a baseline HAQ score, Ritchie index, erythrocyte sedimentation rate (ESR) and C-

reactive protein (CRP), and presence of erosions. Female gender, older age, the number of damaged

joints, RF positivity and the presence of nodules (although usually a later finding in RA) at baseline

are other documented factors. See table 3.

Table 3: Candidate predictors disease severity in early arthritis

• Female gender b

• High tender b and swollen joint a count

• HAQ score b

• Acute phase reactants a, b

• Rheumatoid factor a

• ACPAa

• Shared Epitope a

• Erosive disease a, b

a Predictors of joint damage

b Predictors of functional disability


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VI-3 Individual Factors Predicting Persistence and Disease Severity

VI-3-1 Disease duration Several studies have shown symptom duration at first visit to be a good predictor of disease

persistence (30, 31). In a study by Green et al, 63 patients with mild untreated early inflammatory

arthritis were given a single dose of corticosteroids at presentation. At 6 months 49 patients (78%)

had persistent inflammatory joint disease and 14 (22%) had clinical disease remission. The strongest

predictor of persistence was disease duration of 12 weeks(19). With disease less than 12 weeks, the

chance of remission was increased five-fold. The 1987 ACR classification criteria for RA were found

to be less helpful in predicting persistence in those with shorter disease duration: of those fulfilling the

ACR criteria presentation, 53% with disease duration of less than 12 weeks had persistent disease 6

months later compared to 94% who presented with symptoms greater than 12 weeks.

A further study examined the use of a similar protocol of intra-articular corticosteroid injections in

patients with early oligoarthritis (i.e. four or less joints) followed by an early review to assess for the

presence of persistent synovitis(32). At least 50% of patients with oligoarthritis had complete

response at 2 weeks and the best predictor of response at 12 and 26 weeks was the presence or

absence of synovitis on examination at 2 weeks follow-up. Failure to respond by 2 weeks indicated a

high likelihood of persistent disease and the need for DMARD therapy.

As discussed earlier, disease duration is also an important predictor of severity with better clinical and

radiographic outcomes seen in patients with shorter disease duration (16, 20).

VI-3-2 Early morning stiffness

Early morning stiffness (EMS) is an early symptom of an inflammatory arthritis. It is a complex

symptom and may be difficult to interpret and to discriminate from pain and functional limitation.

Despite this, it is used as a clinical marker of disease persistence (33),(34).

VI-3-3 Joint 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 persistent disease (31). These

findings have been confirmed by several other studies (35, 36).


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Persistent joint inflammation leads to joint destruction. A high joint count is also a marker of disease

severity with the number of swollen joints correlating better with radiographic progression than the

number of tender joints.

VI-3-4 Functional disability

Functional disability as measured by the Stanford Health Assessment Questionnaire disability index

(HAQ) is one of the most reliable predictor of disease outcomes in early arthritis (37). A high baseline

HAQ is an important risk factor for the development of future functional disability and predictive of

both all-cause and cardiovascular mortality in patients with early disease. Analysis from a primary

care-based inception cohort of patients with recent –onset polyarthritis has found the 1 year HAQ

score to be a better predictor of subsequent outcome than the baseline HAQ score(38). The baseline

HAQ score has also been shown to be predictive of quality of life and work disability(39) (40) in

patients with early RA.

VI-3-5 The acute phase response A rise in the level of acute-phase reactants such as the ESR and CRP provide surrogate measures of

inflammation.

Both elevated ESR and CRP levels, especially if sustained, are predictive of long term radiographic

progression. In a study of 130 patients with early RA (median disease duration 3 months), logistic

regression analysis of baseline variables revealed that a high CRP level (≥ 20mg/l) was an

independent predictor of radiographic severe progressive joint damage at 1 year (odds ratio, 3.59;

95% CI 1.53, 8.39)(41). CRP levels at presentation have also been found to be an independent

predictor of functional ability assessed by the Health Assessment Questionnaire (HAQ).

High sensitivity CRP (hs-CRP) assays may be used to identify mild disease activity that is not

detectable by routine CRP testing (42).

VI-3-6 Rheumatoid Factor RF is perhaps one of the most consistent markers of disease persistence and progression of

radiographic damage in patients with inflammatory arthritis. In a large series of UA patients, a

stepwise logistic model was used to determine factors predisposing to development of RA, Wolfe et al

found that RF was the best predictor of persistence(43). The 1987 ACR criteria for RA and disease

duration were other significant factors. In a study of 65 patients where factors predicting persistent or


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self-limiting symmetrical polyarthritis were analysed, RF positivity emerged as the strongest variable,

with a positive predictive value of 85%. Combining this with an erythrocyte sedimentation rate (ESR)

of > 30 mm/hour carried a relative risk for persistent synovitis of 4.33(30).

RF positivity is also a strong predictor of radiographic progression (44, 45). The association between

RF and functional disability is less consistent. In a review, RF positivity or more specifically a high RF

titre was found to be a predictor of disability in some studies, but in others this association was not

significant (39, 46).

VI-3-7 Anti-cyclic citrullinated peptide antibodies Research into autoantibodies other than RF in sera of RA patients led to the discovery of

antiperinuclear factor the 1960s and anti-keratin antibodies in the 1970s. Subsequent studies showed

that these antibodies recognized a similar antigen, citrulline. This non-standard amino acid is

generated by the post-translational modification of arginine residues by the enzyme peptidylarginine

deiminase (PAD). Several tests have been developed to identify the antibodies to citrullinated

peptides/ proteins (ACPA). The assay using the second generation cyclic citrullinated peptide as an

artificial autoantigen (CCP-2) is currently the is the most commonly used test in clinical practice.

ACPA are present early in the disease course and can precede onset of symptoms by up to 10 years,

particularly in the 2 years prior to symptom onset (47, 48). In a study by van Gaalen et al, 93% of

patients with early UA who were ACPA (CCP-2) positive at baseline were diagnosed with RA at 3

years. Conversely, only 25% ACPA negative patients had a diagnosis of RA at followup (49).

