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Rheumatology Advance Access originally published online on June 22, 2007
Rheumatology 2007 46(9):1389-1396; doi:10.1093/rheumatology/kem078
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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Emerging biological therapies in primary Sjögren's syndrome

M. Ramos-Casals and P. Brito-Zerón

Department of Autoimmune Diseases, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clinic, Barcelona, Spain.

Correspondence to: M. Ramos-Casals, Department of Autoimmune Diseases, Hospital Clínic, C/Villarroel, 170 08036-Barcelona, Spain. E-mail: mramos{at}clinic.ub.es


   Abstract
Top
 Abstract
Introduction
 B-cell targeted therapies
 T-cell targeted therapies
 Cytokine targeted therapies
 Concluding remarks
 Acknowledgements
 References
 
Sjögren's syndrome (SS) is a systemic autoimmune disease that mainly affects the exocrine glands and usually presents as persistent dryness of the mouth and eyes. SS primarily affects white perimenopausal women, with an incidence of 4–5 cases per 100 000. Recent studies have analysed new therapeutic approaches, focusing mainly on the use of biological agents. B-cell targeted therapies seem to be the most promising agents in primary SS, especially rituximab, which has been used in more than 50 reported cases. Other promising B-cell targeted therapies include epratuzumab and belimumab, while T-cell targeted agents (efalizumab, abatacept, alefacept) should currently be considered as possible future options. In the near future, biological agents will play key roles in the treatment of severe involvement, broadening the therapeutic options in primary SS and offering a more optimistic point of view of the treatment of this disease, which, at present, is often considered to lack adequate specific therapy. However, the possible risks and benefits of using these agents should be carefully balanced, and a reasonable assessment of the risk of serious adverse events versus the benefits of treatment should be made. The use of biological agents targeting molecules and receptors involved in the aetiopathogenesis of primary SS opens a new era in the therapeutic management of patients with primary SS.


   Introduction
Top
 Abstract
 Introduction
B-cell targeted therapies
 T-cell targeted therapies
 Cytokine targeted therapies
 Concluding remarks
 Acknowledgements
 References
 
Sjögrens syndrome (SS) is a systemic autoimmune disease that mainly affects the exocrine glands and usually presents as persistent dryness of the mouth and eyes due to functional impairment of the salivary and lachrymal glands [1]. An estimated 2–4 million persons in the USA have SS, of whom ~1 million have an established diagnosis [2]. The prevalence in European countries ranges between 0.60% [3] and 3.3% [4], although recent studies using the new 2002 American–European classification criteria have found lower figures [5]. The incidence of SS has been calculated as four cases per 100 000 [6]. SS primarily affects white perimenopausal women, with a female–male ratio ranging from 14 :1 [7] to 24 : 1 [8] in the largest reported series. The disease may occur at all ages but typically has its onset in the fourth to sixth decades of life, although some cases are detected in younger female patients, especially in mothers of babies with congenital heart block [9]. When sicca symptoms appear in a previously healthy person, the syndrome is classified as primary SS. When sicca features are found in association with another systemic autoimmune disease, most commonly rheumatoid arthritis (RA), systemic sclerosis (SSc) or systemic lupus erythematosus (SLE), it is classified as associated SS. Although most patients present with sicca symptoms, there are various clinical and analytical features that may indicate an undiagnosed SS. The variability in the presentation of SS may partially explain delays in diagnosis of up to 9 yrs from the onset of symptoms [10].

Although not a benign condition, primary SS usually progresses very slowly, with no rapid deterioration in salivary function or dramatic changes in symptoms. The exceptions to this benign course are the development of extraglandular manifestations and the high incidence of lymphoma features closely related to B-cell hyper-reactivity [1]. Primary SS represents a pathological model of the evolution from polyclonal B-lymphocyte activation to oligo-monoclonal B-cell expansion, which may culminate in the development of a malignant lymphoproliferative disease [1, 2, 10]. Significant polyclonal activation of B-lymphocytes in exocrine tissues is frequently observed in patients with primary SS; the permanent stimulation of autoreactive B-cells favours oncogenic events and may lead to the development of B-cell lymphoma [11].

At present, there is no treatment capable of modifying the evolution of SS and the therapeutic approach is based on symptomatic replacement or stimulation of glandular secretions, using substitutive and oral muscarinic agents, while extraglandular involvement requires an organ-specific therapy with corticosteroids and immunosuppressive agents, similar to that applied in SLE patients. The use of biological agents targeting molecules and receptors involved in the aetiopathogenesis of primary SS, most of which have been evaluated in SLE, opens a new era in the therapeutic management of patients with primary SS (Table 1).


