Latest Advances in Connective Tissue Disorders
Simon Bowman, PhD, FRCP, Vijay Rao, MRCP
Ther Adv Musculoskel Dis. 2013;5(4):234-249.
Primary Sjögren's Syndrome
In primary Sjögren's syndrome (PSS), focal lymphocytic inflammation of exocrine glands is associated with clinical features of glandular dysfunction, particularly of oral and ocular dryness. The immunological features, apart from these histological features, are of anti-Ro with or without anti-La antibodies found in around 70% of patients. Therapy has been principally symptomatic with a focus on oral and ocular hygiene and topical therapies. Glandular stimulants such as pilocarpine have been shown to be effective in symptomatic improvement in patients with residual glandular function [Vivino et al. 1999].
For the past 10 years the gold standard classification criteria for PSS has been the American-European Consensus Group criteria [Vitali et al. 2002]. Recently, alternative classification criteria, the preliminary ACR criteria, have been proposed [Shiboski et al. 2012; Whitcher et al. 2010]. Neither set of criteria include salivary gland ultrasound. In clinical practice, the presence of hypoechoic areas and other features on ultrasound are frequently seen in PSS [Takagi et al. 2010; Milic et al. 2012]. Magnetic resonance imaging may yield similar results [Regier et al. 2009].
In order to reach the point at which biological therapies can be studied in PSS there has been considerable development over the past decade of patient-related outcome measures such as the Profile of Fatigue – Sjögren's International Collaborative Clinical Alliance (SICCA) Symptoms Inventory [Bowman et al. 2009] and more recently the EULAR Sjögren's Patient Reported Index [Seror et al. 2011]; and disease activity measures such as the Sjögren's Clinical Activity Index [Bowman et al. 2007] and Sjögren's Syndrome Disease Activity Index [Vitali et al. 2007]. More recently, a collaboration, the EULAR Sjögren's working group, has developed the EULAR Sjögren's Syndrome Disease Activity Index [Seror et al. 2010a, 2010b]. Damage measures have also been developed [Vitali et al. 2007; Barry et al. 2008]. Other collaborations include the UK Primary Sjögren's Syndrome Registry, which has been set up to facilitate clinical and basic science research into Sjögren's syndrome [Ng et al. 2011]. The SICCA group in the USA has proposed the above alternative criteria sets as well as establishing the SICCA Registry as a repository of clinical and biological samples [Daniels et al. 2009].
Generally, the prognosis for PSS is good unless patients develop lymphoma when it is more variable [Voulgarelis et al. 2012]. Although rituximab has not yet been established as routine therapy for PSS, it is now standard practice to incorporate it in regimes, for example, with CHOP Rituximab-cyclophosphamide, Hydroxydaunorubicin, Oncovin (Vincristine), Prednisolone (R-CHOP) for salivary gland lymphoma. A paper by Theander and colleagues demonstrated that salivary gland biopsy at diagnosis provided important data on long-term lymphoma risk depending on whether B-cell germinal centre (GC) structures were present in the biopsy or not [Theander et al. 2011]. In a long-term cohort of 175 patients, 6 of 43 patients with GCs on salivary gland biopsy developed lymphoma compared with only 1 of 132 without. The positive predictive value for GC was 16% and the negative predictive value was 99%.
Attempts at using biological therapies have been mixed. Antitumour necrosis factor therapy was ineffective in a double-blind randomized trial [Mariette et al. 2004]. In the past few years evidence of B-cell and B-cell cytokine involvement, such as BLyS/BAFF, has been of particular interest [Ittah et al. 2006; Lavie et al. 2007]. A randomized double-blind controlled trial of a single course of rituximab versus placebo in France [Tolerance and Efficacy of rituximab in Sjögren's syndrome (TEARS)] [ClinicalTrials.gov identifier: NCT00740948] failed to meet its primary endpoint but suggested an approximately 10% benefit over placebo (Professor Xavier Mariette, oral presentation at EULAR Congress 2012). A second trial in the UK of two courses of rituximab against placebo funded by Arthritis Research UK is currently ongoing.
There is a theoretical basis for trying other existing biologics such as belimumab (anti-BlyS/BAFF) or tocilizumab (anti-interleukin-6) as well as tackling other biological pathways [Ng and Bowman, 2011].