A recent review of data has shown that ACPA (CCP-2) has a similar sensitivity to RF in early RA

cohorts (41% to 63% vs. 41%-66%), but a greater specificity (91% to 100% vs. 87% to 97%). The

positive predictive value for ACPA in the setting of UA was 78% to 96% in early RA cohorts with most

values ranging from 90 to 95%, and the negative predictive value 62-96% (50). Testing for ACPA may

be of particular value in detecting the seronegative group of patients with RA.

The presence of ACPA has also been shown to be an independent predictor of baseline and long-

term disease severity in patients with inflammatory polyarthritis (51) as well as radiographic damage

and progression in patients with RA (52). ACPA titres have also been related to disease severity (53).

VI-3-8 Genetic markers

Genetic factors are the ideal prognostic markers because they are present at disease onset and

unchanged by treatment. The shared epitope (SE), a group of HLA-DRB1 alleles that share a similar


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amino acid sequence, is strongly associated with RA. Several studies have shown a correlation

between SE and disease persistence (19, 54) and found this to be a particularly useful marker among

patients who were negative for RF (19). Others, however, have found the presence of SE of less

value as an independent predictor of disease persistence (34, 55) but rather an indicator of disease

severity once the diagnosis of RA is made (55, 56).

Among the different HLA-DRB1 alleles examined, HLA-DRB1*401 and DRB1*0404 have been

consistently associated with radiographic erosions in different ethnic groups. This association appears

to be dose dependant as patients with two RA-associated alleles (DRB1*04 or DRB1*01) have had

more radiographic erosions and more joint replacement than patients with non-disease associated-

alleles (57). Studies have shown that individuals who were homozygous for HLA-DRB1*0404 were 4

times more likely to develop erosions than those who were SE negative (54, 58).

Since ACPA tests have been performed and introduced in multivariate analyses, however, HLA DR

B1 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. They are therefore not

recommended for routine clinical practice in early RA and early arthritis. (Further discussion on the

association with the SE and smoking and the development of ACPA can be found in the module on

the pathogenesis of RA).

A number of other genetic polymorphisms have been studied in patients with early RA. Several

groups have described the association between PTPN22, a negative regulator of T-cell activation,

and RA (59, 60). This is the first non-HLA (human leucocyte antigen) genetic variation consistently

associated with the susceptibility to a number of autoimmune diseases including RA. The abnormality

is a missense single nucleotide polymorphism (SNP) in this haematopoietic-specific protein tyrosine

phosphatase gene. In a study examining sera of blood donors pre-RA, a strong association was

documented between the PTPN22 1858T variant and the future development of RA (61). More

recently, TRAF-1 C5 (62) and STAT4 (63) have also been identified as genetic markers associated

with the development of RA.

The 150V IL4 single-nucleotide polymorphism and the TNFA-308 polymorphism have also been

shown to be markers for early radiographic bone erosions. Since these genes encode for cytokines,

these studies suggest that functional alterations in cytokine regulation are involved in the disease

pathogenesis and may have an effect on disease persistence and damage.


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VI-3-9 Smoking Smoking is the most recognised environmental risk factor for the development of RA. There is also a

strong association between smoking and the development of rheumatoid nodules in early seropositive

rheumatoid arthritis.

Recent studies have gained insights into the potential role of smoking in the pathogenesis of RA.

Smoking has been shown to increase the risk for the development of ACPA. In the presence of

shared epitope alleles, this risk is further increased – up to 20 times in homozygotes as compared to

shared epitope negative non-smokers (64, 65). It is possible that, smoking, in a genetically

predisposed individual, induces apoptosis and protein-citrullination, followed by an anti-citrulline

specific immune response. Former smokers are also at an increased risk for RA up to 20 years after

smoking cessation with a gradual decreasing risk over time (66).

Outcomes of studies assessing the effect of smoking on disease severity, however, vary. Several

cross sectional studies have demonstrated significant associations between radiographic joint

damage and smoking (67, 68) and disease activity, response to treatment and smoking with poorer

outcomes seen in smokers compared to non-smokers (69). Others, including a large observational

study of 2004 RA patients(70) , have found no effect of overall current or past smoking (71, 72),

suggesting that smoking may be more important in the initiation of RA than in the perpetuation of the

erosive disease process.

VI-3-10 Imaging

Conventional radiographs

X-rays remain the conventional imaging modality in many centres. Radiographic erosions have a high

specificity in discriminating between self-limiting and persistent arthritis(33). Early radiographic

changes are also predictive of disease progression. In a cohort of patients with undifferentiated

arthritis the presence of 2 or more erosive joints at baseline showed a positive predictive value for

persistent disease of 68% (73).

Radiographic examination should include the assessment of the hands and feet as erosions often

start in the feet and in approximately 14-18% of cases are only detected in the feet (74).


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Figure 6: Conventional radiograph of the foot showing erosions of the fifth metatarsal head

Radiographic damage at baseline also represents the best predictive factor of poor structural

outcome. Irrespective of the scoring systems (e.g. Larsen or Sharp scores) used, the initial

radiographic score consistently predicts future radiographic damage (41).

Joint erosions and joint space narrowing seen on X-rays, however, are generally late findings. Newer

imaging modalities have shown to provide additional diagnostic and prognostic information at an

earlier stage.

Magnetic resonance imaging

Magnetic resonance imaging (MRI) can assess all structures of the inflamed joint. It is more sensitive

than clinical examination and radiography for the detection of synovitis and erosions in early

rheumatoid arthritis. There is also evidence that MRI findings (synovitis, bone oedema, and bone

erosions) may predict subsequent radiographic progression. Changes resembling mild synovitis or

small bone erosions however are occasionally found in the joints of healthy subjects. Higher costs,

longer examination times and lower availability are some disadvantages of MRI compared to

conventional radiographs. Issues including accessibility, standardisation and reliability of MRI have

been addressed and are ongoing.

Ultrasound The role of ultrasonography (US) for the management of patients with early arthritis has increased

over the recent years. US is useful for detecting synovitis in small joints of the hands and feet with


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greater sensitivity than clinical examination. It is also more sensitive for visualising synovitis and bone

erosions in the finger joints than conventional X-rays. The advantages of US are that it is relatively

inexpensive, non-invasive and allows many joints to be assessed at any one time. The main

disadvantage is its dependency on the skills of the operator and potential problems with

reproducibility.

