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Rheumatology 2005;44:434442 doi:10.1093/rheumatology/keh532

Advance Access publication 18 January 2005

Review

Multiple sclerosis, neuropsychiatric lupus andantiphospholipid syndrome: where do we stand?

S. Ferreira, D. P. DCruz1 and G. R. V. Hughes1

Multiple sclerosis (MS), systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) are chronic, immune-

mediated, relapsingremitting disorders affecting young adults, the pathogenesis of which is still largely unknown. Neurological

manifestations and magnetic resonance imaging (MRI) can be indistinguishable and there are no specific diagnostic tools.

Treatment and prognosis are quite different. There is controversy about the prevalence and significance of antiphospholipid

antibodies (aPL) in MS. A significant number of patients with APS/SLE are misdiagnosed as MS but evidence suggests they

are distinct nosological entities. However, it is essential to differentiate them since APS may be responsive to anticoagulation.

When assessing MS patients, clinicians should consider APS/SLE, especially if the MS has atypical features. A trial of

anticoagulation might be worthwhile in some patients with atypical MS and consistently positive aPL.

KEY WORDS: multiple sclerosis, multiple sclerosis-like illness, neuropsychiatric lupus, antiphospholid syndrome, differential diagnosis.

Multiple sclerosis (MS) is the commonest cause of neurologicaldisability in young adults [13]. Its aetiology and pathogenesisare unknown [110]. The course and prognosis are variable andthere is no definitive long-term treatment [13].

Systemic lupus erythematosus (SLE) is a multisystem diseaseand central nervous system (CNS) involvement occurs in about50% of patients and carries a poor prognosis [1, 1113]. A widespectrum of neurological and psychiatric features are recognized[1115]. Demyelinating syndromes resembling MS are a rarefeature of SLE (lupoid sclerosis) and are a diagnostic challenge[1221]. The pathophysiology of CNS lupus remains poorlyunderstood [1, 1113, 22, 23] but there is increasing evidencethat it is often associated with antiphospholipid antibodies (aPL)and only rarely caused by vasculitis [1214, 2232]. This isparticularly true for myelopathy [2729, 32, 34]. Combinedtherapy with immunosuppression and anticoagulation is oftenrequired [3234].

Antiphospholipid (Hughes) syndrome (APS) was first describedin 1983 [35] and it can occur on its own (primary APS; 53%)or in association with other diseases (secondary APS), mostcommonly SLE (36%) [1113, 36, 37]. It is characterized bythrombosis (venous or arterial) and/or pregnancy morbidity in thepresence of persistent aPL [37, 38]. Although only stroke and

transient ischaemic attack (TIA) are included in the classificationcriteria [37, 38], more complex neurological manifestations arebeing recognized [12, 13, 1921, 3947] and multifocal white matterlesions on brain magnetic resonance imaging (MRI) are common[12, 13, 46]. In the Euro-Phospholipid Project cohort of 1000European APS patients (primary and secondary), myelopathyand optic neuropathy were rare manifestations (0.4 and 1%,

respectively) [36]. However, the number of patients diagnosed withMS and later shown to have APS has grown substantially [4547]and the true prevalence of aPL in unselected MS populations iscontroversial [20, 21, 4758]. Anticoagulation is very effective bothin treatment and prevention of APS [59, 60].

The immunological nature of these diseases, the affectedpopulation, the relapsingremitting course, the neurological mani-festations and the presence of multifocal white matter lesionson MRI can make them indistinguishable [1921, 4549]. Someauthors even question whether they could represent the samenosological entity [21]. It is important to clarify these issues sincecost-effective treatments may be useful in young patients whowould otherwise be disabled. Here we review the literature with aview to improving differential diagnosis. Three clinical groupsare considered: MS, primary APS (PAPS) and neuropsychiatriclupus with/without APS (NPLE/APS).

Epidemiology

MS, SLE and APS mainly affect women of childbearingage [13, 11, 37] but there is a lower female to male ratio inMS (2:1 versus 9:1 in SLE and 5:1 in PAPS) [13, 36]. Black

and Japanese populations are rarely affected by MS [13] butthey have one of the highest incidences of SLE [1, 11].SLE is a relatively common autoimmune connective tissue

disease [1, 11] and neurological involvement is common(2570%) [1, 1113] and frequently associated with aPL/APS(5060%) [1214, 2532, 44, 45]. The rising incidence of bothdiseases is possibly due to better recognition [13, 11]. At the

Correspondence to: D. David DCruz, The Lupus Research Unit, The Rayne Institute, Lambeth Wing, St Thomas Hospital, London SE1 7EH, UK.

