Best Practice & Research Clinical Rheumatology

Vol. 21, No. 5, pp. 907–927, 2007

doi:10.1016/j.berh.2007.05.007
available online at http://www.sciencedirect.com

Extra-articular manifestations and

complications of rheumatoid arthritis

Adam Young * MD, FRCP

Consultant Rheumatologist
West Hertfordshire Hospitals NHS Trust, St Albans, AL3 5PN, UK
Honorary Professor, University of Hertfordshire, Hatfield, UK

Gouri Koduri MRCP

Specialist Registrar in Rheumatology
West Hertfordshire Hospital NHS Trust, Waverly Road, St Albans, Hertfordshire, AL3 5PN, UK

Rheumatoid arthritis (RA) is a systemic inflammatory disease that can involve other tissues and
organs as well as synovial joints. This chapter reviews the clinical aspects of extra-articular RA,
from the early descriptions in rheumatology texts to reports from more recent cross-sectional
and inception cohort studies. There is no agreed classification for these manifestations and, be-
cause criteria and definitions vary so much, this report includes not only the classic extra-artic-
ular features but also the non-articular complications of RA, for example normochromic
normocytic anaemia and chronic leg ulcers, and the important disease-associated comorbidities,
including non-Hodgkin’s lymphoma, ischaemic heart disease and osteoporosis.
Incidence and frequency figures for extra-articular RA vary according to study design. Nod-
ules are the most common extra-articular feature, and are present in up to 30%; many of the
other classic features occur in 1% or less in normal clinic settings. Sjögren’s syndrome, anaemia
of chronic disease and pulmonary manifestations are relatively common – in 6–10% – are fre-
quently present in early disease and are all related to worse outcomes measures of rheumatoid
disease, in particular functional impairment and mortality.
Currently, there are no reliable predictors for these features in early RA, although they are
associated with men, smokers, more severe joint disease, worse function, high levels of inflam-
matory markers, and the presence of rheumatoid factor (RF), antinuclear antibodies (ANA) and
the RA HLA-related shared epitope.
Many of these manifestations are related to the more active and severe RA, so early
and more aggressive RA drug therapies are being employed and, although evidence from rand-
omised studies is not available, this approach would seem appropriate in view of the adverse
effect of extra-articular manifestations on RA outcomes. Unfortunately, specific therapies for

* Corresponding author. Tel.: þ1 727 897362; Fax: þ1 727 897033.

E-mail address: adam.young@whht.nhs.uk (A. Young).
1521-6942/$ - see front matter ª 2007 Elsevier Ltd. All rights reserved.
908 A. Young and G. Koduri

extra-articular manifestations of RA are largely disappointing or unavailable, except for steroids

and cyclophosphamide for vasculitis. The place for biological therapies is still not clear. Pulmo-
nary fibrosis in RA has a poor prognosis whether treated with large doses of steroids, cytotoxic
or disease modifying drugs like cyclosporine, or biologics.
In summary, extra-articular features and non-articular complications of RA are common and
are generally related to worse disease. They need to be recognised early and managed promptly.

Key words: extra-articular rheumatoid disease; RA comorbidity; RA complications; rheumatoid

arthritis.

INTRODUCTION

Rheumatoid arthritis (RA) is a systemic inflammatory disease, which, in addition to the

characteristic peripheral polyarthritis, can involve other tissues and organs. Clinical
and pathological aspects of these manifestations of extra-articular RA (ExRA) have
been well described in rheumatology texts. A common belief has been that they occur
mainly in patients with long-standing or severe disease1 but it is now known that even
severe ExRA can occur in recently diagnosed RA.2,3 There are a number of different
definitions for these extra-articular manifestations, which vary according to the clinical
and/or pathological criteria employed. The fact that there is no internationally agreed
and unifying classification partly accounts for the differences seen in rheumatology
texts, descriptive reports and incidence studies. Other reasons are discrepancies in
case definition and variations in inclusion of manifestations other than classic ExRA
features. Some non-articular features have been correctly classified as complications
of RA rather than ExRA. Others are neither ExRA nor complications, but are included
because of their increased risk in RA. The important disease-associated comorbidities
have therefore also been included in this chapter. An important distinction is when RA
occasionally evolves into a form with systemic rather than articular features, resem-
bling those of systemic lupus erythematosus (SLE) or scleroderma, often described
as ‘overlap syndromes’.

Box 1. Published extra-articular features of rheumatoid arthritis (RA)

and complications of RA

Extra-articular RA
 Nodules
 Raynaud’s phenomenon
 Secondary Sjogren’s syndrome
 Interstitial lung disease – pulmonary fibrosis
 Pericarditis*
 Pleuritis*
 Felty’s syndrome*
 Polyneuropathy, mononeuropathy, mononeuritis multiplex*
 Myopathy, polymyositis*
 Episcleritis, scleritis, kerato-conjunctivitis perforans*
 Glomerulonephritis*
 Systemic vasculitis*
 Extra-articular manifestations and complications of RA 909

 Severe cutaneous vasculitis*

 Benign cutaneous and nail-fold vasculitis
 Lymphadenopathy
 Weight loss, cachexia
 Malaise, fatigue, fever
 Amyloid

Complications of RA
 Atlanto-axial and subaxial subluxation, cervical myelopathy
 Chronic leg ulcers
 Normchromic normocytic anaemia
 Osteoporotic fracture
 Carpal tunnel syndrome
 Lymphoedema, reflex sympathetic dystrophy
 Hyperviscosity, cryoglobulins
 Ischaemic heart disease
 Non-Hodgkin’s leukaemia
 Infections:
 septic arthritis, septicaemia
 upper and lower respiratory tract

*Malmo criteria for severe extra-articular rheumatoid arthritis (see ref. 4).