Figure 7: Rheumatoid arthritis.

Second metacarpophalangeal joint. A. Conventional radiography shows juxta-articular osteoporosis.

B. Ultrasonographic examination, in the longitudinal dorsal scan, reveals proliferative synovitis with

marked intra-articular power Doppler signal. m = metacarpal bone; p = proximal phalanx; t = extensor

tendon

Further discussion on the use of MRI and US in early arthritis can be found in in-depth discussion 1.

VI-3-11 Hand bone densitometry With newer therapies 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 absorbtiometry (DEXA) measures bone density with high

precision, making it sensitive enough 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


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(56) and hand (75) with disease activity. In a study comparing the role of hand DEXA and radiography

in 58 patients with early RA (mean disease duration 8.5 months), DEXA was found to be a more

sensitive tool than radiology for measuring disease related bone damage. Fifty percent of patients

demonstrated significant loss of hand BMD after 24 weeks compared to only 22% showing

radiographic deterioration as measured by the modified Sharp score at 48 weeks (76).

VI-3-12 Histology Studies using arthroscopy have confirmed imaging findings of subclinical synovitis examining

asymptomatic joints of newly diagnosed RA. Distinct macroscopic vascular patterns have been seen

in early RA and psoriatic arthritis. Comparison of histopathological features of synovial tissue in early

RA and non-RA synovitis has shown subtle differences in histological features, cytokine and protease

expression patterns, as well as apoptosis. An analysis of synovial biopsies of 95 patients with early

arthritis showed that the higher scores for the number of CD38+ plasma cells and CD 22+ B cells in

RA were the best discriminating markers comparing RA to non-RA patients. The number of CD68+

macrophages in the synovial tissue of patients with RA was also increased (77). Thus far, however,

the clinical value of the histopathological characteristics of synovial tissue in early arthritis is yet to be

proven (78). Widespread use of synovial biopsies in the clinical setting is also limited by its

invasiveness.

Figure 8: Arthroscopy showing rheumatoid synovitis. Hypertrophic, rounded, polypoid-like villi with an

opaque, ill-defined background due to congestion and oedema.


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VI-3-13 Biomarkers of joint destruction Molecular markers that reflect synovial, bone and cartilage turnover have been studied as potential

tools for early identification of patients with RA at high risk of rapid disease progression(29). These

include urinary glucosyl-galactosyl-pyridinoline, a marker of destruction of the synovium, and C-

terminal crosslinking telopeptides of type I and type II collagen (CTX-I and CTXII), markers of bone

and cartilage destruction. High baseline levels of CTX-I and CTX-II have shown to predict an increase

risk of radiographic progression. Elevated levels have also been described in patients with no

radiographic evidence of joint destruction at baseline suggesting that they may be useful for detecting

patients at risk of joint damage early in the course of the disease.

Raised levels of matrix metalloproteinases (MMP), enzymes involved in the degradation of articular

cartilage in RA, have been found in tissue, synovial fluid and the systemic circulation of patients with

RA. Several studies have shown a correlation with increased MMP levels and progression of joint

damage.

The ratio between OPG: RANKL may be another 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 in the stimulation of osteoclast formation and activation and

the soluble receptor-like molecule osteoprotegerin (OPG) is a natural inhibitor of RANKL. Bone

resorption is regulated by the balance between RANKL and OPG..

High levels of calprotectin, a major leukocyte protein, have also been associated with joint damage.

Recent analysis of cartilage and bone biomarkers in predicting 10 year radiographic progression in

RA have shown a weak association between CTX-1 and radiographic damage. Neither this nor any

of the other tested biomarkers however were found to be more useful than current predictors e.g.

ACPA and the presence of early radiographic damage (79). In daily clinical practice therefore, the role

of these biomarkers is yet to be demonstrated.

VI-4 Prediction Models for the Progression of Early Arthritis

In general, a combination of predictive factors has been found to be superior to single variables in

predicting those who will develop a persistent erosive arthritis. Several prediction models have been

developed using a combination of the most reliable markers to determine which patients with UA will

progress to develop RA (defined by the 1987 ACR classification criteria) (34), disease severity(80),

radiographic progression(81, 82) and functional outcome.(83).


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VI-6 The 2010 ACR-EULAR RA classification criteria (84) Recent work through a collaborative initiative between ACR and EULAR to define RA at an early

stage has enabled the development of new classification criteria for RA. The emphasis of the 2010

ACR-EULAR RA classification criteria is on identifying patients with a relatively short duration of

symptoms who will benefit from early diagnosis early institution of DMARD therapy.

Patients must meet 2 mandatory requirements for the classification criteria to be applied. First, there

must be clinical evidence of synovitis (i.e. swelling) in at least one joint. All joints of a full joint count

may be assessed for this purpose with the exception of the DIP joints, the 1st MTP joint, and the 1st

CMC joint as these joints are typically involved in osteoarthritis. Second, the synovitis should not be

better explained by another diagnosis e.g. SLE, psoriatic arthritis, and gout. Classification as definite

RA is then based on achieving a total score of 6 or greater (out of 10) from individual scores in four

domains (table 4). These are (1) number and site of involved joints (score range 0-5), (2) serological

abnormality (score range 0-3), (3) elevated acute phase response (score range 0-1) and (4) symptom

duration (score range 0-1). As a caveat, patients with RA type erosions on X-ray with a typical history

of RA may also be classified as such and the scoring system need not be applied. Further details can

be found in ‘Indepth Discussion II’.

Table 4. Classification criteria for RA (Score-based algorithm: add score of categories A-

D) A score of ≥ 6/10 is needed for a definite classification of a patient with RA.

