Long‐term risk of mortality and lymphoproliferative disease and predictive classification of primary Sjögren's syndrome

Abstract

Objective. Primary Sjögren's syndrome (SS) may lead to lymphoproliferative disease (LPD) and death in certain patients. We sought to determine the incidence and predictors of adverse long-term outcomes to achieve a rational predictive classification of the syndrome.Methods. Predictive modeling was performed in a cohort of 723 consecutive patients with primary SS (587 newly diagnosed [incident] cases and 136 prevalent cases).Results. During 4,384 person-years of followup, we recorded 39 deaths (7 due to lymphoma) and 38 diagnoses of LPD. The standardized mortality ratio was 1.15 (95% confidence interval [95% CI] 0.86-1.73) compared with the general population of Greece. In incident cases, the probability of LPD was 2.6% at 5 years and 3.9% at 10 years. Mortality rates were significantly higher in patients with low C4 levels at the first study visit (hazard ratio [HR] 4.39, 95% CI 2.18-8.83). LPD was independently predicted by the presence of parotid enlargement (HR 5.21, 95% CI 1.76-15.4), palpable purpura (HR 4.16, 95% CI 1.65-10.5), and low C4 levels (HR 2.40, 95% CI 0.99-5.83) at the first study visit. All patients who eventually developed lymphoma resulting in death during the followup period had either low C4 levels or palpable purpura at the first study visit. Training-validation split-cohort modeling confirmed the predictive importance of low C4 levels and palpable purpura, both of which were present in 20.9% of patients at their first visit.Conclusions. In patients with primary SS, 1 in 5 deaths is attributable to lymphoma. The presence of palpable purpura and low C4 levels at the first visit adequately distinguishes high-risk patients (type I primary SS) from patients with an uncomplicated disease course (type II [low-risk] primary SS). Primary Sjögren's syndrome (SS), also known as autoimmune epitheliitis (1,2), is characterized by dry eyes and dry mouth. It affects ϳ0.2-1.0% of the general female population (3). The most worrying complication is the development of lymphoproliferative disease (LPD), most commonly lymphoma (4). Nevertheless, there are no specific data concerning the incidence of such serious sequelae and their impact on patient survival. Studies of primary SS have been limited by the sample size (5-7), and the largest studies have covered only a few hundred person-years of followup. Moreover, since the syndrome affects mostly middle-aged women, in whom the death rate is low, mortality studies require a large number of person-years to capture a meaningful number of deaths.Over the last 20 years, a total of 723 consecutive patients who have met strict criteria for a diagnosis of definite primary SS have been followed up at the University of Ioannina and the University of Athens. In the present study, we systematically evaluated the longterm outcomes of this cohort and performed predictive modeling for its major outcomes in order to identify high-risk patients. Meticulous efforts were made to ensure that information on the current status of all these patients would be retrieved. The resulti...

Mortality and causes of death in primary Sjögren's syndrome: A prospective cohort study

“…Thus, we support the proposal by Ioannidis and coworkers that patients with primary SS can be classified into type 1 and 2 as early as at the time of diagnosis (11). This spares the majority of patients (ϳ75%) from worry about premature death.…”

“…In addition, we found that a low C3 level (Յ0.83 gm/liter) at diagnosis was a predictor of death, mainly due to lymphoproliferative disease. This tendency was also seen in the Greek study, but was not significant in that study (11). The main explanation for the difference between the studies could be the different cutoff levels for C3: 0.50 gm/liter in the Greek study versus 0.83 gm/liter in ours, while the cutoff levels for low C4 were the same in the 2 studies.…”

“…In the literature there are reports of a number of studies, mainly from southern Europe (Greece and Spain), in which cryoglobulinemia, hypocomplementemia, and lymphoma development are associated in SS (11,20,21). Other reports on lymphoma development in SS do not include information on the presence of cryoglobulins (22)(23)(24)(25).…”

“…Finally, Ioannidis et al extended the earlier Greek study to 723 patients and demonstrated an SMR of 1.15 (95% CI 0.86-1.73). Those authors were also able to identify palpable purpura and low C4 level at the time of diagnosis as predictors of unfavorable outcome (lymphoma and death), and based on this, they defined high-risk and low-risk types of SS (11).…”

Unusual association of two cases of acute myeloblastic leukaemia and possible Sjogren’s syndrome and review of literature

“…Although many studies have focused on the risk of neoplasia in SS [10][11][12][13][14], we found only four publications in which acute leukaemia was cited ( Table 1) [15][16][17][18]. The first publication reported on a 59-year-old woman with primary SS diagnosed in 1963.…”