Introduction · PDF file• However a group of CTD does not fulfill criteria for ... • Dynamics of the evolution to defined CTDs, ... etiopathogenesis of systemic lupus erythematosus

Introductionwww.fisiokinesiterapia.biz

• Connective tissue diseases (CTD) are systemic conditions characterised by heterogeneous and overlapping clinical and serological manifestations.

• In order to identify the single disease for communication classificative criteria have been proposed and validated.

• However a group of CTD does not fulfill criteria for any CTD and are generally termed UCTD

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Historical landmarks

Latent lupusGanczarczyk et al1989

Undifferentiated connective tissue diseasesDijkstra et al1999

Undifferentiated connective tissue diseasesDanieli et al1998

Undifferentiated connective tissue diseasesDanieli et al1999

Subclinical LupusSwaak et al2001

Undifferentiated connective tissue diseasesMosca et al1998

Early Undifferentiated connective tissue diseasesAlarçon et al1991

Incomplete lupus erythematosusGreer et al1989

Undifferentiated connective tissue syndromesLe Roy et al1980

Main issues

How frequent are the UCTD?Which are the clinical and serological manifestations of UCTD?Do UCTD display a peculiar antibody specificity?Do UCTD evolve to defined CTD or rather UCTD are definite clinical entities?Are there features predictive of a future evolution to defined CTD?How are UCTD treated?How do we classify UCTD?

Prevalence of UCTD

20% of followed patients

after 1 year of disease

Bombardieri (1998)

52% among 410 patients

at disease onset

Alarçon (1991)

How frequent are the UCTD?

Epidemiological data first study

Mean 7 (min 3 max 24)Follow up (years)

91 (M: 4- F: 87)N° of patients

Diagnosis of UCTD for at least 1 yearInclusion criteria

RetrospectiveType of study

To evaluate the clinical and serological featuresand the evolution over time of a large series of UCTD

Aim

Mosca M et al. Lupus 1998


International Multicenter Follow up Study on “Subclinical SLE”

All patients were evalueted annually1) clinical and serological changes recorded2) disease activity scored (SLEDAI,ECLAM)

Protocol study

1) Recruitments in the last three months of 19942) “sublinical SLE” for at least one year

Inclusion criteriaProspectiveType of study

To investigate the disease course of “sublinicalSLE”

Aim10 European Rheumatology CentersPartecipants


Swaak AT et al, Rheumatology 2000

Epidemiological data

Mean 3Follow up (years)

4.5 (1-40)Mean disease duration (years)

40 ± 13Average age at onset study

122 (M: 1- F: 121)N° of patients


Swaak AT et al, Rheumatology 2000

0 10 20 30 40 50 60 70 80 90

Arthralgias

Raynaud

Alopecia

Arthritis

Leukopenia

Xerophtalmia

Xerostomia

Photosensitivity

Fever

Anemia

Thyroiditis

Thrombocytopenia

Malar rash

Lymphoadenopatia

Serositis

Oral aphtosis

Clinical manifestations ofUCTD patients

Which are the clinical and serological manifestations of UCTD?


Autoantibody profile of UCTD patients

62% defined specificity

100% ANA positivity

67% single specificity49% anti-SSA36% anti-RNP

15% anti-dsDNA

33% multiple specificities



Autoantibody profile in patient with UCTD

n.r.28%12%Anti-RNP

n.r.1%1%ANTI-Sm

n.r.5%1%Anti-SSB

14%30%8%Anti-SSA

5%19%4%Anti ds-DNA

58%100%83%ANA

Danieli et al (1998)

Mosca et al (1998)

Clegg et al (1991)


Clinico-serological correlations of the91 UCTD patients

P< 0.05

P< 0.001

P< 0.001

Photosensitivity

Xerophtalmia

Xerostomia

Anti-Ro/SSA

P < 0.001Raynaud’s phenomenon

Anti-RNP


The anti-Ro/SSA antibodies insystemic CTD

• Ro antigen is a small cytoplasmic ribonucleoproteinconsisting of a 60 KD protein (Ro60) associated with RNAs and ‘La’ protein. A third protein of 52 KD has been considered as part of the complex

• Autoantibodies against Ro complex are commonly present in CTD and are not disease specific

• Autoantibodies against Ro60 are directed both against linear and conformational epitopes.