A. Joint involvement1

1 large2 joint 0

2-10 large joints 1

1-3 small3 joints (with or without involvement of large joints) 2

4-10 small joints (with or without involvement of large joints) 3

>10 joints4 (at least one small joint) 5

B. SEROLOGY5 (at least one test result is needed for classification)

Negative RF AND negative ACPA 0

Low positive RF OR low positive ACPA 2

High positive RF OR high positive ACPA 3

C. ACUTE PHASE REACTANTS6 (at least one test result is needed for classification)

Normal CRP AND normal ESR 0

Abnormal CRP OR abnormal ESR 1

D. DURATION OF SYMPTOMS7

<6 weeks 0

≥6 weeks 1


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VI-4 Predictors of Persistence and Disease Severity: Practical Points In practice, the clinical features and investigations listed in tables 2 and 3 may be used to identify

patients with early inflammatory arthritis who are at risk of a persistent and more severe disease

course. Conventional radiography is the mainstay imaging modality although the use of US, MRI (see

‘Indepth Discussion I’) and DEXA are coming to the fore. At present, non-HLA genetic markers,

histology and biochemical markers remain more research based tools rather than investigations for

day to day patient care.

Several prediction models have been developed using a composite of the most reliable markers of

disease progression. Development of the 2010 ACR- EULAR classification criteria has beens another

step forward setting a new benchmark for the early identification of patients with RA – using these

criteria should be of practical value towards the commencement of early effective treatment thus

preventing the adverse sequelae of the disease.

VII TREATMENT STRATEGIES (26, 85-87) Patients with early arthritis will require a combination of pharmacological and non-pharmacological

therapy.

• The first principle of pharmacological therapy for early arthritis is early intervention with

effective / appropriate treatment.

• The second is one of treating to target (87) to achieve ‘tight control’ of disease activity. In

practice, for RA this means that therapy is increased if disease activity is not suppressed

below a predefined level (ideally remission).

A suggested algorithm for the management of early arthritis is shown in figure 9.


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VII-1 Non-pharmacological Treatment and Lifestyle Measures As discussed earlier in this review, lifestyle factors, such as smoking, increase the risk of developing

RA. These factors impact on the progression of the disease and lead to an increase in the associated

pain and functional limitations of RA. The reduction or cessation of smoking is therefore advised.

Ensuring an appropriate body weight by following a healthy diet and maintaining physical activity can

also influence pain in RA.

Several non-pharmaceutical interventions- such as dynamic exercises, occupational therapy, and

hydrotherapy – have shown beneficial symptom relieving effects in established RA. These are

recommended as adjuncts to pharmaceutical interventions in patients with early arthritis.

VII-2 Patient Education

As part of the management of any chronic disease, patients should be provided with information

concerning the disease and its treatment. Education programmes may be used as adjunctive

measures, aimed at coping with pain and disability and the maintenance of work ability.

Patients with an inflammatory arthritis who do not meet criteria for a specific diagnosis and do not

have poor prognostic factors are much more likely to do well. Approximately fifty percent of

unclassified cases, often those with fewer joints involved, less symmetry, and more lower-extremity

Figure 9: AN ALGORITHM FOR THE MANAGEMENT OF EARLY INFLAMMATORY ARTHRITIS

Yes No

No

Yes

Yes

No

Fulfils the 2010 ACR/EULAR criteria for RA

Recurrence after a corticosteroid dose

Undifferentiated arthritis Self limiting Confirm RA

Symptomatic treatment

Inflammatory Arthritis

Assess prognostic

factors & treat


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disease, have been found to be in remission at follow-up. Although patients may feel disappointed

when a specific diagnosis is lacking, they may be reassured of a better outcome.

.

VII-3 Pharmacological Treatment

VII-3-1 Symptomatic treatment Simple analgesics may be required for pain management. These are often employed in combination

with other therapies to control the inflammatory process.

There is substantial evidence in established RA that both classical and COX-2 selective, non-steroidal

anti-inflammatory drugs (NSAIDS) are more effective than simple analgesics in relieving the signs and

symptoms of active disease. These observations have been extrapolated to early arthritis with the

recommendations that NSAIDS be considered in symptomatic patients after evaluation of

gastrointestinal, renal, and cardiovascular status. (Further discussion may be found in the module on

the Treatment of Rheumatoid Arthritis.)

VII-3-2 Glucocorticoids

Glucocorticoids have anti-inflammatory and immunosuppressive effects and are widely used for the

treatment of RA (88).

An approach for patients who present with very early inflammatory arthritis (less than 12 weeks of

symptoms) may be to give a single dose of corticosteroid to provide rapid improvement of symptoms

and demonstrate the reversibility of disease(19). Results of an open study of 100 patients with

undifferentiated arthritis suggest that a single dose of intramuscular or intra-articular steroids may

induce remission (89).

Two randomised placebo-controlled studies have also investigated the benefits of a limited course of

intramuscular (IM) steroids in patients with early undifferentiated arthritis. The steroids in very early

arthritis’ (STIVEA) trial (90, 91) aimed to determine whether treatment of recent onset inflammatory

polyarthritis with 3 weekly injections of IM glucocorticoids could suppress evolution to RA. Two

hundred and sixty-five patients with 4–11 weeks of symptoms, 2 or more tender and swollen joints

and hand involvement were enrolled and randomised to receive 3 weekly doses of

methylprednisolone 80 mg IM or placebo. Patients were followed up for 12 months and assessed for

the initiation of DMARD therapy. At 6 months, 76% of the placebo group and 61% of the steroid group

had either started or been referred for DMARD therapy [odds ratio (OR) 2.11, 95% confidence interval

(CI) 1.16, 3.85, p=0.015]. At 12 months, the arthritis had resolved in 20% (22/111) of patients in the


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glucocorticoid arm compared with 10% (11/111) in the placebo arm. In the SAVE study, a similar

patient population, however, a single dose of intramuscular methylprednisolone 120mg was not

effective in inducing remission or delaying development of RA. Of 383 patients, 17.0% (65/383)

achieved persistent remission: 17.8% (33/185) of the placebo group and 16.2% (32/198) of the

patients receiving methylprednisolone (OR=1.13, 95% CI 0.66 to 1.92, p=0.6847). DMARDs were

started in 162 patients: 56.7% in the placebo arm and 50.3% methylprednisolone arm (OR=0.78, 95%

CI 0.49 to 1.22, p=0.30). Significantly more patients with polyarthritis than with oligoarthritis received

DMARDs (OR=2.84, 95% CI 1.75 to 4.60, p<0.0001). Although study outcomes differ, the use of IM

steroids in some patients with very early inflammatory polyarthritis may postpone the initiation of

DMARD therapy.