The main extra-articular features and non-articular complications of RA included in

most texts and recent reviews or reports are shown in Box 1.
Published criteria for extra-articular manifestations are limited. One set of criteria
includes only severe features (Table 1)4, whereas other reports describe only those
that are characteristic and unique to the immunopathological process of RA (e.g. nod-
ules, Felty’s). Others include a wide range of features5, some of which might be con-
sidered constitutional or complications of RA. For example, carpal tunnel syndrome is
due to localised synovial inflammation and is considered an extra-articular manifesta-
tion by some and a complication of RA by others. Details of extra-articular features
and complications of RA not covered in Table 1 are summarised in Table 2.
A relatively common feature of RA is a normochromic normocytic anaemia6, which
has been defined either as an extra-articular feature or as a complication of RA. This
condition has served as a model for the anaemia of chronic disease. It is considered
a laboratory marker of disease state in RA because it varies inversely with markers
of disease activity. The mechanism is complex but includes failure of incorporation
of iron into red cell precursors. Blood loss, iron, folate and vitamin B12 deficiency
all need to be excluded in diagnosis.
Several constitutional symptoms can precede the onset of RA and can also be ma-
jor problems during the course of the disease. These include weight loss, fevers, pro-
found fatigue and malaise, generalised muscle weakness, low mood, depression,
prolonged early morning stiffness and – the most extreme form – ‘rheumatoid
cachexia’. These features are less easy to define and measure and their inclusion in
descriptions of the manifestations of RA vary.
910 A. Young and G. Koduri

Table 1. Criteria for inclusion of extra-articular manifestations of rheumatoid arthritis.32

Manifestation Diagnosis
Pericarditis, Clinical suspicion, X-ray,
pleuritis echocardiography
Felty’s syndrome Splenomegaly (clinically
evident or on US) and
neutropenia (neutrophils <
1.8*10/l) on two occasions
and other causes improbable
Cutaneous Purpura or major cutaneous
vasculitis ulcer in the absence of
significant
atherosclerosis verified by
biopsy or clinical judgement,
dermatologist
Neuropathy Clinical exam, EMG or nerve
conduction studies
Scleritis, Clinical judgement/
episceleritis ophthalmologist
Retinal vasculitis
Glomerulonephritis Clinical judgement by
Vasculitis involving organ specialist
other organs and biopsy compatible
with vasculitis
EMG, elecgromyography; ExRA, extra-articular features of rheumatoid arthritis; IgG, immunoglobulin G;
IV, intravenous; MTX, methotrexate; Rx, treatment; US, ultrasound.
Comment and treatment
Not commonly diagnosed in vivo
Pleural thickening e occasional chance
X-ray diagnosis
Symptomatic Rx  steroids
Uncommon (w0.5%), other ExRA often
present
HLA DRB1 shared epitope
Not necessarily related to articular disease
Rx includes MTX, splenectomy, IV IgG
May be part of systemic vasculitis
Rx ¼ pulsed steroids and cyclophosphamide
Mononeuritis multiplex, purely motor
and sensory peripheral neuropathies all
described (< 1%)
Benign, variable forms not uncommon
Severe forms that progress to
scleromalacia perforans rare
Rx ¼ local steroids
Uncommon and mainly involving cutaneous,
renal, pulmonary, peripheral nerves, and
ocular systems
Rx ¼ pulsed steroids and cyclophosphamide

RA confers an increased risk for the development of a number of other medical

conditions, some of which appear to be related to severity or duration of disease.
Whether these are included in published studies or reviews as extra-articular features
or complications of RA, or if they are included at all, varies considerably. Given their
frequency in association with RA and the immune pathological process involved, some
should at least be considered complications of RA. Most inflammatory rheumatic con-
ditions, including RA, carry an increase risk of non-Hodgkin’s lymphoma (NHL) and
this risk might be further increased by immunosuppressive agents. The question still
remains concerning the relative contribution of underlying disease severity and effects
of immunosuppressive drugs used in RA, especially azathioprine.7 It is not clear to
what extent secondary Sjögren’s syndrome contributes, but Felty’s appears to carry
an increased risk, which is independent of treatment.
Other important examples are generalised osteoporosis and cardiovascular dis-
ease, and RA has been established to be an independent risk factor for both these con-
ditions. However, the increased risk has been attributed not just to the severity of
rheumatoid disease but to drug therapies for RA, including steroids 8–10 and COX2/
NSAIDs.11 RA involvement of heart tissue has been well described, although it is
 Extra-articular manifestations and complications of RA 911

Table 2. Other extra-articular features and complications of RA.

Sjögren’s Xerostomia and keratoconjunctivitis Common: w 25%, associated with
syndrome (SS) sicca lymphadenopathy
Symptoms and signs of dry eyes Pathology can involve all exocrine glands
and mouth
Shirmer’s test positive Usually benign
Autoantibodies distinguish primary Symptomatic treatment
and secondary SS
Biopsy lower lip salivary glands Incidence of lymphomas possibly increased
Raynaud’s Episodic digital ischaemia Common, usually mild symptoms
phenomenon Pain and biphasic colour changes Benign
in digits of hands and feet, Symptomatic Rx, e.g. calcium antagonists
worse in cold (nifedipine) and vasoactive drugs
Inflammatory Symptoms: dry cough, dyspnoea 5e10% with poor prognosis
lung disease
Pulmonary Clinical: inspiratory crackles Steroids and chemotherapy disappointing
fibrosis Chance clinical or CXR finding May be increased incidence of lung cancer
Lung function tests and HRCT
diagnostic
Amyloid No routine lab test available Rare, related to long term uncontrolled RA
(secondary) Renal involvement in chronic Rx is control of RA disease
severe RA
Histological diagnosis by biopsy Prognosis poor
Benign nail-fold Dermal infarction Usually benign
vasculitis Usually asymptomatic No Rx required
Pain a poor prognostic sign
Nodules Subcutaneous, painless and classically Common: ~ 30%, often asymptomatic
on extensor surfaces, e.g. elbows
Classical histological changes Pathognomonic of RA, predicts worse RA
Can be complicated by ulceration and
infection
Chronic leg Secondary to immobility, Symptomatic treatment unless vasculitic
ulcers steroid Rx,or underlying Other causes: venostasis, immobility,
vasculitis or neuropathy steroids
Atlanto- and Preoperative X-ray of Usually asymptomatic and chance finding
subaxial cervical spine: flexion, extension
subluxation and open-mouth views
> 3 mm atlas-axis peg Radiculopathy and myelopathy uncommon
even in late disease when prognosis poor
Anaemia Usually anaemia of chronic disease: Common, associated with worse RA
NcNc
Can mimic true iron deficiency MCV > 70, ferritin normal/raised
Folate and vitamin B12 might May respond to iron supplements
contribute
Carpal tunnel Pain in hands/wrist at night relieved Common
syndrome by shaking, median nerve signs, Wrist splint and cortisone injection
confirmed by NCS/EMG Decompressive surgery
(continued on next page)
912 A. Young and G. Koduri

