Update on Rheumatoid Arthritis
Cheuk-wan Yim 嚴卓雲
HK Pract 2019;41:11-17
Summary
Rheumatoid arthritis (RA) is an autoimmune disease
which results in damage to joints as well as to multiple
organs. The American College of Rheumatology /
European League Against Rheumatism (ACR/EULAR)
2010 Classification criteria help physicians to diagnose
RA early. Conventional disease-modifying anti-rheumatic
drugs (DMARDs) and biological agents have
improved RA's long-term outcome. Early aggressive
treatment is now considered the standard of care. The
task of managing the various co-morbidities and healthcare
issues of RA is challenging which would require
close collaboration between rheumatologists and family
physicians.
摘要
類風濕性關節炎(RA)是一種自身免疫性疾病,除了會影響患者的關節外,隨著病情演進,其他的身體器官,亦可能受到不同程度的影響。American College of Rheumatology / European League Against Rheumatism (ACR/EULAR) 2010分類標準可幫助醫師儘早診斷RA。傳統的改善病情抗風濕藥
(DMARDs)和生物製劑改善了長期的結果。早期的積極治療現在被認為是護理的標準。管理RA的各種合併疾病和保健問題的任務是具有挑戰性的,這需要風濕病學家和家庭醫生的密切合作。
Case vignette
Ms Chan is a 56-year-old housewife, non-smoker
and non-drinker. She suffered from diabetes mellitus
and hypertension and was under the care of her private
family doctor. She developed symmetrical arthritis
affecting both wrists, finger joints (metacarpophalangeal
and proximal interphalangeal joints and knees) in 2013.
Her family doctor suspected that she was suffering from
rheumatoid arthritis and referred her to a Rheumatology
clinic for review. However she defaulted SOPD
appointment and simply took over-the-counter 'painkillers'
which contained indomethacin and prednisolone.
In 2015 she was admitted into the Medical ward of her
local Hospital Authority (or private) hospital for non-ST-elevation
myocardial infarction (NSTEMI). She
was noted to have early deformities of both hands with
active arthritis (Figure 1), mild pulmonary fibrosis and
cardiomegaly (Figure 2), collapsed lumbar vertebra L1
and 2 (Figure 3). Blood test revealed rheumatoid factor
960 (ref <12), ESR 96 mm/hr, CRP 26 (ref<8). She
was diagnosed as suffering from severe Rheumatoid
Arthritis (RA) with joint deformities, interstitial lung
disease, osteoporosis and coronary artery disease ( CT
coronary angiogram showed multiple calcified plaques
at all coronary arteries with significant stenosis).
She was initially treated with sulphasalazine for her
rheumatoid arthritis, denosumab for her osteoporosis,
percutaneous coronary intervention (PCI) followed
by clopidogrel, aspirin, losartan, atorvastatin for her
coronary artery disease. However, her arthritis remained
active at 6 months. Abatacept injection as self-financed
item was added. Her rheumatoid arthritis responded
well to treatment, with resolution of arthritis and
normalisation of ESR and CRP. Her functional status
was restored and her RA remained in remission.
Introduction
Rheumatoid arthritis (RA) is an autoimmune
disease that primarily causes chronic inflammation in
the joints. The pictures of symmetrical polyarthritis
leading to progressive multiple deformities of limbs
have been the hallmark features of RA. However, it is
a multisystem disorder which may cause complications
in various organs and tissues. With the rapid advances
in diagnostic tools and the therapeutic options in the
past two decades, we are now more confident in the
ability to induce remission of the arthritis, restoration of
function and prevention of deformities in our patients.
Early identification of cases at the primary care by
means of new diagnostic tools and prompt referral to
rheumatologists would enhance the treatment outcome.
Epidemiology and etiology
The annual incidence of RA varies from 5 to 50
every 100,000 population1,2,4. The global prevalence
is between 0.3-1.0%.3,5 Hong Kong has a reported
prevalence of 0.35%.6 RA affects all ages, with peak
between 35 and 50 years old. The exact cause of
rheumatoid arthritis remains unknown. Current evidence
suggests that it is a multifactorial disease. Genetic,
environmental, hormonal, immunologic, and infectious
factors may play significant roles in the initiation and
perpetuation of this illness. First-degree relatives have
a 2- to 3-fold increase in risk7 while the concordance
rate in monozygotic twins is approximately 15-20%.8,9
Individuals having certain shared epitopes of the human
leukocyte antigen (HLA) are at an increased risk (e.g.
HLA-DR beta *0401, 0404, or 0405, HLA-DR beta
*0101)10,11. Females are affected approximately 3 times
more often than males12 but the difference diminishes
in older age groups, suggesting the possible role of sex
hormones.