Do UCTD display a peculiar antibody specificity?

Aim of the study

To characterize the specificity

of Anti Ro antibodies


Materials and Methods

ELISAMethods:

Biochemically purified fromhuman spleen (Wo DH)W. van Venrooji

Antigen:- native (hRo60)

- recombinant (rRo60, rRo52)

50 anti-Ro positive on routine CIE (23 SLE, 17 UCTD, 10 SS)

Sera:


Results 1

• hRo60-Elisa recognise 84% of Ro positive CTD sera

• rRo60-Elisa recognise 52% of Ro positive CTD sera

• 32% of Ro positive CTD sera were positive onlywith h Ro60


Results 1

60%80%70%SS

35%52%35%SLE

54%54%69%UCTD

Ro60+Ro52Ro52Ro60


Results 2

78% (11/14)UCTD

88% (7/8)SS

40% (8/20)SLE

% Positivity r-Ro60


Anti-Ro antibodies in UCTD,Conclusions

• Similarly to Systemic Lupus Erythematosus, anti-Roantibodies in UCTD recognise the Ro52 lessfrequently than in primary Sjögren Syndrome

• Similarly to primary Sjögren Syndrome and not to SLE anti-Ro60 antibodies are directed to linear rather thanconformational epitopes


Evolution to SLE in UCTD patients with at least one year of follow up

Follow up mean = 5 (min 1 - max 21)

Follow up mean = 7 (min 3 - max 24)

75 ‘STABLE’ 4 SLE


91 UCTD(M: 4 / F: 87)

Tot.16 SLE (17%)

Do UCTD evolve to defined CTD?

Evolution to SLE in a group of UCTD patientswith at least one year of follow up (Swaak et al)

Tot.25 SLE (20%)

Follow up 1 year

Follow up 3 years

100 ‘STABLE’

22 SLE


122 Subclinical SLE>1 year of duration


Evolution to defined CTDs

SLE, RA, SS2451Dijkstra (65pts)1999

SLE, SS, MCTD, PMn.r.6Danieli (165 pts)1999

SLE, SSc, RA , MCTD4837Danieli (84 pts)1998

SLE, SSc, RA, PM/DM6029Danieli (84 pts)1998

SLE3613Mosca (91 pts)1998

SLE17.55Greer (38 pts)1989

SLEn.r.32Ganczarczyk (22 pts)

1989

SLE27.468Lom Orta (31pts)1980

Type of CTDTime (months)

% evolvedAuthorYear


Causes of the discrepancies amongdifferent studies

1) Disease duration at the moment of selection

2) Patient’s selection criteria

3) Work up

Predictive factors for the evolution to SLE

Anti-Sm, anti-dsDna, ANA, alopecia, Coomb’s, serositis

Anti-dsDNA, anticardiolipin

Calvo-Alèn:

Danieli:

3° group, predictive variables

MoscaGanczarczyk

2° group, no predictive variable

Lom OrtaGreerDanieliDijKstra

1° group, variables notevaluated

VariablesAuthors


Predictive factors for the evolution to SLE

Anticardiolipin antibodies and the presence of multiple antibody specificities were associated with the development of SLE.


Evolution to defined CTDs

• The evolution of UCTD to defined CTDs (SLE and pSS) occurs in average 20% of the patients.

• In average 65% of the cases the evolutionoccurs within the first 5 years of follow up.


Therapy

2%--Azathioprine

17%11%29%Antimalarials

38%53%32%Oral corticosteroid

--47%NSAID

SwaakBombardieriGreerTherapy

Conclusions• UCTD represent a consistent proportion of CTD’s patients of

tertiary referral centres.