Table 2 (continued)
Septic arthritis Classic signs acute septic joint, Prompt and correct diagnosis vital
e.g. knee
Classic signs often absent in Maximum antibiotic Rx
immunosuppressed patient, and
aspiration and culture vital
Staphylococcus most common,
but unusual organisms also common
CXR, chest X-ray; EMG, electromyography; HRCT, high-resolution computerised tomography; MCV,
mean corpuscular volume; NcNc, normochromic normocytic anaemia; NCS, xxxxxxxxxxx; RA, rheu-
matoid arthritis; Rx, treatment; SSA, xxxxxxxxxxx.

not commonly encountered clinically.12 However, decreased survival in RA due to

cardiovascular disease has been recognised as a greater problem and the inflammatory
process itself has been implicated in the development of ischaemic heart disease
(IHD).13 In addition, inflammatory markers, including high sensitive C-reactive protein
(CRP), have been identified as independent risk factors for IHD.14
Several well-recognised associations between RA and other medical conditions are
not normally considered extra-articular. Most notable are other autoimmune condi-
tions, like thyroid disease. Other examples include some malignancies (e.g. cutaneous),
upper and lower respiratory infections. Bronchiectasis occurs in up to 10% of RA, but
there is little evidence to classify it as an ExRA feature.15
ExRA manifestations can have a major impact on disease outcome, morbidity and
mortality. Although the figures vary considerably, premature mortality in patients
with classic ExRA features, compared to RA in general, has been reported in most
studies1,2,10,16,17, but not all.18 This might partly be due to study design, a factor
that could also account for the variation in figures for the frequency of ExRA and
the impact on other outcomes.
Other important complications of RA include joint deformity, the need for ortho-
paedic surgery to tendons and joints, and work disability. These will be addressed later
in this chapter in conjunction with the effect of ExRA on RA outcomes.

SUMMARY OF PUBLISHED CLINICAL STUDIES

The frequency and type of ExRA depends on the method of investigation. In autopsy
series, a large proportion of RA patients have evidence of pericarditis, pleuritis and in-
terstitial lung involvement (ILD).12 Vasculitis was reported in 20% of post-mortems,
a much higher figure than in in vivo reports.19 If looked for intensely with modern di-
agnostic tools, evidence of non-articular organ involvement can often be detected; this
is not apparent clinically but might affect both morbidity and mortality. Examples in-
clude ILD [detected with either high-resolution computerised tomography (HRCT)
scanning or diffusion capacity tests], which can be abnormal in up to 40%; a high inci-
dence of pericarditis (based on autopsy or echocardiography) in 30–50% compared
with < 10% in severe RA; and neuromuscular involvement, which might be evident
only on electromyographic (EMG) and muscle biopsy studies. Whether hepatic or re-
nal involvement occurs in RA, except as part of a systemic vasculitis or amyloid, has
been controversial for many years. Renal and hepatic disturbance as a result of the
drugs used in RA are well documented, and often difficult to distinguish from RA itself.
 Extra-articular manifestations and complications of RA 913