Cigarette smoking has been shown to promote
citrullination of peptides in the lungs13, which would
trigger the production of anti-citrullinated peptide
antibodies (ACPA) production. Various infectious agents
(such as Epstein-Barr virus, Mycoplasma species) have
been postulated for decades to have an association.
There is emerging evidence pointing to an association
between RA and periodontopathic bacteria such as
Porphyromonas gingivalis14,15, and treating the gum
disease has been shown to improve RA.16
Pathophysiology
Recent histopathological and immunopathological
studies envisage RA as a clinical syndrome with
different subsets. These subsets represent various
dysregulatory interaction of helper T-cells,
B-lymphocytes, macrophages and fibroblasts, as well
as the consequent pro-inflammatory cytokines such
as Interleukin (IL)-1, IL-6, IL-10, IL-18, Tumour
Necrosis Factor (TNF)-alpha.17,18 They all lead towards
a final common pathway in which persistent synovial
inflammation and associated damage to articular
cartilage and underlying bone are present.18 While the
majority of RA would have rheumatoid factor (RF) or
anti-citrullinated peptide antibodies (ACPA), around
20% of the cases would be double-negative19. For the
same reason, certain inflammatory parameters such as
erythrocyte sedimentation rate (ESR) and C-reactive
protein level may be normal in some active cases.
Clinical presentation
The classical presentation of RA is persistent
symmetrical polyarthritis that affects the hands and feet.
However, the distribution of joint involvement at disease
onset is quite variable. Most of the cases would start as
arthritis in one or few joints with gradual progression
to other joint areas in the subsequent weeks to months.
Small joints of the hands (including wrists) and feet are
the most common, followed by elbows, knees, ankles
and shoulders. Some patients may begin with systemic
features (e.g. fever, malaise, arthralgias, and weakness)
before the appearance of overt joint inflammation and
swelling. A small percentage (approximately 10%) of
patients have an explosive onset of polyarthritis and
extra-articular manifestations.
On physical examination, the typical swelling,
tenderness, warmth, and decreased range of movements
(ROM) of the affected joints would be present. There
may be wasting of muscles around the joints, of
which interosseous muscles of the hands being the
most frequent. Deformities such as ulnar deviation,
boutonniere and swan-neck deformities, hammer toes,
and joint ankylosis may be present in advanced cases.
RA is a multisystem disorder. Inflammation
and damage may occur in skin (rheumatoid nodule,
vasculitis), eyes (episcleritis, scleritis, sicca syndrome),
lung (interstitial lung disease, pleuritis and pleural
effusion), heart (pericarditis and pericardial effusion).
Active RA is associated with subclinical carotid
atherosclerosis and stiffness. Large cohorts have
confirmed rheumatoid arthritis as an independent
cardiovascular risk factor.20,21,22 In the Fracture Risk
Assessment Tools (FRAX) for osteoporosis, rheumatoid
arthritis has a significant weighing on the overall
fracture risk.23,24 In additional to the multi-organ
involvement, pain and functional decline frequently lead
to emotional instability, depression and unemployment
in the individuals, and cause profound socioeconomic
impact to society.
Autoantibodies in RA
i) Rheumatoid factors (RF) are autoantibodies
directed against the Fc fragment of immunoglobulin
(IgG) G molecules. They are present in 70-80% of
RA cases.25 However, RF may be present in a variety
of other conditions such as infectious mononucleosis,
chronic hepatitis, leukaemia, Dermatomyositis, SLE,
Sjogren, systemic sclerosis. The specificity of RF for
RA is only 85%.
ii) Anti-citrullinated peptide antibodies (ACPAs)
are antibodies directed against citrullinated proteins.
Proteins (e.g. fibrin, vimentin) can undergo citrullination
during cell death and tissue inflammation. ACPAs
have been demonstrated to predict the development of
rheumatoid arthritis26,27, more active and severe disease
course, more aggressive radiological damage.28 They
have a sensitivity of 50-80% and specificity of 95-98%
for RA.
Diagnosis
There is no single confirmatory test for RA. The
diagnosis is established by a combination of clinical,
laboratory, and imaging features. The American College
of Rheumatology (ACR) 1987 criteria had been used
for more than two decades.29 They were limited by
poor sensitivity and specificity for patients with early
inflammatory arthritis who subsequently developed
rheumatoid arthritis. Thus the ACR and European
League Against Rheumatism (EULAR) jointly proposed
a new set of criteria in 201030 which has a better
performance in the identification of early cases.31,32
In the ACR/EULAR 2010 criteria, the patients must
1) have at least 1 joint with definite clinical
synovitis (swelling)
2) with the synovitis not better explained by
another disease
There are 4 categories of assessment (Table 1):
a) Joint involvement (score 0-5)
b) Serology (RF or ACPA, score 0-3)
c) Acute phase reactant (score 0-1)
d) Duration of symptoms (score 0-1)
The maximum number of points possible is 10.