In established RA, several randomised controlled trials and systematic reviews (92, 93) have shown

that systemic low dose glucocorticoids, typically prednisone ≤ 10 to 15 mg/day, are effective in

relieving short-term signs and symptoms in patients. They are therefore often used as bridging

therapy at the start of DMARD therapy or when switching from one DMARD to another to improve

symptom control until treatment with the new drug has become effective. Studies have also shown

that glucocorticoids – either alone or in combination with other DMARD therapy – are effective in

slowing radiographic progression in early and established RA (94-97). Glucorticoids are also used as

part of tight control treatment strategies (discussed later in this module).

Concerns are often raised about the side effects of glucocorticoids. Evidence suggests the side effect

profile depends on the dose used and the disease being treated. A review of the published literature

has shown that in RA, low doses of glucocorticoids may have very few side effects (98). Those known

to occur in other diseases treated with higher doses of glucocorticoids may not occur when low dose

glucocorticoids are used to treat RA. These include increased cardiovascular risk, lipid abnormalities

and osteoporosis.

Newer glucocorticoids and glucocorticoid analogues that will target inflammatory tissues or specific

gene activations are under investigation to obtain the anti-inflammatory effect of the drug with minimal

or no increased risk of adverse reactions (99, 100).

VII-3-3 Synthetic disease modifying antirheumatic drugs (DMARDs)(101)

Early treatment with disease modifying drugs is one of the key principles in the treatment of early

arthritis. Patients at risk of developing persistent and/or erosive arthritis should start treatment with

DMARDs as early as possible even if they do not yet fulfil established classification criteria for

inflammatory rheumatologic diseases.


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There is good evidence that patients with recent onset polyarthritis who receive earlier DMARD

treatment have better outcomes with regards to radiographic progression, function, and ability to work

than those in whom DMARD treatment is delayed by a few months (11).Disease duration at the time

of synthetic DMARD initiation was shown to be the main predictor of response to treatment in the

meta-analysis of 14 RCTs by Anderson et al. The best response was seen in those with less than 1

year of symptoms at commencement of therapy (102). Another meta-analysis of 12 studies examined

the effect of early synthetic DMARD therapy on the long-term radiographic progression in patients

with early RA (less than 2 years at presentation). Six were open-label extensions of randomised

control trials (RCTs) in which placebo patients later started synthetic DMARD therapy and 6 were

observational cohort studies. The average delay between early and late therapy was 9 months. After

a median of 3 years of observation, those patients who received early treatment had 33% less

radiologic progression compared to those with delayed treatment (103).

Synthetic DMARDs have an effect on the disease process within weeks to months. Methotrexate,

sulphasalazine and leflunomide are commonly used DMARDs which have been shown to improve

clinical outcomes and delay radiological progression. (Details of these drugs can be found in the

module on the treatment of RA). Of the synthetic DMARDs, methotrexate (MTX) is considered the

anchor drug and is generally used first in patients at risk of developing persistent disease or erosive

disease because of its relatively beneficial safety profile, clinical and radiological efficacy, and its

beneficial properties in treatment combinations with biological DMARDs. Leflunomide and

sulphasalazine have similar clinical efficacy and are considered best alternatives.

Despite early treatment, substantial structural damage may still occur in some early RA patients

treated with synthetic DMARDs alone (45). In a cohort of very early RA patients with symptom

duration of less than 3 months, 64% developed erosive disease by 3 years.

Earlier use of synthetic DMARD therapy - in patients with UA before the stage of fulfilling ACR criteria

for RA - was first addressed in the PROMPT study. In this double-blind randomized-controlled trial,

110 patients were randomized to treatment with MTX or placebo for 12 months. Forty percent (22/55)

of patients in the methotrexate group progressed to RA compared with 53% (29/55) in the placebo

group In the methotrexate group patients also fulfilled the ACR criteria for RA at a later time point than

in the placebo group (P = 0.04) and fewer patients showed radiographic progression over 18 months

(P = 0.046). This study suggests that methotrexate may delay the development of RA and retard

radiographic joint damage in UA patients. Further analysis showed that these findings were mainly

seen in the subgroup of patients who demonstrated the presence of ACPA(104).


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VII-3-4 Synthetic DMARD monotherapy versus combination therapy (105) Several studies have addressed the issue of whether initial combination therapy of early RA confers

benefit over more conservative strategies. In the COBRA trial, a combination of methotrexate (7.5mg

weekly), sulphasalazine (2g/day) and prednisolone (starting with 60mg/day and tapering over 6

months) resulted in long-term effects on radiographic progression, compared with sulphasalazine

monotherapy in 155 patients with RA of duration under 2 years (94, 106). These results were

consistent with those from the FIN–RACo study in which 197 patients with onset of RA within 2 years

were randomly assigned to receive either four-drug regimen, with methotrexate, sulphasalazine,

hydroxychloroquine, and prednisolone (maximum doses: 15mg/week, 2g/day, 300mg/day and

10mg/day) or a single DMARD(95, 107, 108) for 2 years. After 18 months, a greater proportion of the

combination therapy group were less likely to have radiographic progression, and the work disability

rate was lower compared with patients on monotherapy. Although in the latter study, steroid was

permitted in the single treatment group, this was introduces later, at up to 93 weeks from baseline.

The effects achieved in the combination treatment arms may therefore be attributed, at least in part,

to the use of steroids rather than the combination of DMARDs alone.

Other trials comparing methotrexate/ sulphasalazine combination versus single agents (109, 110)

were unable to identify better outcomes for any treatment arm over the other. Results from the BeSt

study demonstrated that after a failure of methotrexate 25 mg/week, adding sulphasalazine to

methotrexate resulted in an original DAS of 2.4 or less in only 22% of patients. An equally low

response was obtained when switching from methotrexate to sulphasalazine (111).