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  		TABLE 1. New and possible therapeutic approaches in primary SS using biological agents

 

   B-cell targeted therapies
Top
 Abstract
 Introduction
 B-cell targeted therapies
T-cell targeted therapies
 Cytokine targeted therapies
 Concluding remarks
 Acknowledgements
 References
 
Rituximab
A promising treatment for primary SS is rituximab (anti-CD20). CD-20 is considered a specific marker for B cells, highly expressed on the surface of pre-B lymphocytes and both residing and activated mature B cells, but not expressed in other cells [12]. In late 1997, rituximab became the first therapeutic monoclonal agent approved by the Food and Drug Administration (FDA) for the treatment of B-cell lymphoma, and it has been used to treat patients with non-neoplasic autoimmune disorders, such as autoimmune thrombocytopenia, RA, haemolytic anaemia and mixed cryoglobulinaemia [13]. The specific target of rituximab (B-cells) might suggest a role in modifying the aetiopathogenic events of patients with primary SS. Recent studies [14, 15] have shown excellent results in patients with SLE, a systemic autoimmune disease also characterized by B-cell hyperactivity. Three recent studies, all with an open-label design, have evaluated the therapeutic role of rituximab in small series of patients with primary SS (Table 2). Gottenberg et al. [16] described six patients with primary SS treated with rituximab for associated lymphoma (n = 2) and systemic features (n = 4). Pijpe et al. [17] conducted a phase II trial in eight patients with active primary SS of short duration (<4 yrs) and seven patients with primary SS and mucosa-associated lymphoid tissue (MALT)-type lymphoma. Patients were treated with four infusions of rituximab (375 mg/m2) given weekly after pre-treatment with prednisolone (25 mg) and clemastine. In the third study, Seror et al. [18], made a retrospective analysis of 16 patients with primary SS who received rituximab for lymphoma (n = 5) or systemic manifestations (n = 11). There are 15 additional reported cases of individual patients treated with rituximab [19–28]. In these reports, the main clinical indications for the use of rituximab were sicca features, extraglandular involvement and associated lymphoma (Table 3). A randomized, double-blind, placebo-controlled study sponsored by the University Medical Centre of Groningen is currently recruiting patients with primary SS in The Netherlands. The study started in August 2006 and completion is expected by the middle of 2008.


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  		TABLE 2. Therapeutic role of biological agents in primary SS: reported studies

 

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  		TABLE 3. Clinical indications for the use of rituximab in primary SS

 
Improvement of sicca features
The effect of rituximab on sicca features has been specifically analysed in three studies. Gottenberg et al. [16] described a significant improvement in subjective feelings of dryness in three patients and stabilization of diagnostic tests in two. Pijpe et al. [17] also found a significant improvement in subjective symptoms and an increase in salivary gland function in those patients who conserve a residual function. In contrast, Seror et al. [18] found that dryness improved in only a minority of patients. Due to the low number of patients included in these studies, larger controlled trials should be performed to evaluate the efficacy of rituximab on sicca features of patients with primary SS.

Extraglandular manifestations
Rituximab has been successfully used to treat the systemic manifestations of primary SS. Gottenberg et al. [16] reported therapeutic efficacy in five out of the six patients with extraglandular features, with lowering of corticosteroid dosage in four out of five patients. Similar results were described by Seror et al. [18] in 11 patients with primary SS treated with rituximab for mixed cryoglobulinaemia (n = 5), refractory pulmonary disease with polysynovitis (n = 2), severe polysynovitis (n = 2), thrombocytopenia (n = 1) and mononeuritis multiplex (n = 1). Treatment efficacy was observed in nine of these 11 patients, with corticosteroid doses being lowered in all cases.

Rituximab has been used to treat other SS-related systemic features in isolated cases. Ahmadi et al. [23] described a successful response in one SS patient with refractory anterior scleritis (a very rare ocular manifestation associated with primary SS), while Gorson et al. [27], described a significant improvement in neurological symptoms in a patient with sensory neuronopathy. Touma et al. [28] reported a substantial improvement in a patient with cutaneous purpura and glomerulonephritis. In contrast, Ring et al. [24] found no effect of rituximab on renal tubular acidosis. Thus, current data suggest that rituximab seems to have a significant effect on the majority of extraglandular manifestations associated with primary SS.