Some ExRA features might be benign and/or silent, only becoming manifest depending
on their site. Subcutaneous nodules present clinical problems if they ulcerate, break
down and become infected, often at pressure points like the elbow and toes, or the
sacrum in bed-bound patients. Within other tissues, nodules can cause flexor tendon
deformities and thinning of the sclera. Clinically manifest nodule involvement of pleura,
lung, pericardium and myocardium are fortunately uncommon, but can present real
diagnostic problems.
The descriptions of ExRA in rheumatology texts arise mainly from retrospective
reports from specialist centres with poorly defined catchment areas. This reflects
the more severe end of the spectrum of RA and is not an accurate estimate of the
frequency of ExRA in normal practice. The best way to study the occurrence and im-
pact of these features on RA is through inception cohorts with at least 10-year follow-
up and sufficient numbers to account for the less common manifestations. Very few
inception cohorts have published specifically on ExRA, and small numbers limit the
findings of those that have. This review covers the main and recent studies examining
the frequency and type of ExRA seen in normal clinical settings.
Recent studies of inception cohorts of patients with early RA have reported ExRA
manifestations in a substantial proportion of patients3,5,20, although comparability is
limited by differences in case selection and definition, reporting methods and fol-
low-up time. Estimates of the occurrence of ExRA tend to be higher in clinic-based
than in community studies, as the former are selected for disease severity and com-
plications. No significant decline in the incidence of ExRA has been detected in com-
munity-based studies over the decades21, although the impression of clinicians is that
these features are less frequently seen. This is partly confirmed by recent hospital-
based studies, which have indicated a decrease in the incidence of rheumatoid vascu-
litis, possibly due to more energetic management of RA.22,23
Geographical variations have been reported for both the incidence and severity of
ExRA, suggesting that environmental and genetic factors might be involved. Table 3
summarises the important published studies on ExRA.
A period prevalence study of RA patients admitted to hospital in Malmo, Sweden,
with mean disease duration of 17 years, used the ‘severe’ criteria shown in Table 1 and
reported a cumulative incidence of severe ExRA manifestations of 7.9% in 489 patients
over 4.5 years, predominantly pericarditis/pleuritis and major cutaneous vasculitis.2
Standard mortality ratio (SMR) was greater in ExRA (2.50 vs. 1.82) and mainly due
to cardiovascular disease. An important observation was the major part of excess
mortality occurred soon after onset of ExRA.
In a community-based cohort of incident cases of RA residing in Rochester, USA,
169 of 424 had ExRA of all types (40% at median follow-up 14.8 years), a cumulative
incidence rate of 3.67/100 person-years.16 Sixty-three (15%) had ‘severe’ ExRA man-
ifestations with a cumulative incidence rate of 1.0/100 person-years at risk. This latter
group was strongly associated with increased mortality [relative risk (RR) 4.25]. Sub-
sequent reports from this group showed no secular ) change in incidence of ExRA dur-
ing 1955–2000, and the occurrence of these extra-articular features was independent
of the stage or duration of RA21, findings that contrast with the perception of many
clinicians.
One of the first RA inception cohorts, started in 1965 in the UK, reported on early
ExRA in great detail in 102 patients followed in a hospital clinic over a mean of 4.5
years from onset of RA.5 A wide range of ExRA clinical features were described, in-
cluding non-specific ankle swelling and hepatomegaly. Nodules occurred in 31% and
low BMI (11%) was a poor prognostic sign.
 914 A. Young and G. Koduri
Table 3. Summary of main studies reporting on extra-articular disease.
Location and reference Type of study Number (follow-up) % with ExRA ExRA features Comments
Rochester, USA Ref 16 Population based, 424 14.8 years 1955-85 40% 3.67/100 person Severe ExRA: 15% Increased mortality in
retrospective, incident years severe group only
cases
Malmo, Sweden Ref 2 Period prevalence 489 17 years 7.9% had severe ExRA Severe ExRA only Worse survival with
(4.5 years) Mainly serositis and severe ExRA
major cutaneous
vasculitis
London, UK Ref 5 Inception cohort (RAPS) 102 4.5 years High incidence in early Hand muscle wasting ExRA all common in
1965e1973 RA 94/102 58%, lymphadenopathy early stages
41%, hepatomegaly Low BMI ¼ worse
21%, CTS 52%, outcome
nodules 31%, low
BMI 11%, non-specific
ankle swelling
Rochester, USA Ref 21 Population based, 609 11.8 years median All: 40% No change in incidence
incident cases Severe: 12.8% over decades. Smoking
1955e2000 and early disability risk
factors for ExRA
Lund, Sweden Ref 4 Inception cohort 189 15.5 years Severe: 12.3% Severe ExRA only Associated with RF
Multicentre (ERAS), UK Inception cohort 732 5 years At baseline: nodules
Ref 3 11%, Sjögren’s 7%,
pulmonary 2%
Spain Ref 25 Random sampling, 34 788 285 (36%) Nodules 14.3%, Sjögren’s Spanish: fewer ExRA than
centres 1989e1997 9.1%, AAS (10-year Anglo-Saxon but similar
incidence) 3.2%, CTS 8%, to other Mediterranean
ILD 1.9%, serositis 0.4%, countries
eye disease 1.5%, RA less severe, although
vasculitis 0.4% structure and function
not benign
Italy Ref 26 Prospective study 587 240 (41%) Sicca 17.5%, nodules Less ExRA but more Sicca
16.7%, pulmonary 6%, than British
cutaneous vasculitis 3.7%, Southern Italians higher
peripheral neuropathy risk of ExRA
2.2%, amyloid 0.7%, Felty’s Pulmonary in early ExRA
0.7% cutaneous vasculitis and
nodules late
Chilean Prospective study 992 112 38% Nodules 27%, Sjögren’s RA milder than British/
29%, vasculitis 8% Greek
Joint damage and function
similar to British, possibly
due to high prevalence of
Dw13 0403
Greek/British Ref 24 Comparative study 108 Greek, 107 British 20% (71% in British) Nodules 6% (55% in Destructive arthritis:

Extra-articular manifestations and complications of RA 915

British), Sjögren’s 43% Greeks 29%, British 61%
(17% in British), Raynaud’s Duration of RA, age, sex,
3% (15% in British) RF, ANA, CRP all equal
Ro/SS-A more common
in Greeks.
Finish Population based 103 33% had AAS
British and Malaysian Comparative, hospital- 70 Nodules (13:5) and Serology same
Ref 30 based, cross-sectional vasculitis (4:1) more X-rays worse in British
common in British, AAS more common in
Sjogrens (3:16) more Malaysian
common in Malay
AAS, atlanto axial subluxation; ANA, antinuclear antibodies; BMI, body mass index; CRP, C-reactive protein; CTS, carpal tunnel syndrome; ExRA, extra-articular fea-
tures of rheumatoid arthritis; ILD, interstitial lung disease; RA, rheumatoid arthritis; RF, rheumatoid factor.
916 A. Young and G. Koduri