• On follow up only few UCTD evolve into defined diseases, such as SLE.

• UCTD are characterised by a mild systemic involvement and a limited autoantibody repertoire stable over time.

• UCTD are not characterized by a peculiar antibody specificity, although anti-Ro60 antibodies are mainly directr to linear epitopes and anti-Ro52 antibodies are less frequent.

• Discrepancies attributable to different disease definitions, follow up duration, selection criteria and, finally, to a different patient’s work-up.

Suggested preliminary classificationcriteria for UCTD

• Signs and symptoms suggestive of a connective tissuedisease, but not fulfilling the criteria for any of the definedCTDs for at least 3 years;

• Presence of antinuclear antibodies and antiphospholipidantibodies determined on two different occasions.

If the disease duration is less than three years, patients may bedefined as having an Early Undifferentiated Connective TissueDisease.

Mosca M, Neri R, Bombardieri S. Clin Exp Rheumatol 1999; 17: 615

Undifferentiated connective tissue disease: analysis of 83 patients with a minimum

follow-up of 5 years.

Mosca M, Neri R, Bencivelli W, TavoniA, Bombardieri S

J Rheumatol. 2002 Nov;29(11):2345-9.

Second study: New Issues

• Dynamics of the evolution to defined CTDs,

• Existence of triggering factors for this evolution

• Clinical picture of defined CTDs which began as UCTD

Mosca M et al. J Rheumatol 2002

Aim of the study

• Analysis of the extended follow up of 91 UCTD patients followed at our Unit (minimum 5 years) to:

– re-assess the rate of evolution to a defined CTD

– to evaluate the clinical and serological characteristics of UCTD patients

– to look for predictors and triggering factors for diseaseevolution

– to describe the clinical and serological features of thosepatients who developed a CTD during the follow-up


Patients selection criteria

I) Diagnosis of UCTD made on the basis of the followingcriteria:

– signs and symptoms suggestive of a connective tissuedisease but which did not fulfil the criteria for any of the defined CTDs

– presence of at least one non-organ-specificautoantibody

II) A follow up of at least one yearMosca M et al. J Rheumatol 2002

Methods

• Clinical and serological data on these patients were prospectively collected and the diagnosis was re-evaluated yearly

• Environmental factors (i.e. hormones, ultraviolet light, drugs, infections) believed to play a role in the etiopathogenesis of systemic lupus erythematosus were taken into consideration as possible triggering factors

• Patients who developed a CTD were divided into groupsbased on the timing of their evolution to the defineddisease, arbitrarily taking 5 years as the cut-off value.


Results

• Of the original 91 patients, 8 were lost to follow-up; the remaining 83 patients, were included in our analysis

• During the follow-up 18 patients (23%) developed systemic lupus erythematosus and one patient developed Sjögren's syndrome within a mean period of 54 months after the onset of the disease (min. 17 – max. 96)

• The rate of evolution was higher in the first years of follow-up and decreased over time


Risk of evolution to SLE calculated based on data from 84 UCTD patients. At 5 years the survival rate was 83% (66 patients at risk), while at 10 years the survival rate was 76% (25 patients at risk).

0

0.2

0.4

0.6

0.8

1

Prob

abili

ty o

f evo

lutio

n to

SLE

0 50 100 150 200 250 300

Time (months)

Clinical manifestations at onset in patients who still had undifferentiated disease at the end of the follow-up compared with patients who developed SLE

0 10 20 30 40 50 60 70 80

Arthralgias

Arthritis

Leukopenia

Sicca symptoms

Photosensitivity

Alopecia

Anticardiolipin ab

Thrombocytopenia

Fever

Anti-DNA ab

Anemia

Serositis

Malar rash

Undifferentiated patients

Evolved patients


Predictors and triggering factors fordisease evolution

• Anticardiolipin antibodies

• Coexistence of multiple antibody specificities

• No triggering events for the evolution to SLE emerged from our analysis.