E-mail: [email protected]

Internal Medicine Department (B), S. Joa o Hospital, Alameda Prof. Herna ni Monteiro, 4200 Porto, Portugal and 1The Lupus Research Unit, The Rayne

Institute, Lambeth Wing, St Thomas Hospital, London SE1 7EH, UK.

Submitted 15 June 2004; revised version accepted 26 November 2004.

Rheumatology Vol. 44 No. 4 British Society for Rheumatology 2005; all rights reserved

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same time, there has been a marked increase in the diagnosis ofMS variants with the widespread use of MRI [48]. The potentialsignificance of aPL and its variable prevalence in MS [20, 21,4658] will be explored later in this review.

Pathophysiology

The pathophysiology of MS, neuropsychiatric lupus erythema-tosus (NPLE) and APS remains largely unknown. Immunologicalmechanisms in genetically predisposed individuals, triggered byenvironmental factors, are a reasonable explanation for both MSand SLE [2, 23]. Thrombosis is a key feature in APS andvessels of the CNS are frequently affected [13, 37, 4447]. Thepathogenic role of aPL in the development of thrombosis issupported by experimental models [61, 62]. However, thepossible effects of aPL are unlikely to be exclusively thromboticand cross-reactivity with cerebral structures, inflammation,vasculopathy and accelerated atherosclerosis are all potentialmechanisms [22, 23].

SLE is a B-cell-mediated disorder in which these cells arehyperactive and spontaneously produce a range of immuno-globulins against self antigens [22, 23]. Neurological injury in

lupus is multifactorial but aPL seem to play a major role [2226].There could be a direct injury to neurones or glia (immunecomplex- or complement-mediated) and antibody-induced rheo-logical disturbances leading to infarction and possible micro-vasculopathy [22, 23]. Toubi et al. [24] studied an unselected SLEpopulation of 340 patients and found a significant difference inaPL positivity between patients with/without CNS involvement(55 vs 20%, respectively; P


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improvement after oral anticoagulation has been observed[20, 32, 34, 47, 49, 50]. SLE patients with transverse myelitishave a higher prevalence of aPL than SLE patients without it[29]. MS patients with aPL may present with myelopathy aloneor associated with optic neuritis [21, 48, 49, 52, 53]. Anischaemic aetiology of visual symptoms is suggested by theabruptness of onset and shorter duration [13, 30, 43]. Opticneuritis associated with APS is usually unilateral but in SLE asin MS it may be bilateral [30].

Symptoms suggestive of peripheral nervous system involvementsuggest SLE since MS only affects the CNS [2, 3]. Othermanifestations would suggest underlying APS (thrombosis,

miscarriages, pregnancy morbidity, livedo reticularis, thrombo-cytopenia) or connective tissue diseases (photosensitivity, rash,arthralgias or sicca syndrome) [12, 13, 32, 4249].

Diagnostic tests

There is no specific diagnostic test [2, 3, 12, 13, 4547, 65]but the most useful are brain and spinal MRI, CSF exami-nation including immunoglobulin G (IgG) index and immuno-electrophoresis, visual evoked potentials and autoantibodyserology.

B

A

C

FIG. 1. MRI from a patient with antiphospholipid syndrome. A, B: Brain MRI showing periventricular lesions indistinguishable from

those seen in MS. C, T2-high-signal widespread lesions in spinal levels C25, T13, T57.

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MRI. MRI is an important diagnostic tool but small strokesin the white matter may produce lesions resembling demyelin-

ating plaques in the brain and spinal cord. Similar multifocalwhite matter lesions can be found in MS, NPLE and APS(3070%) [12, 13, 46, 6773] and they are often clinically silent[25, 41, 46]. Gadolinium enhancement is more suggestive ofinflammation but immune complexes can also induce leakage ofthe bloodbrain barrier [6870] and MRI is unable to ascertainthe inflammatory nature of the underlying disease [48, 65,6870].

The MRI criteria of Barkhof et al. [67] provide the bestcombination of sensitivity and specificity for an accuratediagnosis of MS [2, 65, 67]. MRI should be periodically repeated(ideally every 3 months) when there is no definite diagnosisand whenever new neurological symptoms appear [2, 65, 67].The absence of multifocal lesions on brain MRI has a goodnegative predictive value for later development of MS [68].

Lesion distribution could be helpful, since subcortical lesionspredominate in APS/SLE and periventricular and especiallycorpus callosum lesions are more common in MS [12, 13, 4346,6870]. Elongated ovoid shaped lesions (Dawsons fingers)and black holes are more characteristic of MS but theyare not pathognomonic [6870]. In our experience, the lesionsseen in association with APS are usually static on repeat MRIcompared with the dynamic nature of lesions seen in MS.Furthermore, lesions associated with APS may improve withanticoagulation [73].