Based on recent reviews of the literature (101),(112) EULAR recommendations for the management

of RA have therefore suggested that in DMARD naïve patients, irrespective of the addition of

glucocorticoids, synthetic DMARD monotherapy rather than combination therapy of synthetic

DMARDs may be used. Where disease control is not achieved switching to an alternative DMARD

strategy should be considered.(86)

VII-3-5 Biological DMARD therapy (113-115)

An alternative approach to treating patients with early arthritis is to target the subgroup of patients

with very early synovitis who are at high risk of developing RA with potent anti-inflammatory therapy.

Tumour necrosis factor alpha (TNF-α) is a cytokine that is central to the inflammatory cascade. It has

pleiotropic effects driving the immune response, with powerful modulatory effects on many aspect of

cellular and humoral immunity and has an important role in persistence of early RA.


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The concept that intensive interventions early in the course of persistent arthritis may improve clinical

activity and profoundly affect long-term radiographic progression is supported by several RCTs with

TNF blockers in early rheumatoid arthritis. In patients with disease duration of less than three years,

the use of a TNF blocking drug (adalimumab, etanercept, or infliximab) – especially in combination

with methotrexate – has shown an increased rate of clinical remission and slowing of radiographic

progression compared with methotrexate monotherapy (116-119). In addition, it has been

demonstrated that, even in cases in which clinical activity was not optimally suppressed (‘poor

response’), radiographic progression appeared to be significantly retarded in comparison with

methotrexate monotherapy (120).

In the Combination of Methotrexate and Etanercept (COMET) study (121), the first major study

looking at remission as the primary endpoint in patients with early RA, patients with symptom duration

of 2 years or less were randomized to receive methotrexate or methotrexate and etanercept for a

year. At week 52, remission as defined by a DAS 28<2.6 was achieved in 49.8% with methotrexate

plus etanercept vs. 27.8% with methotrexate alone (p< 0.001) (Figure 10). Radiographic progression

at week 52 was also significantly lower in the group receiving combination therapy. No differences

were seen between the 2 groups in terms of serious adverse events, serious infections or

malignancies. No cases of tuberculosis were reported in either group.

Figure 10: Percentage of patients achieving DAS28 Remission (Primary Endpoint) and DAS

Remission at Week 52 in the groups receiving methotrexate vs. methotrexate plus etanercept(121).

During the second year, patients in the methotrexate group were randomised to receive methotrexate

(M/M) alone or methotrexate +etanercept (M/EM) and those in the methotrexate + etanercept group to

continue with combination therapy (EM/EM) or to receive etanercept alone (EM/E). At year 2 clinical

outcomes were superior in the groups that received etanercept compared to the group receiving

0

10

20

30

40

50

60

DAS28 Remission DAS Remission

MTXETN +MTX

49.8*

*P<0.001

51.3*

27.8 27.8


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methotrexate alone. DAS28 remission was achieved in 62/108 (57%) and 51/88 (58%) for the EM/EM

and M/EM groups respectively – this was significantly greater than that in the M/M group (33/94

[35%]) (p 0.002 for the EM/EM group vs. the M/M group; p = 0.003 for E/M group vs. the M/M group)

but not significantly greater that that in the EM/E group (54/108 [50%]). Radiographic progression was

also lower in those who received etanercept with the lowest rate of progression seen in the groups

treated with etanercept early (Figure 11)(20).

Figure 11: Radiographic progression over 2 years. Mean changes in modified Sharp/ van der Heijde

score (mTSS) from week 0 to week 104, based on the last observation carried forward analysis. (ETN

= etanercept: MTX = methotrexate. * = 1 subject did not have a valid radiograph at week 52 but did at

baseline and week 106; changes from week 52 to week 104 cannot be assessed.)(20)

Randomised trials using newer TNF inhibitors as well as other biological DMARDs with different

modes of action have been used in established RA. These include golimumab and certolizumab, the

2 newer TNF inhibitors; rituximab, a B cell depleting agent; abatacept, an inhibitor of T-cell co-

stimulatory pathways and tocilizumab, an IL-6 receptor antagonist, have also demonstrated efficacy in

early RA. A study of abatacept in patients with UA also suggests a role for biological therapy in

preventing the onset of RA and delaying radiographic progression in this group of patients (122).

The biological DMARDS, therefore, provide rapid control of inflammation and have proven efficacy

both in terms of clinical outcomes and structural damage in early disease. They are, however,

substantially more expensive than traditional DMARDs, limiting their widespread use in early disease

(123). Selecting patients with poor prognostic factors may improve this cost-benefit balance.


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VII-3-6 Induction with biological and maintenance with synthetic DMARDS

Induction with biologics and maintenance with conventional DMARDS is another therapeutic strategy

in patients with early RA. This concept was introduced in a placebo controlled study by Quinn et al

(118). The study demonstrated that early RA patients with poor prognostic factors treated with

infliximab and MTX developed less MRI detected erosions at 12 months than patients treated with

MTX alone. The functional and quality of life benefits obtained in patients treated with infliximab after

1 year was sustained at 2 years without further infliximab infusion.

Another study that compares the use of these various therapeutic options and addresses the optimal

treatment paradigms for early RA is the Behandel Strategieёn (BeSt) trial. This multi-centre single

blinded trial of 508 RA patients with less than 2 years of symptoms, compared four treatment

strategies including a sequential monotherapy (group1), step-up combination therapy (group2), a

triple step-down strategy with methotrexate, sulphasalazine, and high dose prednisone(group3), and

initial combination therapy with infliximab plus methotrexate(group4) (124). Treatment was adjusted at

3 monthly intervals with a goal of achieving a DAS of 2.4 or less. The two groups with initial intensive

treatment (groups 3 and 4) showed a more rapid clinical response and a better radiographic outcome

than groups 1 and 2 at 2 years. Progression of joint damage remained better suppressed in groups 3

and 4 (median Sharp-van der Heijde scores of 2.0, 2.0, 1.0 and 1.0 in groups 1, 2, 3 and 4

respectively (p=0.004)). In addition, less treatment adjustments were required in groups 3 and 4 to

achieve suppression of disease activity. No significant differences in toxicity were noted between the

groups.