Clinical and laboratory manifestations in UCTD patients who evolved to SLE compared with our SLE cohort and with the data on SLE patients reported

in the literature.

30-785839Anemia

7-452328Thrombocytopenia

31-632933Serositis

10-591233Lymphoadenopathy

21-373533Skin vasculitis

41-862644Fever

31-605344Renal involvement

18-584944Raynaud’s phenomenon

41-664250Leukopenia

39-615572Malar rash

11-456078Photosensitivity

53-956972Arthritis

3-456389Alopecia

53-958294Arthralgias

LiteratureOur SLE cohort (350)Evolved UCTDManifestation

Clinical and laboratory manifestations in UCTD patients who evolved to SLE compared with our SLE cohort and with the data on SLE patients reported in the literature.

0 10 20 30 40 50 60 70 80 90 100

Arthralgias

Alopecia

Photosensitivity

Arthritis

Malar rash

Leukopenia

Raynaud

Renal inv

Fever

Skin vasculitis

Lymphoadenopathy

Serositis

Thrombocytopenia

Anemia

Evolved UCTD

Our SLE cohort

Evolved patients

• The clinical manifestations presented by the 16 SLE patients who completed the study (mean 101 months, min. 10 – max. 240, median 102) resulted similar to the cohorts reported in the literature

• The most serious organ involvement was renal (44% of the patients), consisting of type IV glomerulonephritis in 63%, type III glomerulonephritis in 25%, and type II glomerulonephritis in 12% of the patients.

• Those patients whose SLE had appeared within the 5th year of follow-up had a higher incidence of renal involvement (55% versus 28%) and type IV glomerulonephritis (observed only in this group).


Pregnancy in UCTD

• Pregnancy is considered to be an important factor that may alter the course of autoimmune diseases

• We examined 32 pregnancies in 22 UCTD patients being followed at our unit in order to evaluate

– the pregnancy outcome,

– whether pregnancy is associated with flares of disease activity,

– whether pregnancy may be a trigger for the development of a defined CTD.


Pregnancy outcome

• 6/32 (19%) first trimester abortion

• 26/32 (81%) SUCCESSFUL

• 2/32 (6%) obstetric complications

• Six patients (19%) experienced a disease flare during pregnancy or puerperium,


Flares during pregnancy

• 1/6 major flare with development of SLE.

• In the other 5 patients the manifestations at flare were mild and included arthritis, fever, and skin rash.

• The incidence of flares in a control population of non-pregnant UCTD patients over a period of 1 year was 7%.


UCTD and pregnancy

• The outcome of pregnancy is good in UCTD patients

• The rate of flares during pregnancy appears increase with respect to the non-pregnant population

• UCTD pregnancies should be monitored as carefully as those in patients with definite CTDs.


Conclusions• The evolution of UCTD to a defined CTD (usually SLE) is not

frequent, although it did occur in 23% of our patients

• The rate of evolution to a defined CTD is high in the first years of follow-up and decreases over time

• The presence of anti-cardiolipin antibodies and multiple autoantibody specificities are prognostic factors for the evolution to SLE

• No specific triggering factors for the evolution could be identified in our patient series

• Pregnancy in UCTD patients has a favorable outcome, although there is an increased incidence of disease flares

• The clinical profile of patients who develop SLE from UCTD is comparable to the profile reported for other SLE cohorts

A new frontier?

• Clinical– Better health care and the availability of newer powerful

diagnostic tools are leading to earlier recognition of CTD in their initial forms

– The earliest identification of true UCTD from false UCTD would avoid the overtreatment of the first and undertreatment of the second ones

• Research– As CTD with a very restrictive and constant autoimmune

repertoire they can be considered the ideal model to study clinical-serological correlations

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Introduction · PDF file• However a group of CTD does not fulfill criteria for ... • Dynamics of the evolution to defined CTDs, ... etiopathogenesis of systemic lupus erythematosus