CSF examination. CSF examination may be useful whenclinical or imaging features are unusual [65] and it is the onlymethod that can directly assess inflammation [2, 3, 65]. Mildlymphocytic pleocytosis, high IgG index or oligoclonal bands notpresent in serum (intrathecal production) are common in MS and

NPLE and they are not usually found in primary APS [21, 49,

54, 55]. However, their presence does not exclude that diagnosis[20, 21, 49]. The absence of oligoclonal bands makes the

diagnosis of MS unlikely [2, 3, 65].Visual evoked potentials. Of the neurophysiological tests,

only visual evoked potentials have shown sufficient discrimina-tive diagnostic usefulness [3]. They are particularly helpfulwhen MRI abnormalities are few (e.g. primary progressive formwith progressive myelopathy) or have less specificity (e.g. olderpatients with risk factors for microvascular ischaemic disease) [65].Normal visual evoked potentials are unusual in MS [2, 3, 65].

Antinuclear antibodies. The frequency of antinuclear anti-bodies (ANA) in MS and their significance are uncertain [48, 53,7476]. Variable prevalences have been reported [7476] probablyreflecting differences in patient selection and sensitivity oftechniques [49, 54]. Barned et al. [74] retrospectively studied 150patients with MS and found 27% to be positive for ANA. Similarfindings were reported in a prospective study [54]. Other authors

also found a positive correlation between titre/persistence of ANAand MS activity [75]. These data were not corroborated by others[76] and ANA can be found in healthy individuals (28%) andin infectious diseases [74]. Despite these results, when ANA titresare high and persistent and they appear in the context of otherautoimmune abnormalities, a diagnosis of connective tissue diseaseshould be considered [48, 49, 76].

Antiphospholipid antibodies. Antiphospholipid antibodiesare present in 25% of the general population, usually at lowtitre and without symptoms [21, 37] but they are associated withincreased cardiovascular risk [7779]. They also can be foundin infections, neoplasms and even after administration of somedrugs, where they are usually transient and not related tothrombotic events [37, 50].

Higher prevalences are reported in autoimmune diseases,mainly in SLE (36%) [1113, 36, 37] where they are associated

TABLE 1. Pointers to the differential diagnosis between MS, PAPS and NPLE/APS

PAPS NPLE/APS MS

Clinical ThrombosisMiscarriages/pregnancy

morbidityHeadachesSeizures May be present May be present Absent

Livedo reticularisThrombocytopeniaRaynauds phenomenonPhotosensitivityRash Absent Usually present AbsentArthritis/arthralgiasSicca syndromePeripheral nervous

system involvementMay be present May be present Absent

Optic neuritis Unilateral, abrupt onset Usually bilateral May be bilateralLaboratory aPL 100% 5060% (244%)

ANA Usually negative 98% (2.525%) low titreAnti-DNA Usually negative 60% Usually negativeCSF oligoclonal bands Usually negative 1550% 98%

MRI Brain MRI High-signal lesions High-signal lesions High-signal lesionsSubcortical Subcortical Periventricular, corpus

callosum, brainstemStatic (may improve

after anticoagulation)Static Dynamic

Spinal MRI >4 segments in length >4 segments in length


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with CNS involvement (5060%) [1214, 2532]. aPL havebeen described in neurological conditions such as myastheniagravis, LambertEaton syndrome and migraine [50]. They alsohave been reported with variable frequency in patients with MS[20, 21, 4558], especially of the neuromyelitic type [21, 49, 50].Whether this is an incidental finding, an epiphenomenonreflecting underlying immune activation, the result of nervoussystem damage or is in fact pathogenic is a matter of discussion.

Specific characteristics of the selected populations and studyprotocols, utilization of different techniques and interlaboratoryvariation, type of aPL measured (lupus anticoagulant (LA) notdetermined in most cases) and no uniform cut-off value forpositive results are possible explanations for the wide variabilityof the results. aPL titres can fluctuate and they are sometimesnegative in the acute phase [48] but most studies have notmeasured aPL sequentially. There is also no consensus aboutroutinely measuring aPL in patients with MS but some authorshave suggested it would be important to add aPL testing todiagnostic criteria [54]. The most relevant published studies aresummarized in Table 2.