A hospital-based RA inception cohort from Lund, Sweden, reported that 12.3% of

183 patients developed ExRA using the same criteria as in the Malmo study during
a mean follow-up of 15.4 years.20 This is a cumulative incidence of ExRA of 0.8/100
person-years.
A large, multicentre inception cohort in the UK started in 1986 reported on var-
ious outcomes at 5 years in 732 patients, including ExRA.3 Nodules, Sjögren’s syn-
drome and pulmonary manifestations were already evident at presentation in 11%,
7% and 2%, respectively. The same group reported that the number of ExRA in the
first year of RA was strongly associated with reduced survival and, although cardiovas-
cular mortality was mainly responsible, pulmonary fibrosis was main cause of death in
6%, the only ExRA feature recorded on death certificates.10
A systematic review of the prevalence and outcomes of anaemia in RA found that
the occurrence of the anaemia of chronic disease ranged between 33 and 60%, de-
pending to some extent on variations in definitions.6 Some studies reported an asso-
ciation between anaemia and severity of joint disease, which improved with successful
treatment of the anaemia.
Among a number of reported geographical variations, several have noted a lower fre-
quency of ExRA in southern compared with northern Europeans. One study compared
Greek with British patients and found that the latter had both more severe RA and more
ExRA, except that Greek patients presented with more sicca manifestations.24 A cross-
sectional analysis of 788 Spanish patients with RA attending outpatients in 34 centres
reported at least one ExRA in 36.2%.25 A cross-sectional study of 587 Italians reported
ExRA in 41%, mainly sicca and nodules.26 Similar findings were reported in another
study of 141 Italian patients, in whom there was also a weak association with HLA
DRB1.27 A number of other studies have investigated genetic factors to explain geo-
graphical variations. In southern France, ExRA was rare, possibly related to variations
in expression of HLA DRB1.28 The HLA-DRB1*0401 allele was observed in 71% of
patients with RA vasculitis in France.29 Compound heterozygosity of HLA-DR4 and
HLA-DR1 antigens was reported to increase the risk of ExRA in Asian Indians.30
Whether ExRA features present uniformly over the course of RA has not been
reported in previous inception cohorts but will be addressed later in this chapter.

WHAT CLINICAL OR LABORATORY FACTORS ARE

ASSOCIATED WITH EXRA?

Based on retrospective reviews, ExRA are thought to be particularly frequent in se-

vere active disease.1 Many studies have reported that patients with ExRA are more
likely in men and to have positive tests for RF17 and/or ANA.18 Another study con-
firmed the association of RF with ExRA but not with antibodies to cyclic citrullinated
peptides (anti-CCP).31 Smoking and early disability were independent risk factors for
ExRA.4,32 Several studies have examined the RA-associated genes specifically as poten-
tial risk factors for developing ExRA. Some, but not all, have reported an influence of
HLA DRB1 genes on manifestations of ExRA, the findings depending on the populations
studied. Turesson et al reported that double-dose shared-epitope-positive DR4 geno-
types were associated with ExRA in two populations of northern European descent, in
whom DR4 was over-represented compared to DR1.33 No individual ExRA was asso-
ciated, except Felty’s with DRB1*0401/0401. A higher risk of vasculitis was reported in
RA patients who carried two HLA DRB1 susceptibility genes [odds ratio (OR) 3].29 In
contrast to this, a meta-analysis of Mediterranean European populations concluded
 Extra-articular manifestations and complications of RA 917

that shared epitope (SE) alleles determine articular destruction without increasing the
risk of ExRA manifestations.34 In one study, cervical spine subluxation was related to
HLA DR2 and HLA B2735, and this feature of RA was more likely but not exclusive to
patients with peripheral erosive disease.36 Occupation has been reported as a risk fac-
tor in Welsh miners with RA, who can develop a rare type of pneumoconiosis consist-
ing of pulmonary nodules that cavitate, known as Caplan’s syndrome. A number of
studies have identified laboratory markers of ExRA but these are not in general use
at present. They include IgA RF37 and low C4.38 However, studies of early predictors
of ExRA manifestations in well-defined patient samples are lacking.

WHAT IS THE SIGNIFICANCE OF EXRA ON THE COURSE OF RA?

ExRA features that do not respond to therapy clearly can have an adverse effect on the
course of RA. Fortunately, they are not common, but they include systemic and ocular
vasculitis, Felty’s, interstitial pulmonary fibrosis (IPF), neuromyopathies, amyloid and
cryoglobulins. IPF has a poor prognosis and although there is some evidence that
the natural history in RA is better than in cryptogenic fibrosis39, there is paucity of
data in the literature on IPF. Sicca symptoms can be very troublesome for patients
but are not usually progressive, and adverse outcomes are uncommon.40 Complica-
tions of RA with poor outcomes include septic arthritis, cervical subluxation with my-
elopathy and osteoporotic hip fracture. Some generalised and systemic symptoms of
RA are undoubtedly related to the anaemia of chronic RA, which might improve how-
ever this is corrected. The effect of other, less severe, ExRA on RA outcomes in the
long term has not been well studied.

DO THESE MANIFESTATIONS OF RA HAVE PREDICTIVE

QUALITIES FOR OUTCOME IN RA?

The presence and severity of ExRA do not necessarily correlate with, or predict, the
development of severe joint disease. Both rheumatoid nodules and Felty’s can exist
with minimal joint damage. Mortality is an important and well-defined outcome and
two studies have reported that multiple ExRA are associated with reduced sur-
vival.10,38 Although ischaemic heart disease is mainly responsible for reduced survival
in RA, the most important classic ExRA condition associated with reduced survival in
one inception cohort of RA was pulmonary fibrosis, which was evident even early on
in RA.10 A key question is whether modern early and aggressive therapy for RA, in
particular biological therapies, will have any effect on ExRA and will reduce the impact
of ExRA on the course and outcome of RA. Randomised studies cannot be conducted
for long enough to answer this, but observational studies provide some indicators.
To examine some of the questions posed above we have analysed a large inception
cohort with a maximum follow-up of 20 years. The Early RA Study (ERAS) was started
in 1986 in nine general hospitals in separate regions of England, the details of which
have been described elsewhere.3 In brief, consecutive patients diagnosed with RA
were recruited from centres representing all social strata in England. Entry criteria in-
cluded less than 2 years of symptoms and no prior treatment with DMARDs. Presen-
tation features included type of onset, family and medical histories. Baseline and yearly
assessments included standard clinical, laboratory, functional and socio-economic de-
tails, as previously described.3 Clinicians also recorded, on a yearly basis, previously
agreed features of extra-articular RA and coexistent medical conditions and all
918 A. Young and G. Koduri