A classification of RA requires a score of 6/10 or
higher. Patients with a score lower than 6/10 should
be reassessed over time. If patients already have
erosive changes characteristic of RA, and they meet
the definition of RA, application of this diagnostic
algorithm is unnecessary.
This set of criteria has a better performance in
the identification of patients with early arthritis. They
subsequently evolve into rheumatoid arthritis and
these criteria are currently used in the RA studies and
guidelines.
Imaging in Rheumatoid arthritis
Radiography
Plain radiography remains the readily available and
inexpensive choice for RA.33 Views of the hands, wrists,
knees, feet, elbows, shoulders, hips, cervical spine, and
other joints should be assessed when indicated. Erosions
may be present even in the absence of pain. However,
the radiographic changes lag behind the disease process
in RA by months or even years and change after
treatment is slow. Other imaging with better dynamic
changes to therapy would be warranted.
Ultrasonography (US)
Musuloskeletal (MSK) ultrasonography is an
attractive method of imaging for RA.34,35 The operating
cost is relatively low. It is free from harmful radiation.
The advances in US imaging technology may permit
better imaging of inflamed joints which can differentiate
joint effusion, synovial proliferation, tenosynovitis
and erosions.35 With the Doppler technology, the
rheumatologist can monitor disease progression
treatment response.36 Moreover, US-guided aspiration,
biopsy and injection of medication are low risk
intervention that could be performed in the day-care
setting.
Magnetic Resonance Imaging (MRI)
MRI offers excellent detection and differentiation
of soft-tissue, effusion and erosion at an early stage.37
However, it is a more expensive investigation comparing
with X-ray or MSK ultrasonography. Currently low-field
MRI machines (of 0.2-0.5T) targeting at peripheral
joints are capable of detecting inflammatory signals.38
Treatment options
Once the diagnosis of rheumatoid arthritis is
established, disease modifying anti-rheumatoid drugs
(DMARDs) should be started as soon as possible.39, 41
The goal of treatment should be aimed at achieving
sustained remission or low disease activity in every
patient40, restoring the function of the affected joints
and preventing deformities as well as systemic
complications. Currently available DMARDs are
classified under three categories: conventional synthetic
DMARDS, biological DMARDs and target synthetic
DMARDS.
Conventional synthetic DMARDS (csDMARDs)
Methotrexate, leflunomide, sulphasalazine,
hydroxychloroquine are common treatment choices that
are used alone or in combination.
Methotrexate (MTX) is the first-line choice in RA
because many clinical trials have clearly established
its short and long-term efficacy.42,43,44,45 The relative
efficacy to safety profile of methotrexate in RA is
superior to other DMARDs. Regimens using MTX
in combination with other DMARDs (cs-, b- or ts-)
have been shown to be more effective than MTXmonotherapy
or b-/ts-DMARD monotherapy.46-49 Thus
methotrexate is considered as the ‘anchor drug’ in RA.
Leflunomide (LEF) and sulphasalazine (SSZ) are
alternatives for moderate to severe RA who cannot
tolerate or when MTX is contraindicated.
Hydroxychloroquine (HCQ) is usually used in mild
RA cases or in combination with MTX.
Other csDMARDs include cyclosporine A,
azathioprine, penicillamine, and gold salt may be used
in selected cases of RA
Biological DMARDs (b-DMARDs)
Biological DMARDs (b-DMARDs) are monoclonal
antibodies or receptor proteins targeting at specific
inflammatory cytokines. At the moment there are 4
classes of agents available:
1) TNF inhibitors- adalimumab, certolizumab,
etanercept, golimumab, infliximab
2) anti-CD 20 antibodies - rituximab
3) T-cell co-stimulatory inhibitor - abatacept
4) Interleukin-6 (IL-6) inhibitors- tocilizumab
They offer more rapid onset of action and better
efficacy than cs-DMARD alone. However, they are
expensive items and are listed as self-financed items in
the public health care system. Patients whose disease
remain highly active despite trying several csDMARDs
and/or are having financial difficulty may be referred to
apply for subsidy for b-DMARDs under the Samaritan
Fund Scheme.