In the United States, Scott et al. [20] reported four patientsdiagnosed as MS. aCL of the IgG isotype were positive atmedium to high titre in all patients, LA were also found in three

and all but one patient had previous clinical manifestationssuggestive of APS. In Japan, SLE is very common [1, 11] whileMS is rare [13] and characterized by a high incidence ofneuromyelitis optica and transverse myelitis [80]. Fukazawa et al.[51] studied a Japanese MS population and found a significantprevalence of aPL (5.3%, two of 38 patients) when comparedwith controls. Both patients presented with recurrent opticneuritis and transverse myelitis. Both had normal brain MRI,swelling of the spinal cord, no oligoclonal bands on CSF exami-nation, abnormal visual evoked potentials and no evidence ofconnective tissue disorders. Similar results were reported byothers in a similar population but with a predominance of theaCL IgM isotype [52]. Karussis et al . [21] found an aPLprevalence of 5.7% in patients with classic MS but much higher(20%, mainly of IgG isotype) in patients with atypical features

(myelitis alone or associated with optic neuritis/cerebellar signs,migraine, absence of oligoclonal bands in CSF). MRI findingstypical of MS were found in the majority of these patients. Thisgroup had a slower progression and the authors suggested it mayrepresent a specific subset of patients with MS or a differentnosological entity. All patients were treated with acetylsalicylicacid (100 mg o.d.) and most remained stable.

In a study involving 322 patients referred to a rheumatologyclinic, 59% (n189) had positive aPL and 8% (n26) hada previous diagnosis of MS [48]. In these patients transversemyelitis and optic neuritis were common. Most of them wereaPL positive [23/26 (88%), most commonly of IgM isotype].Almost all MRI studies were abnormal, but only 50% werelabelled as diagnostic or compatible with MS by a radiologistblind to the diagnosis. Also, 50% of patients had previous

manifestations suggesting APS/SLE. Cuadrado et al. [49] cor-roborated these data when evaluating 27 female patients withatypical MS (symptoms suggesting underlying connective tissuedisease, uncommon findings for MS on MRI, atypical evolution,aPL positivity). All were aPL positive and fulfilled theclassification criteria for APS (16 PAPS, 11 secondary to SLE).Transverse myelitis was the commonest presenting featureand most of them had MRI abnormalities indistinguish-able from the patients with definite MS. These findingssuggest that a significant number of patients with aPL areinitially diagnosed as MS and the authors advised screening foraPL in MS population, at least when atypical features arepresent.

Some negative studies have also been published and theauthors argued that occasionally higher prevalences of aPL inMS populations are merely an epiphenomenon [50, 5358].

They do not recommend screening for aPL in MS patients butthey agree that APS should be considered in the differentialdiagnosis.

Tourbah et al. [53] found that about 50% of an unselectedMS population of 161 patients had atypical features (e.g. isolatedclinical abnormalities, ANA and/or aCL positivity). No signifi-cant difference was found between them and patients with classicMS. However, after 5 yr of follow-up, a diagnosis of MS was not

established in about 20% of patients in the atypical group. Thesewere characterized by a combination of clinical, biological andMRI abnormalities suggesting APS/SLE as an alternativediagnosis (positive ANA in combination with positive aPL inabout 40%; anti-DNA antibodies in about 30%; punctiform ordiffuse T2 hyperintense lesions in about 40%).

Roussel et al. [54] studied a population of 89 MS patients andabout 30% had aPL, either aCL (21%) or 2-glycoprotein (GPI)(16%) but, contradicting other studies, they did not observea different clinical presentation or evolution in these patients.Nevertheless, they actually found one of the highest prevalencesof aPL in an unselected MS population, even higher than inpatients with stroke. Heinzlef et al. [55] reported similar resultsin a larger unselected MS population, but only patients withdefinite MS were included. Sastre-Garriga et al. [56] studied

the largest unselected MS population to date and they did notfind either a higher prevalence of aPL than in general popula-tion (2%) or specific characteristics in the positive patients.Similar findings have been reported by other authors in smallerpopulations [50, 57, 58].

Despite discordance in these results, because APS is atreatable disease and aPL screening is a non-invasive, widelyavailable and inexpensive diagnostic test, it seems reasonable toconsider it in patients with MS, especially in those with atypicalfeatures. Repeated negative results make a diagnosis of APSunlikely. Consistently positive aPL might suggest a differenttreatment approach.

Other diagnostic tests. More specific neuroimaging tech-niques are being developed. The application of single photonemission computed tomography has been studied in patients with

APS where it can show focal low-perfusion areas that improvewith anticoagulation [49, 81]. Rovaris et al. [72] suggested thatmagnetization transfer imaging combined with standard MRIcould discriminate MS from APS, but images were indistinguish-able from SLE.