After 5 years, 48% of patients were in clinical remission (DAS <1.6). Of those, 46%, 51%, 65% and

81% of patients in groups 1–4 had achieved that on the initial therapy. Fourteen percent were in drug-

free remission, irrespective of initial treatment. Less joint damage was seen in the initial combination

groups in year 1. Thereafter, in years 2-5 annual progression was comparable across the groups. By

year 5, there was significantly less joint damage progression with initial combination therapy,

reflecting the earlier clinical response (125).

A further analysis from the BeSt trial comparing patients who received initial infliximab treatment

(group 4) with patients receiving infliximab at a later stage (groups 1-3) showed that 56% of patients

in group 4 were able to successfully stop infliximab compared to only 15% in the other groups at 2

years. This suggests that by achieving remission within the ‘therapeutic window of opportunity’,

patients may require less treatment later on in the disease course (114).


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Discontinuation of infliximab after achieving low disease activity (LDAS) has also been evaluated in

the RRR (remission induction by Remicade in RA) study (126). The mean disease duration of 114 RA

patients was 5.9 years, mean DAS28 5.5 and mean modified total Sharp score (mTSS) 63.3.

Infliximab was discontinued in 102 patients after maintaining LDAS for >24 weeks. At 1 year, 55%

continued to have DAS28<3.2 after stopping infliximab. Radiographic non-progression (mTSS

(DeltaTSS) <0.5) was achieved in 67% and 44% of the RRR-achieved and RRR-failed groups,

respectively.

These studies provide evidence for rationale for the use of early intensive treatment strategies, with

the potential to de-escalate therapy when good disease control is achieved.

VII-3-8 Treatment Strategies: Practical Points

• Nonpharmacological and lifestyle measures form part of the treatment strategy. Of these,

reduction or cessation of smoking is a known factor that could and prevent the development of

early RA and decrease the risk of cardiovascular complications of the disease and should

therefore be strongly encouraged.

• Early institution of effective therapy is the cornerstone of treatment for early arthritis. Delaying

treatment may be considered (if at all) only in those with very mild disease less than 3 months

from onset. A single dose of intramuscular steroid therapy may be advocated in this group.

Arthritis that is persistent for more than 12 weeks is unlikely to resolve spontaneously (89): many

of these patients will progress to develop RA. Disease modifying therapy should be commenced

in all early arthritis patients in whom the disease is likely to develop into a persistent and/or

erosive arthritis classifiable as RA. The biological DMARDs, in particular TNF blockers, have been

shown to confer additional benefits.

• Regarding the risk –benefit ratio and the cost effectiveness of these strategies, a reasonable

course of action in early arthritis should be initial DMARD therapy with NSAIDS and steroids as

adjunctive therapy. In most cases methotrexate is generally considered the first DMARD of

choice. Other DMARDs e.g. sulphasalazine and leflunomide are suitable alternatives.

• In patients with significant disease activity and/ or risk factors for adverse outcome e.g. (high titre)

rheumatoid factor or ACPA, early use of a more intensive strategy including the use of TNF

blockers may be necessary.

• Induction with biologics and maintenance with conventional DMARDS is another potential

therapeutic strategy.


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VII-4 Monitoring of disease activity and achieving tight control (127)

The objective of therapy is to achieve a state of low disease activity and ideally remission in order to

prevent structural damage and long-term disability. Regular monitoring of disease activity is therefore

necessary, increasing treatment if disease is not controlled. Imaging may further assist with decisions

with regards therapeutic escalation. The ‘best’ initial treatment may be less of a matter of drug choice

and more of a question of whether treatment aims (‘remission’ or ‘low disease activity’) as defined by

available scores (e.g. remission: DAS 28 ≤ 2.6 or DAS ≤ 1.6) are strictly followed. As patients may

still have some ongoing disease activity despite fulfilling these criteria for remission, ACR/ EULAR

have recently proposed and published 2 new definitions for application in RA clinical trials – these are

summarised in table 5 (128).

In the TICORA (129)(‘tight control in RA’) study, 110 patients with RA of less than 5 years duration

were randomly assigned to an intensive treatment in order to reach a low activity state (DAS44< 2.4)

close to remission, or to regular clinical care. Patient in the TICORA group were examined monthly

and DMARD therapy was escalated according to a predefined strategy if the DAS44 was above 2.4.

Those in the routine care group were seen every 3 months without formal assessment or feedback on

disease activity scores and therapy adjusted according to the clinical judgement of the

rheumatologist. The intensive treatment group had significantly more remissions and developed less

radiographic damage than the control group after 18 months of follow up. This strategy also resulted

in higher treatment retention rate, a lower rate of discontinuations due to side effects, and lower costs

per patient (based on lower admission costs) than routine care over the 18 month of observation. Of

note, however, more intraarticular steroids were used in this treatment group.

The CAMERA (computer-assisted management of early RA) trial (130) also showed intensive

treatment and monitoring to be more beneficial than routine care. Two hundred and ninety nine

patients with early RA were randomised to intensive treatment or routine treatment, with oral

methotrexate. If necessary, therapy was changed to subcutaneous methotrexate and cyclosporine

added to achieve disease control. Patients in the intensive treatment group were seen more

frequently in clinic and dosages were adjusted based on predefined criteria and tailored to achieve

remission using a computer assisted programme. At 2 years, results showed that more patients in the

intensive-management group achieved sustained remission for at least 3 months than in the routine

care group (50% vs. 37%: p<0.03). Median area under the curve for all clinical variables (erythrocyte

sedimentation rate (ESR), early morning stiffness, visual analogue scale for pain, visual analogue

scale for general well being, number of swollen joints and number of tender joints) were significantly

better in the intensive-management group than in the routine-care group. Patients in the intensive-

management group also used less non-steroidal anti-inflammatory drugs than the routine care group.


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Results of the BeSt study, showing good clinical outcomes in all patients irrespective of the initial

treatment group and sustained clinical and functional benefit for up to 4 years, reinforces the

importance of early intervention and tight control in the treatment of RA (131).Further trials have also

shown better outcomes where intensive care was based on regular monitoring of disease activity and

treatment to target (124, 132) (133).