Target synthetic DMARDs (tsDMARDs)
These novel agents, also called small molecules,
inhibit the signal transduction of the inflammatory
cytokines through intracellular kinase (Januse kinase or
JAK) pathways. Tofacitinib is a JAK 1 & 3 inhibitor
which is an oral preparation proven to be effective as
monotherapy or in combination with MTX.49
EULAR recommendation:
The European League Against Rheumatism
(EULAR) has published recommendations on the
treatment algorithms of RA50:
Pre-treatment assessment
Baseline investigation including complete blood
count, renal and liver function test, X-ray of affected
joints and Chest-X-ray would be performed in all
RA patients. As Hong Kong has a high prevalence of
chronic hepatitis B infection and the fact that various
DMARDs and corticosteroid may impose low to high
risks of hepatitis B reactivation, hepatitis B serology is
mandatory. For patients who plan to receive biological
or target synthetic DMARDs, additional screening
for latent TB infection (with Tuberculin skin test or
Interferon Gama Release Assay), assessment of cardiac
profile and counselling on the risk of herpes zoster is
necessary.
Monitoring of disease activity and side effects
According to the recommendation of ACR and
EULAR, the patients should be assessed every 1 to 3
months for treatment response and adverse events.39, 50
If there is no improvement by 3 months after the start
of treatment, or the target (remission or low disease
activity) has not been reached by 6 months, the
DMARDs should be escalated or adjusted. There are
numerous disease activity measures to assess the disease
severity: Disease Activity Score-28 joints (DAS 28),
Simple Disease Activity Index (SDAI), Clinical
Disease Activity Index (CDAI), Health Assessment
Questionnaire (HAQ) are some of the widely used tools
in clinical practice*.51
As the DMARDs may give rise to various adverse
events, it is important to alert the patient to take note
of any skin rash (especially after HCQ, SSZ, LEF,
or b-DMARDs are used), oral ulcer (MTX, LEF,
azathioprine), hair loss (MTX, azathioprine), visual
problem (HCQ). Regular blood test should be performed
to screen for hepatitis (MTX, LEF, SSZ, tocilizumab,
tofacitinib), leucopenia (MTX, LEF, tocilizumab,
tofacitinib), hyperlipidaemia (tocilizumab, tofacitinib).
Common viral (e.g. URTI) and bacterial infection
(pneumonia, urinary tract infection, soft tissue infection)
would occur more frequently. Tuberculosis, herpes
zoster and other opportunistic infections may occur.
General advice including smoking cessation, healthy
diet and habits, avoidance of crowded places, wearing
mask if necessary should be offered to minimise the
risk of infection.
Concerning vaccination, killed vaccines (e.g.
pneumococcal/ influenza/Hepatitis B) are generally
safe52* while recombinant vaccine (e.g. Human
Papilloma virus) is probably safe in patients on
DMARDs. Live attenuated vaccines (e.g. MMR,
zoster) are not recommended if the patient is receiving
biological DMARDs*.39,52
Role of primary care practitioner in the management of RA
In order to capture the window of opportunity of
early aggressive treatment, early referral of patients
with clinical diagnosis of RA to rheumatologists is
important. Primary care practitioners play a pivotal
role in the identification of cases by performing
autoantibody testing (RF or ACPA) and inflammatory
markers (ESR or CRP) on patients with arthritis
matching the distribution of RA according to the
EULAR/ACR criteria. The medical history including
hepatitis status, other medical illnesses, family history
and allergic history are valuable. With sufficient
information the rheumatologists can triage the cases
for an early assessment and initiation of treatment.
While the patient is waiting for the rheumatology
appointment, prescription of analgesics and arrangement
of physiotherapy would alleviate symptoms. Moreover,
primary care physicians can manage the co-morbidities
of the patients (e.g. hypertension, diabetes mellitus
and cardiovascular diseases) in collaboration with the
rheumatologists so as to provide the most suitable
treatment and minimise the complications. Furthermore,
the provision of care and advice on smoking, dental
care and vaccination would have significant impact on
RA management.
Conclusions
Rheumatoid Arthrits is an autoimmune disorder that
can cause joint deformities, multi-organ involvement,
increased risk of cardiovascular disease and
osteoporotic fracture. ACR/EULAR 2010 classification
criteria help the identification of early RA cases.
Early initiation of DMARDs and intensive monitoring
with appropriate drug titration is essential to treat
the disease to achieve remission, restore the function
and prevent complications. The biological and target
synthetic DMARDs have expanded the armamentarium
of RA. The concerted collaboration between primary
care practitioners and rheumatologists is essential to
optimise the management of RA. Hopefully the images
of advanced RA would soon become history.
Cheuk-wan Yim, FRCP(Edin.), FHKCP, FHKAM
Associate Consultant,
Rheumatology Unit, Department of Medicine, Tseung Kwan O Hospital, Kowloon East Cluster, Hospital Authority
Correspondence to: Dr Cheuk-wan Yim, Department of Medicine, Tseung Kwan O Hospital, 2 Po Ning Lane, Hang Hau, New Territories, Hong Kong SAR.
E-mail: yimcw1@ha.org.hk
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