B-cell lymphoma associated with primary SS
Recent reports have been published in SS patients with lymphoma. Shih et al. [19] described the resolution of parotid Non-Hodgkinlymphosim (NHL) in a patient with SS treated with rituximab, and Somer et al. [20] treated a patient with SS and lymphoma with rituximab, observing improvement of parotidomegaly, ocular tests and salivary flow rate and Harner et al. [21] successfully treated a marginal zone lymphoma associated with SS.

The three main studies of rituximab in patients with primary SS included patients with associated lymphoma. Gottenberg et al. [16] observed complete remission in one of the two patients with lymphoma. Of the seven patients with MALT included in the study by Pijpe et al. [17], complete remission was achieved in three cases, the lymphoma remained stable in three and progressed in one case. Seror et al. [18] reported better results, with treatment efficacy in four out of the five patients with lymphoma. Overall, a successful response to rituximab was observed in eight out of the 13 SS patients with lymphoma.

Rituximab has also been postulated as adjuvant chemotherapy in patients with primary SS diagnosed with aggressive B-cell lymphomas. In a recent study, Voulgarelis et al. [26] described long-term remission of aggressive diffuse large B-cell lymphoma in six patients with primary SS who received combined cyclophosphamide/doxorubicin/vincristine/prednisolone (CHOP) and rituximab. These results were better results than those of the nine cases treated only with CHOP.

Recently we have successfully treated two hepatitis C Virus (HCV)-related SS patients who developed B-cell lymphoma [22], a clinical challenge due to the confluence of various specific characteristics. When considering the age of the patients, the concomitant features related with both autoimmune and liver disease, the other drugs in use and the usual indolent course of low-grade NHL, conventional chemotherapy for B-cell lymphoma seem much more aggressive than useful for HCV-related SS patients. In comparison with standard chemotherapy regimens, rituximab is generally well tolerated, and serious adverse effects are uncommon in patients either with B-cell lymphoma, HCV infection or autoimmune diseases [29, 30]. In addition, few and minor side effects were observed in the recent trials performed in HCV patients, with no worsening of the underlying liver disease [30]. In spite of the limited number of cases presented, our results provide preliminary evidence that rituximab may be a worthwhile therapeutic option for indolent B-cell lymphoma in patients with HCV-related SS, and could be an alternative to aggressive chemotherapy options currently available. Rituximab may be considered as a safe and effective therapy for indolent B-cell lymphoma in elderly patients with SS, either in its primary or HCV-associated form.

Adverse effects
The tolerability and safety of rituximab has been well described in review articles on B-cell lymphoma and in clinical trials on RA [31]. The most frequent adverse events are infusion reactions (30–35%), usually mild to moderate. Currently, no available data suggest an increased risk of opportunist infections (including tuberculosis) or the development of malignancies. Neutropenia has been reported in 8% of patients with B-cell lymphoma treated with rituximab and should be taken into account due to its frequent detection in patients with primary SS [32]. As rituximab is a chimeric antibody, human anti-chimeric antibodies (HACAs) have been reported in 9% of patients with RA, although adverse events related to HACAs are rare [31]. Some cases of severe infusion-related events including serum sickness disease have been reported [33].

Contrasting results have been found in the two main studies using rituximab in patients with primary SS. Four of the 15 patients (27%) included in the study by Pijpe et al. [17] developed HACAs. All had early primary SS and three of the four patients developed a serum sickness-like disorder. Three (19%) of the 16 patients treated by Seror et al. [18] experienced adverse events, although only one developed a mild serum sickness-like reaction with positive HACAs. Five of the 16 patients were retreated with good efficacy and tolerance, except for a probable serum sickness-like reaction in one patient. The different prevalences of adverse events described in these studies may be related to the concomitant use of corticosteroids. This suggests that in primary SS, rituximab should be used together with daily corticosteroids (as occurs with the use of immunosuppressive agents) rather than as to monotherapy. Recent evidence suggests that the use of humanized anti-CD20 might be an alternative in patients with autoimmune diseases who develop HACAs after receiving rituximab [34].