inpatient episodes. The date and main cause of death were based on death certificates,
which allow the recording of three other contributing causes and three comorbid con-
ditions, as previously described.10 These were provided and coded by the Office for
National Statistics (ONS) using ICD-10. Mortality data on ERAS patients is>99% com-
plete because all patients were tracked by the National Health Service Central Regis-
ter, which holds computerised records of all patients registered with general
practitioners in England and Wales.
This study has already reported on presenting features, prognostic factors and ma-
jor outcomes at 3, 5 and 10 years. The results reflect standard practice in the manage-
ment of early RA in the UK, prior to the biologic era, which was mainly sequential
DMARD monotherapy in the 1980s, with escalating DMARD use and combination
therapies for more severe RA in the 1990s.
The cohort consists of 1429 patients, with a median follow-up of 9 years, median
duration of symptoms to presentation 6 months and median time from presentation
to start of first DMARD 2 months. Demographic and presentation features have been
fully described3 and are typical of early RA studies, including median age 55 years, 946
(66%) were women, 62% seropositive and 26% erosive.

Frequency and cumulative incidence of extra-articular features

and complications of RA

The most common ExRA and complications of RA over 10-year follow-up were nod-
ules, sicca syndrome, pulmonary lesions and anaemia of chronic disease [whether de-
fined as haemoglobin (Hb) < 10 g at least once or mean Hb < 11 g]. The total number
of individual ExRA and RA complications is shown in Table 4. The frequencies shown

Table 4. Total number of extra-articular features and complications of rheumatoid arthritis (RA) in
ERAS by 10-year follow-up.
Feature/complication Total number (%)
Extra-articular features of RA
Nodules 451 (32%)
Sjögren’s 141 (10%)
Raynaud’s 139 (10%)
RA lung 65 (5%)
Malaise/fatigue 47 (3%)
Vasculitis 39 (3%)
Neuromyopathies 17 (1%)
Felty’s 6 (< 1%)
Complications of RA
NcNc anaemia* 230 (16%)
Carpal tunnel 76 (5%)
Osteoporotic fracture 70 (5%)
Low BMI 36 (3%)
Cervical spine subluxation 20 (1%)
Leg ulcers 17 (1%)
Septic arthritis 5 (< 1%)

BMI, body mass index, NcNc, normochromic normocytic anaemia.

*
NcNc anaemia < 10 g at least once.
 Extra-articular manifestations and complications of RA 919

Table 5. Development of the main extra-articular features and complications of rheumatoid arthritis
over 10 years.
Nodules Sjögren’s RA lung Anaemia*
Year1 159 (11%) 54 (4%) 27 (2%) 77 (5%)
Year3 216 (15%) 80 (6%) 39 (3%) 152 (11)%
Year5 266 (23%) 93 (8%) 40 (3%) 154 (13)%
Year7 304 (30%) 98 (10%) 35 (3%) 163 (16)%
Year10 302 (35%) 106 (12%) 27 (3%) 148 (7)%
*
NcNc anaemia < 10 g at least once.

are not dissimilar from other studies, although this is a more comprehensive list than
most other inception cohorts. Vasculitic manifestations included cutaneous, ocular and
systemic vasculitis. To compare with other studies, the cumulative frequencies of the
more common features at baseline, 3, 5, 7 and 10 years are shown in Table 5. The
more common features are shown as cumulative incidence in Figure 1. These results
show that of patients who develop these features during the course of RA, around
a third of them already had these manifestations at baseline, including nodules, sicca,
pulmonary, and CTS. After this, ExRA and RA complications manifest at a fairly steady
rate over 10yrs, but this does mean that, in contrast to other studies, these manifes-
tations and complications are features of early RA.

7
Are there any clinical or laboratory markers for ExRA?

Demographic features and baseline measures of disease were compared with ExRA
manifestations and RA complications. As some other studies have shown, some
Complications

Fractures
Cx spine
Leg ulcers
CTS

Oculo Cut
Felty’s
Vascultis
ExRA

Scleritis
RA lung
Sjorgren’s
Nodules

20% 10% 0% 10% 20% 30% 40%

Basleline prevalence (%) 10-year cumulative incidence
(per 100 person/years)

Figure 1. Baseline prevalence and 10-year cumulative incidence of the ExRA manifestations. CTS, carpal
tunnel syndrome; Cx, cervical spine; ExRA, extra-articular features of rheumatoid arthritis; Oculo cut,
ocular or cutaneous vasculitis.
920 A. Young and G. Koduri

ExRA were more common in men, including nodules and RA lung, but Sjögren’s and
osteoporotic fracture were more likely in women. Patients more than 60 years at on-
set were more likely to have RA lung, severe fatigue/malaise and fracture, and smokers
more likely to develop nodules. Other significant baseline clinical measures are shown
in Table 6. Several standard measures of disease activity (joint scores,erythrocyte sed-
imentation rate) were associated with nodules, sicca, RA lung and vasculitis, summar-
ised here with the Disease Activity Score (DAS). Of note was the relationship between
ExRA and reduced functional ability, whether measured by functional grade or Health
Assessment Questionnaire (HAQ). Only nodules and Felty’s were associated with the
RA-HLA-related shared epitope, and although only six patients had Felty’s, all were ho-
mozygous for this. The odds ratios for these baseline factors were generally too mod-
est to be of predictive value for ExRA manifestations in clinical settings; for some
features, the numbers were too small to demonstrate significance.

How do extra-articular features and complications of RA affect outcomes?

