Chapter 34

Prognostic Factors and Survival

Andreas V. Goules and Fotini N. Skopouli

34.3Clinical and Immunological Prognostic Factors:

34.1Introduction

The histological hallmark of primary Sjögren’s syndrome (pSS) is the focal lymphocytic infiltrates that slowly and steadily replace the epithelium of salivary and lacrimal glands and produce exocrine gland dysfunction, manifested mainly by xerostomia and xerophthalmia [1]. These two clinical manifestations are determinants for the term “exocrinopathy” in SS. Studies in the last 20 years have delineated the type and spectrum of other organ involvement in SS. Lungs, liver and the kidneys are usually affected in pSS. The histology and the evolution of the lesion in the above parenchymal tissues do not differ from that observed in salivary and lacrimal glands. These extragrandular manifestations are mild in severity in most cases, evolve slowly, and do not appear to respond to glucocorticoids or other immunosuppressive agents. The central role of the epithelial cell as the main target of the immune injury in the exocrine glands as well as in the lungs, the liver and the kidneys has led to the introduction of the term “autoimmune epithelitis” [1].

A.V. Goules

Department of Pathophysiology, School of Medicine, University of Athens, Athens, Greece

F.N. Skopouli (*)

Department of Dietetics and Nutritional Science, Harokopio University of Athens,

Athens, Greece

A subset of patients, in addition to epithelitis develop extraepithelial manifestations such as palpable purpura, glomerulonephritis, and peripheral neuropathy. These findings are attributed to an immune complex-mediated process [2–4]. This group of pSS patients constitutes a specific subcategory: the vasculitic form of the disease. Patients with the vasculitic form of pSS are characterized by higher morbidity and mortality rates and an increased risk of lymphoproliferative malignancies [2, 3, 5].

The impact of treatment on morbidity and mortality in pSS patients is minimal. Most pSS patients are not treated with glucocorticoids because of their substantial side effect profile as well as their lack of efficacy in most settings. The same is true for conventional immunomodulating agents. In contrast, the introduction of antiCD20 interventions to the treatment of pSS-associated lymphoma has improved patients’ survival [6–8]. Finally, an issue that remains poorly addressed to date is the impact of patients’ psychological distress on morbidity and mortality.

34.2Mortality and Causes of Death in pSS

The association between pSS and lymphoma and the impact of lymphoproliferative malignancies on patients’ survival are important issues. In the early 1950s, Rothman et al. first described a patient with rheumatoid arthritis and SS who died of malignant lymphoma [9]. Talal et al. reported four cases of pSS who developed lymphoproliferative disorders and, based on the sequence of clinical and pathological events, supported the notion that lymphomas could be late sequelae of SS [10]. In a systematic study of 142 patients conducted at the National Institutes of Health [11], the relative risk of lymphoma was estimated to be 44-fold higher than that of the general population. Since then, several studies have confirmed this association. In a recent metaanalysis, the estimated standardized incidence ratio (SIR) of lymphoma in pSS was found to be 18.9 (95% CI 9.4–37.9) [12]. The lifetime risk of developing lymphoma for a patient with pSS is approximately 5–10% [4, 5, 13, 14] (Table 34.1).

Extranodal marginal zone B-cell lymphomas of mucosa associated lymphoid tissue (MALT), known as MALT lymphomas, comprise the most common histologic type of malignancy in pSS. Other lymphoma subtypes have been also described, however, including lymphoplasmacytoid, follicular, and diffuse large B cell lymphomas (DLBC) [4, 11, 15–18]. MALT lymphomas are usually low grade, indolent, and carry a favorable outcome [4, 19]. In contrast, DLBC lymphomas have a poorer prognosis [20]. Lymphomas are often the cause of death among SS patients and have been the leading cause of death in some large series [9, 10, 21, 22]. In a study of 261 pSS patients followed for a mean of 3.6 years the standardized mortality ratio (SMR) was 2.07 (95% CI 1.03–3.71) [2]. The increased mortality rate among pSS patients was attributed to lymphoma.

In a longitudinal cohort study of 110 Finnish pSS patients with a median follow-up of 9 years, 17 deaths occurred, for an SMR of 1.2 compared to the general Finnish population [23]. Two of the 17 deaths in this series were

attributable to lymphoma. Although the number of lymphoma cases in this series was small, the SIR for non-Hodgkin’s lymphoma (NHL) was 13 (95% CI, 2.07–38).