On 19 December 2006, the FDA issued an alert based on two spontaneous reports of fatal progressive multifocal leucoencephalopathy (PML) in patients with SLE who had received rituximab therapy [35]. PML was first reported in rheumatic diseases in 1975 in a patient with RA treated with chlorambucil [36]. Subsequent cases have been reported, including patients with systemic autoimmune diseases such as Wegener's granulomatosis and SLE [37–39]. A total of 20 cases unrelated to biological agents have been reported to date in patients with SLE, most of whom had received high doses of corticosteroids and one or more immunosuppressive agents. Although PML has not yet been reported in patients with SS, candidates for rituximab should be counselled on the possible occurrence of PML and there should be enhanced surveillance of the development of neurological symptoms such as paresis, problems with coordination or cognitive impairment. While waiting for more detailed data on the exact magnitude of the risk of PML in patients treated with rituximab, it may be prudent to consider pre-existing CNS involvement as a precautionary scenario for its use in primary SS. Table 4 summarizes absolute contraindications, precautionary scenarios and advisory considerations for the use of rituximab in primary SS.


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  		TABLE 4. Absolute contraindications, precautionary scenarios and advisory considerations for the use of rituximab in patients with primary SS

 
Epratuzumab
CD22 is a 135-kDa B-lymphocyte restricted type-I transmembrane sialoglycoprotein of the immunoglobulin (Ig) superfamily [40]. CD22 appears intracellularly during the late pro-B-cell stage of ontogeny, shifting to the plasma membrane with B-cell maturation. CD22 is expressed at low levels on immature B cells and at higher levels on mature IgM+, IgD+ B cells, and absent on differentiated plasma cells. It is strongly expressed in follicular, mantle and marginal-zone B cells but is weakly present in germinal B cells [41]. The function of CD22 has not been entirely clarified; it acts as a homing receptor for re-circulating B cells through the affinity of the lectin- like domains for 2,6-linked sialic acid-bearing glycans and as a B-cell antigen receptor (BCR) down-modulating coreceptor [42, 43]. Selective modulation of B cells has been recently achieved using a humanized monoclonal antibody against CD22. This antibody (epratuzumab) was originally developed for the treatment of NML and was found to be effective, with a very good safety profile [44]. More recently, promising results have been obtained with the use of epratuzumab in patients with SLE [45].

Steinfeld et al. [46] have conducted an open-label, phase I/II study investigating the safety and efficacy of epratuzumab in the treatment of patients with active primary SS. Sixteen patients received four infusions of 360 mg/m2 epratuzumab once every 2 weeks, with 6 months follow-up. Fourteen patients received all infusions without significant reactions, one patient received three infusions and one discontinued due to a mild acute reaction to the first infusion. Three patients showed moderately elevated levels of HACA unrelated to clinical manifestations. B-cell levels were reduced by 54% and 39% at 6 and 18 weeks, respectively, but T-cell levels, immunoglobulins and routine laboratory tests did not change significantly. Fifty-three per cent of patients achieved a clinical response at 6 weeks, with 53%, 47% and 67% responding at 10, 18 and 32 weeks, respectively. Additionally, statistically significant improvements were observed in fatigue, and patient and physician global assessments. The authors also found that their SS patients had over-expression of CD22 in peripheral B cells, and this was down-regulated by epratuzumab for at least 12 weeks after therapy. According to this preliminary study, epratuzumab appears to be a promising therapy in active primary SS, suggesting that further clinical trials should be conducted.

Belimumab
The B-cell activity factor (BAFF), a recently described member of the tumour necrosis factor (TNF)–ligand family [47] is essential for the control of B-cell maturation and survival [48], and has generated a great interest in autoimmune diseases such as SS and SLE. BAFF specifically regulates B-lymphocyte proliferation and survival, and is made in both membrane-bound and soluble forms by myeloid cells and dendritic cells, as well as by some T cells [49]. Recent studies describe a higher expression of BAFF in SS. Groom et al. [50] found elevated levels of circulating BAFF, as well as a dramatic up-regulation of BAFF expression in salivary glands, suggesting an altered differentiation and tolerance of B-cells induced by excess of BAFF. Szodoray et al. [51] found a reduced level of apoptosis among BAFF-expressing cells that might lead to a longer BAFF expression in these cells, which maintained positive signals for the infiltrating B cells to proliferate and mature. Gottenberg et al. [52, 53] have demonstrated the capacity of epithelial cells to express and secrete BAFF after Interferon (IFN) stimulation. These experimental studies suggest a key role for BAFF in the development of autoimmune/lymphoproliferative processes in primary SS.