The number and type of manifestations were compared to standard outcome

measures, previously described in detail by this group, including function3,41, socio-

Table 6. Baseline clinical measures compared to extra articular manifestations & RA complications.
Baseline variable ExRA/comp Odds Ratio 95% Confidence Intervals
Gender Men RA Lung 1.72 1.04e2.84
Women Sicca 1.06 1.03e1.10
Hip Fracture 1.07 1.01e1.12
Age >60 RA Lung 2.07 1.25e3.42
Malaise 2.51 1.38e4.58
Hip Fracture 2.38 1.83e3.09
RFactor ++ve Nodules 1.91 1.50e2.44
Malaise 3.03 1.40e6.53
Vasculitis 1.39 1.00e2.96
X-rays Erosions Nodules 1.30 1.01e1.67
C/Spine Sublux 2.91 1.20e7.06
ANA ++ve Nodules 1.52 1.16e1.99
Felty’s 6.86 1.25e37.66
DAS high Sicca 1.81 1.24e2.62
Nodules 1.48 1.17e1.87
RA Lung 2.75 1.52e4.96
Vasculitis 3.54 1.59e7.87
Neuromyopathy 8.24 1.02e66.11
FG/HAQ high Nodules 1.48 1.18e1.87
Sicca 2.19 1.49e3.21
RA Lung 2.14 1.22e3.75
Hip Fracture 1.46 1.11e1.90
HLA DRSE x1/x2 Nodules 1.61 1.14e2.26
Smoking Ever Nodules 1.45 1.10e1.91
ANA, antinuclear antibodies; DAS, disease activity score; FG/HAQ, functional grade/Health Assessment
Questionnaire; HLA DRSE, shared epitope.
 Extra-articular manifestations and complications of RA 921

economic42,43, work disability44 and orthopaedic measures45; radiological damage46;

number of DMARDs and mortality.10 Table 7 shows the 10-year outcomes for
this cohort; . Table 8 shows the associations between extra-articular and complica-
tions of RA with these outcomes. The presence of nodules and anaemia of chronic
disease were related to unfavourable aspects of most outcomes; RA lung and neuro-
myopathies were related with mortality; and Sjogren’s syndrome with worse func-
tional outcome. Again, for some manifestations, numbers were too small for
robust analysis. However, some confirmed previous studies, including increased mor-
tality and worse function with hip fracture, and presence of nodules with erosive
disease.

Mortality

Non-Hodgkin’s lymphoma (NHL) was a primary cause of death in 11 (2.3%) and a sec-
ondary cause in two patients in the ERAS cohort, confirming the well-recognised

Table 7. 10-year outcome in ERAS.

Outcome measures at 10 years Number (%)
10-year status
Alive 907 (73)
Deceased 337 (27)
Functional grade
I 262 (33)
II 357 (46)
III 142 (18)
IV 22 (3)
Job change*
Same job 180 (49)
Stopped work 185 (51)
X-rays hands/feet
Non erosive 151 (20)
Erosive 619 (80)
Inpatient interventions**
None 363 (51)
RA inpatient treatment 138 (19)
Minor operation 62 (9)
Intermediate operation 38 (5)
Major operation 111 (16)
Drug therapies
NSAIDs 107 (12)
DMARD  1 319 (35)
DMARD  2 257 (28)
DMARD  3 238 (26)
*
Those in paid employment at presentation.
**
Medical treatment for rheumatoid arthritis or orthopaedic surgery.
922 A. Young and G. Koduri

Table 8. . ExRA features & RA complications as predictors for RA outcomes.

ExRA Outcome Odds ration 95% Confidence Intervals
RA Lung Mortality 4.45411 2.63e7.54
Malaise/fatigue 2.48220 1.38e4.45
Neuromyopathies 3.94494 1.44e10.73
Hip fracture 4.62500 1.98e10.79
NcNc anaemia* 1.47953 1.11e1.95
Nodules Function 2.18668 1.58e3.00
Sjogrens 2.35085 1.37e4.01
RA Lung 4.16901 1.24e13.97
Hip fracture 1.88978 1.29e2.76
NcNc anaemia 2.48302 1.60e3.83
Nodules Erosions 2.61963 1.74e3.93
NcNc anaemia 2.29639 1.32e3.99
Nodules N DMARDs 3.03774 2.25e4.09
Vasculitis 3.27791 1.07e9.96
NcNc anaemia 2.25137 1.55e3.25
C/Sp subluxation Major surgery 2.95000 1.00e8.64
Hip Fracture 2.58705 1.74e3.84
NcNc anaemia 2.63500 1.74e3.97
*NcNc anaemia. <10gm at least once.

increased risk of NHL in RA. It has also been reported to be associated with Sjögren’s
syndrome, but was present in only two lymphoma deaths in ERAS. Sjögren’s was
equally present in deceased and alive patients (10%).

RA lung

Presence of rheumatoid lung involvement was a strong predictor of mortality in this

study. Pulmonary fibrosis was the only classic ExRA condition cited as a primary cause
of death (N ¼ 18) on death certificates, as previously reported by this group.10 It was
a secondary cause of death in five and contributory in three other deaths; it was a co-
morbid condition in another nine patients who died of other causes. Of the 26 with
pulmonary fibrosis on their death certificate, 17 already had a clinical diagnosis – three
at presentation and ten within 3 years of follow-up (mean 30 months). In nine, the di-
agnosis was made only terminally or at autopsy. Only one patient also had sclero-
derma. Women died from pulmonary fibrosis younger than men, 50% had received
steroids, 85% were on DMARDs, 10 received methotrexate, nine had a diagnosis of
pulmonary fibrosis prior to therapy and none developed pneumonitis. Clinical detec-
tion of pulmonary fibrosis is reported in less than 5% in RA, although HRCT improves
on this.47 It was the third most common condition in a retrospective study of extra-
articular RA (cumulative incidence 6.8%).48 The natural history of pulmonary fibrosis
and RA has not been well studied, although idiopathic pulmonary fibrosis is known to
have a poor prognosis (median survival 3–5 years). Whether pulmonary fibrosis with
RA has a better prognosis is debated, although there are differences in HRCT early
on.47 As pulmonary fibrosis was often recognised clinically early in disease, it raises
 Extra-articular manifestations and complications of RA 923

the issue of pulmonary function screening tests and considering more aggressive inter-
ventional approaches.49