Ioannidis et al. analyzed the records of 723 consecutive Geek patients with pSS who were followed for a mean of 6.1 years (4.4 patient-years) [5]. The SMR was 1.15 (95% CI 0.86–1.73) and 39 deaths were observed, of which 7 were attributable to lymphoma. Although the 10-year risk of developing lymphoma was only 4%, the slight increase of mortality compared to the general population was attributed to lymphoproliferative disease. Other mortality studies have confirmed this finding [5, 24]. Theader et al. found that the specific SMR for lymphoproliferative disorders was 7.89 (95% CI 2.89–17.18) [24]. Nevertheless in more recent studies, the risk of death from lymphoma among pSS patients was not found increased [25, 26].

Besides lymphomas, other causes of death related to the syndrome have been also reported in patients with pSS. Progressive renal involvement occurs in less than 5% of pSS patients and may cause significant renal impairment. In some cases, glomerulonephritis due to cryoglobulinemia may lead to end-stage renal failure that requires hemodialysis [27]. On the other hand, patients with interstitial nephritis and renal tubular acidosis usually present with alkaline urinary pH, a low urine specific gravity, and perhaps slight renal impairment that remains stable for long periods of time. In rare cases, renal tubular dysfunction presents with severe hypokalemia, a potentially lethal electrolyte disorder [28–30].

Vascular involvement in the form of small vessel vasculitis, due to cryoglobulinemia, is usually treatable. However, vasculitis affecting organs such as the peritoneum or the gallbladder is difficult to diagnose and sometimes leads to death [31]. Interstitial lung disease, a rare complication of pSS, occasionally leads to respiratory failure and death [2, 5, 23].

Secondary causes of death in pSS patients can pertain to immunosuppressive treatment. Cyclophosphamide and glucocorticoids are reserved for the

minority of pSS patients who develop systemic vasculitis, glomerulonephritis, or interstitial lung disease. Predisposition to infections is the greatest concern with these patients [5, 23]. Death as the result of direct drug toxicity is much less common [23].

Cardiovascular disease is not a common cause of death among patients with pSS. In contrast to other systemic autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus, pSS does not seem to induce a chronic inflammatory or hypercoagulable state and is not associated with an increased cardiovascular risk from atherosclerosis or thrombosis.

34.3Clinical and Immunological Prognostic Factors: Classification of SS (Types I and II)

Lymphoma development and the systemic form of the disease are observed in less than 10% of pSS patients. However, pSS patients whose clinical courses evolve in this manner have increased morbidity, greater numbers of hospital admissions, and premature mortality. Do these patients express any clinical or serological characteristic that may predict this evolution?

In 1971, Anderson et al. showed that the decline of serum immunoglobulin levels and the disappearance of rheumatoid factors (RF) coincided with the time of any progression lymphoma [32]. In 1978, Kassan et al. demonstrated that patients with lymphadenopathy, splenomegaly, parotid gland enlargement and history of low-dose irradiation or chemotherapy had an increased risk of lymphoma development [11]. In addition, it was demonstrated that the expression of a monoclonal B-cell population in salivary glands and the presence of serum monoclonal immunoglobulins appeared before lymphoma became clinically apparent [11].

In 1986, Tzioufas et al. demonstrated that in patients with pSS, serum monoclonality was expressed by cryoprecipitable IgM-kappa RF [33]. Ten years later, the same investigators showed that patients with pSS and mixed monoclonal cryoglobulinemia were at increased risk for non-Hodgkin’s lymphoma development compared to pSS patients without cryoglobulins [3]. In addition, some of these patients had evidence of immune complex-mediated disease such as purpura, glomerulonephritis, and low C4 complement levels. Recurrent parotid gland enlargement was also a consistent finding. In these patients, cryoglobulinemia heralded the onset of lymphoma by 1–16 months [3].

Lymphoma development was linked in our study to the presence of palpable purpura, low C4 levels, and mixed monoclonal cryoglobulinemia (MMC) [2]. In that investigation, low levels of C4 at diagnosis were the strongest predictor of mortality after adjustments for age (relative risk, 6.5; P = .0041) [2]. Unpublished data from the same study demonstrated that serological evidence of monoclonality