Regular monitoring of disease activity and adverse events, therefore, should guide decisions on

choice and changes in treatment strategies. This includes both traditional DMARDs and biologics.

Monitoring of disease activity should include tender and swollen joint count, patient’s and physician’s

global assessment, ESR & CRP. Arthritis activity should be assessed at one to three month intervals,

for as long as remission is not achieved. Structural damage should be assessed by X-rays

approximately every 12 months during the first few years. Functional assessment (for example the

HAQ) can be used to complement the disease activity and structural damage monitoring.

Table 5: ACR/EULAR 2011 Provisional Definitions of Remission for Clinical Trials (128)

• Boolean Based Definition

At any time point, a patient must satisfy all of the following:

• Tender Joint Count ≤1

• Swollen Joint Count ≤1

• CRP ≤1 mg/dL

• Patient Global Assessment ≤1 (on a 0-10 scale)

• Index Based Definition

At any time point, a patient must have SDAI ≤3.3


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VIII SUMMARY

• Early diagnosis and treatment can prevent or delay the joint destruction, functional

impairment and mortality associated with rheumatoid arthritis.

• Early recognition of an inflammatory arthritis is therefore imperative.

• Patients with an inflammatory arthritis should be referred as early as possible to a

rheumatologist for further management.

• In the earliest stages the arthritis may be undifferentiated. A combination of clinical,

imaging and laboratory measures will allow the clinician to differentiate different causes of

an inflammatory arthritis from rheumatoid arthritis.

• Patients with rheumatoid arthritis or an undifferentiated arthritis must be evaluated in terms

of risk of disease progression and severity.

• Early effective therapy should be instituted for those at risk of developing a persistent

and/or erosive arthritis.

• Therapy includes both pharmacological and non-pharmacological measures.

• The best treatment is a combination of optimal drug therapy and regular monitoring and

intervention to achieve remission or low disease activity.


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A summary of the recommendations for the management early arthritis are summarised in table 6.

Table 6 EULAR recommendations on the management of early arthritis (26)

1. Arthritis is characterised by the presence of joint swelling, associated with pain or stiffness.

Patients presenting with arthritis of more that 1 joint should be referred to, and seen by, a rheumatologist, ideally within 6 weeks after onset of symptoms.

2. Clinical examination is the method of choice for detecting synovitis. In doubtful cases, ultrasound, power Doppler, and MRI might be helpful to detect synovitis.

3. Exclusion of disease other than rheumatoid arthritis requires careful history taking and clinical examination, and ought to include at least the following laboratory tests: complete blood cell count, urinalysis, transaminases, and antinuclear antibodies.

4. In every patient presenting with early arthritis to the rheumatologist, the following factors predicting persistent and erosive disease should be measured: number of swollen and tender joints, ESR or CRP, level of rheumatoid factor and ACPA, and radiographic erosions.

5. Patients at risk of developing persistent or erosive arthritis would be started with DMARDs as early as possible, even if they do not yet fulfil established classification criteria for inflammatory rheumatological diseases.

6. Patient information concerning the disease and its treatment and outcome is important. Education programmes aimed at coping with pain, disability and maintenance of work ability may be employed as adjunct interventions.

7. NSAIDs have to be considered in symptomatic patients after evaluation of gastrointestinal, renal, and cardiovascular status.

8. Systemic glucocorticoids reduce pain and swelling and should be considered as adjunctive treatment (mainly temporary), as part of the DMARD strategy. Intra-articular glucocorticoids injections should be considered for the relief of local symptoms of inflammation.

9. Among the DMARDS, methotrexate is considered to be the anchor drug, and should be used first in patients at risk of developing persistent disease.

10. The main goal of DMARD treatment is to achieve remission. Regular monitoring of disease activity and adverse events should guide decisions on choice and changes in treatment strategies (DMARDs including biological agents).

11. Non-pharmaceutical interventions such as dynamic exercises, occupational therapy, and hydrotherapy can be applied as adjuncts to pharmaceutical interventions in patients with early arthritis.

12. Monitoring of disease activity should include tender and swollen joint count, patient’s and physician’s global assessments, ESR and CRP. Arthritis activity should be assessed at one to three month intervals, for as long as remission is not achieved. Structural damage should be assessed by radiographs of hands and feet every 6-12 months during the first few years. Functional assessment (for example, HAQ) can be used to complement the disease activity and structural damage monitoring.

CRP, C reactive protein; DMARD disease modifying antirheumatic drug; ESR, erythrocyte sedimentation rate; HAQ, Health Assessment Questionnaire: MRI, magnetic resonance imaging.


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X FURTHER RESEARCH Areas for further research include:

• The development and validation of diagnostic tests and strategies that enable general

practitioners to recognise and refer patients with persistent and/ or erosive forms of arthritis early.

• The effect of the temporary use of intensive treatments such as biological agents in early arthritis

to determine whether prevention of erosions and cure (in terms of long-term, possibly drug-free,

remission) of the disease is possible.

• Studies to determine to comparative effectiveness and cost-effectiveness of different therapeutic

strategies.

• Therapeutic strategies in early undifferentiated arthritis to prevent RA.

• Diagnostic and therapeutic strategies in the preclinical phase of RA.


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131. Van der Kooij SM, Goekoop-Ruiterman YP, De Vries-Bouwstra JK. Clinical and Radiological efficacy of Four Different Strategies in Patients with Recent Onset Rheumatoid Arthritis: 4-year follow-up of the Best Study. Arthritis Rheum. 2007;56(suppl 9):S299. 132. Fransen J, Moens HB, Speyer I, van Riel PL. Effectiveness of systematic monitoring of rheumatoid arthritis disease activity in daily practice: a multicentre, cluster randomised controlled trial. Ann Rheum Dis. 2005 Sep;64(9):1294-8. 133. Saunders SA, Capell HA, Stirling A, Vallance R, Kincaid W, McMahon AD, et al. Triple therapy in early active rheumatoid arthritis: A randomized, single-blind, controlled trial comparing step-up and parallel treatment strategies. Arthritis Rheum. 2008 Apr 25;58(5):1310-7.

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2 Early Arthritis Diagnosis and Management