Cardiovascular

Involvement of the heart in RA has been well documented, but is not common in vivo.
12,50
None the less, RA has been established as an independent risk factor for IHD,
inception cohorts have shown that multiple ExRA are associated with reduced sur-
vival10,38 and a recent case-control study has reported an association between severe
ExRA and cardiovascular morbidity.51 The ERAS cohort confirmed recent reports of
the importance of cardiovascular mortality in RA and showed that IHD was the single
most common primary cause of death (24%), was higher than expected (SMR 1.49,
95%CI 121–177), and was most evident within 7years of presentation.10 It was a sec-
ondary cause of death in another 13 and a comorbid condition on death certificates in
six. Cardiac and non-cardiac vascular conditions (aortic aneurysm, thrombo-embolism,
stroke, renovascular disease) were the primary cause of death in a total of 181 (39%)
patients, and recorded as secondary or a comorbidity in another 16 (6%) deaths. Mean
survival from baseline was 1–2 years lower in IHD than in other major categories and
5-year survival was 41% in IHD compared with 69% from other causes. The wealth of
evidence supporting this inflammatory link has prompted the suggestion that IHD
could be considered an extra-articular manifestation of RA.52

MANAGEMENT OF EXTRA-ARTICULAR RA

There are limited specific therapies available for extra-articular manifestations of RA.
Complications should be treated in the normal way and full suppression of RA disease
with DMARDs and judicious use of steroids is vital. Under-treatment is a real possi-
bility given that the usual measures of joint disease activity might not always reflect
the severity of inflammatory activity elsewhere. Pulmonary fibrosis in RA has
a poor prognosis, whether treated with large doses of steroids, cytotoxic or dis-
ease-modifying drugs like cyclosporine, or biologics. There are no controlled studies
for these therapies in RA-associated or idiopathic ILD, only a few case reports. The
distinction between methotrexate toxicity and RA lung disease is of major importance
and can be a problem clinically. However, there is no evidence of a causal relation be-
tween the two.53 Resistant pleural and pericardial effusions might respond to intrale-
sional steroids after adequate drainage. The neutropenia of Felty’s usually responds to
DMARDs like methotrexate, and splenectomy is not usually required. The normo-
chromic normocytic anaemia of RA normally improves with better control of joint dis-
ease. Vasculitic manifestations in RA vary considerably in severity but the conventional
use of large doses of steroids (e.g. methylprednisolone) and cytotoxic drugs (e.g. cy-
clophosphamide) are usually successful. There is limited evidence for the use of bio-
logic agents in ExRA, mainly from case reports, and these patients are excluded
from randomised studies of DMARDs and biologics. Although there is concern about
these agents inducing vasculitis and other ExRA, there is no evidence at present for
a causal role. Therapy for comorbidities should be prompt and active, especially for
infections. Preventive measures available for osteoporotic fracture and IHD offer
opportunities in management; cessation of smoking is a priority.
924 A. Young and G. Koduri

Practice points

 Both extra-articular features and non-articular complications of RA have been

included because existing classifications favour the classic and more severe
manifestations and because of the considerable overlap between them.
 This broad spectrum of features is important and relevant to clinicians. Al-
though underlying pathologies might distinguish them from each other, clinically
they are both common, are often present early and continue to develop at
a steady state during the course of disease.
 Incidence and frequency figures for ExRA vary according to study design. Nod-
ules are the most common and are present in up to 30%, whereas many of the
other classic ExRA features occur in 1% or less in normal clinic settings. Sjög-
ren’s syndrome, anaemia of chronic disease and pulmonary manifestations are
relatively common in 6–10%, are frequently present in early disease, and all are
related to worse outcomes.
 These features are a major component of the disease, and include troublesome
symptoms to the patient, adverse outcomes, increased morbidity and mortal-
ity, even at early stages of RA.
 Specific therapies are largely disappointing or unavailable, except for steroids
and cyclophosphamide for vasculitis. As many manifestations are related to
the activity and severity of RA, early and more aggressive RA drug therapies
are being employed. Although evidence from randomised studies is not avail-
able, this approach would seem appropriate in view of the adverse effect
of ExRA on outcomes. The place for biological therapies in ExRA is still not
clear.
 At the present time, there are no reliable predictors for ExRA in early RA, al-
though they are associated with men, smokers, more severe joint disease,
worse function, high inflammatory markers and the presence of RF, ANA,
and the RA-HLA-related shared epitope.

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Further reading

Anaja JM, Diethelm L, Ortiz LA et al. Pulmonary involvement in RA. Seminars in Arthritis and Rheumatism
1995; 24: 242–254.
Systemic rheumatoid vasculitis: a review. Seminars in Arthritis and Rheumatism 2006; 36: 88–98.
Gorony RA & Weyand CM. Vasculitis. Current opinion in rheumatology 1995; 6: 290–294.
 Extra-articular manifestations and complications of RA 927

Balint GP & Balint PV. Felty’s syndrome. Best Practice & Research Clinical Rheumatology 2004; 18: 631–645.
Voskyl AE. The heart and cardiovascular manifestations in RA. Rheumatology 2006; 45: iv4–iv7.
Bluestone R & Bacon P (eds.). Extra-articular manifestations of RA Clinics in Rheumatic Diseases 1977; vol. 3 (3).
WB Saunders.
Turesson C & Matteson EL. Management of extra-articular disease manifestations in RA. Current Opinion in
Rheumatology 2004; 16(3): 206–211.