Some neurophysiological studies in MS found an increase ofslow frequencies ( and ) in the left frontotemporal-region anddecrease of the band, the significance of which is not wellunderstood [8284]. Similar studies in SLE reported and slowing and sharp wave activity suggesting selective damage tothe left temporolimbic region [85]. Seizures were reported inSLE associated with APS [86] soon after the first description ofthe syndrome [35]. Recently, Lampropoulos et al. (unpublisheddata) observed a significantly higher prevalence of abnormalelectroencephalograms (EEGs) in APS patients when comparedwith those who were only aPL positive and with patients withSLE without aPL (100, 71 and 39.1%, respectively). Twopatients (2/81) who were also diagnosed as MS had focal slowactivity and small periventricular lesions which are unlikely toexplain those abnormalities on EEG. The authors suggested thatEEG may be useful since a normal recording is less compatiblewith APS.

Treatment

The classic treatment for MS is interferon- which reducesrelapses by 30%, but delay in disability progression or long-term benefit is not proven [1, 2]. It is an expensive parenteraltherapy [1, 2] and it may potentially induce or aggravate lupus

activity [87].

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TABLE2.SummaryofstudiesontheprevalenceofaPLinMS

Au

thors,date,country

Studyprotocol

Population

Laboratoryassay

aPLpositivity

Comments

Po

sitivestudies

Fu

kazawaetal.,1993

[51],Japan

Prospective,cas

econtrol

38patients(25F;40.2yr)

aCL(ELISA),LAN.D.

5.3%

inMSpopulation.

67%

inON/TM

SSD

Sugiyamaetal.,1996

[52],Japan

32patients

aCL(ELISA),LAN.D.

44%

IgM,9%

IgG

SSD

Ka

russisetal.,1998

[21],Israel

Prospective,follow-up

(1236mo)


aCL(ELISA),LAN.D.

5.7%

inclassicMS,20%

in

atypicalMS(mostIgG)

Slowerprogre

ssion.

ON/TMcommon

Ijd

oetal.,1999

[48],USA

Prospective

322patients,189aPL,26

MS

orMSL(25F;41yr)

aCL(ELISA),LARVVT

59%

.88%

inMSorMS-like

(m

ostIgM)

8%

MS.ON/TM

common

Cu

adradoetal.,2000

[49],UK

Retrospective,c

asecontrol

27atypicalMS(27F;38.4

yr)

aCL(ELISA),LA(RVVT)

100%

100%

APS60%

primaryAPS;40%

SLE.TMm

ostcommon

Ne

gativestudies

To

urbahetal.,1998

[53],France

Prospective,follow-up(5yr)

161patients,84atypical

MS(104F;31yr)

aCL(ELISA),LA

(Kao/APTT)

6.2%

NSSD.MSdiagnosisnot

established

in20%

ofpatients

withatypicalMS;stabledisease

Ro

usseletal.,2000

[54],France

Prospective,cas

econtrol


aCL(ELISA),LA

(Kao/APTT),2

GPI(ELISA)

32.6

%

(21%

aCL;LAnone)

SSDforIgG.

Prevalencehigher

thanforstr

oke.NSSDinclinical

presentation

orevolution

He

inzlefetal.,2002

[55],France

Prospective,cas

econtrol

285patients(199F;44yr)

aCL(ELISA),LAN.D.

15%

(mostIgM)

NSSDinclinicalmanifestations

orevolution

Sastre-Garrigaetal.,2001

[56],Spain

Retrospective,c

asecontrol

296patients,251MS(156

F),

45MS-like(23F)(38.7yr)

aCL(ELISA),LAN.D.,

2

GPI(ELISA)

2%

NSSD

Ro

mbosetal.,1990

[50],Greece

Prospective,cas

econtrol

42patients(28M;33yr)

aCL(ELISA),LAN.D.

Not

reported

NSSD

Co

rdolianietal.,1998

[57],France

Prospective,cas

econtrol


aCL(ELISA),LAN.D.,

2

GPI(ELISA)

8%

NSSD

Ba

raczkaetal.,2002

[58],Hungary

Prospective,cas

econtrol

35patients(13SLE

withMS-like(12F),22

MS

(20F)(36.5yr)

aCL(ELISA),2GPI

(ELISA),LAN.D.

Not

reported

NSSD

M,male;F,female;yr,yearsold(meanage

);Kao/APTT,kaolinandactivatedpartial

thromboplastinclottingtimes;RVVT,Russelvipervenomtime;N.D.,notdetermined;NSSD,nostatistically

sig

nificantdifference;ON,opticneuritis;SSD

,statisticallysignificantdifference;TM,transversemyelitis.

MS, neuropsychiatric lupus and APS 439
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heumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatology.oxfordjournals.org/http://rheumatol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