Predicting adverse outcomes in primary Sjo ¨ gren’s syndrome:
identification of prognostic factors
P. Brito-Zero ´ n, M. Ramos-Casals, A. Bove, J. Sentis1and J. Fonty
Objective. To identify features present at diagnosis that were prospectively associated with adverse outcomes in a large cohort of patients
with primary Sjo ¨gren’s syndrome (SS).
Methods. Two hundred and sixty-six patients diagnosed with primary SS in our department between 1984 and 2002 were consecutively
included and followed up. Outcomes measured were vasculitis, B-cell lymphoma and death. Cox regression analysis was used to evaluate
the effect of variables at diagnosis on outcomes.
Results. Twenty-five (9%) patients developed vasculitis. Multivariate analysis identified parotid scintigraphy grades III or IV (HR 3.55,
P¼0.05) and C4 levels <0.11g/l (HR 8.26, P<0.001) as variables predicting the development of vasculitis. Nine (3%) patients developed
B-cell lymphoma. Multivariate analysis identified C3 levels <0.82g/l (HR 7.54, P¼0.016) as a predictive factor of lymphoma development.
Twenty-five (9%) patients died during follow-up. Systemic involvement (HR 4.51, P¼0.022), vasculitis (HR 4.58, P¼0.042), C4 levels
<0.11g/l (HR 5.47, P¼0.027) and cryoglobulins (HR 4.58, P¼0.013) were independently associated with death. The presence of at least
two of the above-mentioned predictive factors (parotid scintigraphy, vasculitis, hypocomplementaemia and cryoglobulinaemia) was
associated with a lower survival in comparison with patients with no factor (log rank and Breslow tests <0.001).
Conclusion. The main prognostic factors for an adverse outcome identified in our cohort of patients with primary SS were vasculitis, severe
involvement in parotid scintigraphy, hypocomplementaemia and/or cryoglobulins at diagnosis. Patients with at least two of these factors need
a closer follow-up.
KEY WORDS: Sjo ¨gren syndrome, Mortality, Vasculitis, Hypocomplementaemia, Cryoglobulins.
Sjo ¨ gren syndrome (SS) is a systemic autoimmune disease that
presents with sicca symptomatology of the main mucosa
surfaces . The histological hallmark is a focal lymphocytic
infiltration of the exocrine glands, determined by a biopsy of the
minor labial salivary glands . The spectrum of the disease
extends from sicca syndrome to systemic involvement [3, 4].
Few studies have prospectively analysed the outcome of patients
with primary SS, a disease characterized by a chronic, insidious
evolution [5–9]. However, some patients with primary SS
may present a complicated evolution of the disease due to
incidence of lymphoma, which are closely related to a higher
risk of death [10, 11]. The identification of markers prospectively
associated with a poor prognosis [6, 12] could play a significant
role in identifying those patients requiring a closer follow-up.
The aim of this study was to identify those features present at
diagnosis that were prospectively associated with adverse out-
comes (development of vasculitis, lymphoma or death) in a large
cohort of Spanish patients with primary SS.
Patients and methods
Study cohort and observation time
The study cohort included all patients diagnosed with primary SS
by our Department of Autoimmunes Diseases between 1984 and
2002 according to the 1993 European criteria . Since a new
set of classification criteria appeared in 2002, a retrospective
re-evaluation was performed to exclude patients who presented
both negative salivary gland biopsy and autoantibodies and who
did not fulfil the recently proposed classification criteria .
In 80 patients with negative anti-Ro/La autoantibodies, a salivary
gland biopsy was not carried out. In these patients, it was not
possible to retrospectively evaluate the fulfilment or not of the
2002 classification criteria.
All patients were consecutively included when the fulfilment of
criteria was confirmed by our department and thereafter followed
up prospectively with regular visits at 6–12 month intervals.
Clinical and laboratory data were collected and computerized
according to the standard protocol of our department [15, 16].
The individual observation time for every patient was from the
time of fulfilment of the 1993 classification criteria until the last
hospital visit, transfer out or death. The design of this study
conformed to the ethical standards currently applied in Spain.
Due to the anonymous nature of the study, informed patient
consent was not required.
Systemic involvement was defined as the presence of at least
one of the following features [15, 16]: non-erosive arthritis,
Raynaud’s phenomenon, lung involvement, nephropathy, vascu-
litis, peripheral neuropathy or CNS (central nervous system)
involvement. Vasculitic involvement was defined as previously
described when histological and/or arteriographic confirmation of
vascular damage was available . When a cutaneous biopsy was
topographically difficult to obtain, was clinically contraindicated
or was not possible due to lacking consent, a diagnosis of vascu-
litis was made when cutaneous lesions, evaluated by a consultant
dermatologist, were considered characteristic of vasculitis and
other processes were excluded . B-cell lymphomas were
classified according to the 2001 WHO classification for tumours
of haematopoietic and lymphoid tissues . Immunological tests
were determined as previously described [15, 16].
The outcomes measured were development of vasculitic involve-
ment, B-cell lymphoma and death. Possible predictive variables at
Department of Autoimmune Diseases and1Statistic Unit, Department of Public
Health, Department of Medicine, School of Medicine, University of Barcelona,
Institut d’Investigacions Biome `diques August Pi i Sunyer (IDIBAPS), Hospital
Clı ´nic, Barcelona, Spain.
Revised version accepted 7 December 2006.
yIn memoriam (1953–2006).
Correspondence to: M. Ramos-Casals, Servei de Malalties Autoimmunes,
Hospital Clı ´nic, C/Villarroel, 170, 08036-Barcelona, Spain. Phone: 34-93-2275774,
Fax: 34-93-2275774. E-mail: email@example.com
Advance Access publication 14 June 2007
? The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: firstname.lastname@example.org
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