Clinically, Mariette et al. [54] demonstrated in SS patients a correlation of BAFF levels with circulating levels of autoantibodies (IgG, RF, anti-Ro and anti-La). Pers et al. [55] have recently found increased serum levels of BAFF in 43 patients with SLE, 58 with primary SS and 28 with RA, in comparison with 68 controls. High levels of BAFF were associated with the presence of autoantibodies (anti-double-stranded DNA antibodies in SLE, anti-SSA antibodies in SS and rheumatoid factor in RA), suggesting that high levels of BAFF may be directly associated with the B-cell hyperactivity/proliferation usually observed in patients with Systemic Autoimmune Diseases (SAD).

BAFF-blocking agents may be a promising therapy for primary SS. Belimumab, a human monoclonal antibody against the human protein B-lymphocyte stimulator (BLyS), is under development by Human Genome Sciences, Cambridge Antibody Technology and GlaxoSmithKline. By January 2006, belimumab had completed phase II clinical trials in SLE and RA; a phase III clinical SLE trial is scheduled to begin later this year. Belimumab promises to be an interesting therapeutic agent to be tested in primary SS.


   T-cell targeted therapies
Top
 Abstract
 Introduction
 B-cell targeted therapies
 T-cell targeted therapies
Cytokine targeted therapies
 Concluding remarks
 Acknowledgements
 References
 
Adhesion molecules participate in many stages of the immune response, regulating leukocyte circulation, lymphoid cell homing to tissues and inflammatory sites, migration across endothelial cells and T-cell stimulation. During the T-cell immune response, adhesion molecules form a specialized junction between the T-cell and the antigen-presenting cell. For this reason, in the search for new therapeutic agents, many researchers have focused their attention on targeting adhesion molecules. Most of these efforts are intended to develop drugs for autoimmune diseases. Therapeutic agents like efalizumab and alefacept have been approved by the FDA for the treatment of some inflammatory autoimmune diseases such as psoriasis [56].

After the initiation of the autoimmune process in primary SS, autoantigens are expressed on the surface of epithelial cells, with T lymphocytes migrating to exocrine tissue and being activated in situ and B cells producing autoantibodies locally [57]. Several studies have recently analysed the role of T-cell dysfunctions in the pathogenesis of primary SS.

Efalizumab
Efalizumab (Raptiva®) is a humanized monoclonal antibody targeting the CD11a component of leukocyte function-associated antigen-1 (LFA-1), preventing its binding to intercellular adhesion molecules. Blocking this interaction results in interference with T-cell activation and reactivation, inhibition of leukocyte extravasation and adherence to keratinocytes in psoriatic epidermis. Efalizumab has recently been approved by the FDA and European Agency for the Evaluation of Medicinal Product (EMEA) for the treatment of psoriasis [58]. Some studies have suggested a potential role for LFA-1 in controlling the migration of lymphocytes to exocrine glands [59, 60], suggesting a possible therapeutic role for efalizumab in primary SS.

A phase II study sponsored by the National Institute of Dental and Craniofacial Research (NIDCR) is currently recruiting patients with primary SS in the USA. Patients will be randomly assigned to receive either Raptiva® or placebo for the first 3 months of the study. For the next 3 months, all participants will receive Raptiva®. Both Raptiva® and placebo are injected under the skin once a week. The study started in June 2006.

Alefacept
Alefacept (Amevive®) is a selective immunomodulating drug that blocks the LFA-3/CD2 interaction necessary for the activation and proliferation of memory effector T cells by binding to the CD2 expressed on the T-cell surface. Among biological agents, alefacept has demonstrated the longest remission in psoriasis [61], and appears to be well tolerated, even with long-term use. The primary concern with alefacept is T-lymphocyte depletion. Because the CD4+ count is reduced by alefacept, it should be monitored on a regular basis to ensure it does not drop below 250 cells/µl. The reported side effects are minor and include: headache, nasopharyngitis, rhinitis, influenza, upper respiratory tract infections, pruritus, arthralgia, fatigue, nausea and elevated liver enzymes. Severe infections and malignancies have not been linked to the use of alefacept, and few patients develop anti-alefacept antibodies. Alefacept seems to be a safe biological therapy for moderate-to-severe chronic plaque psoriasis with few side effects reported and will probably be tested in coming years in patients with systemic autoimmune diseases such as SLE, RA and SS.

Abatacept
Abatacept (Orencia®) is a soluble fusion protein that consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to the modified Fc portion of human IgG1. Specifically, abatacept blocks the CD80 and CD86 ligands on the surface of antigen-presenting cells that interface with the T-cell's CD28 receptor to activate T cells.

Abatacept has recently been approved for the treatment of RA refractory to other agents and seems to be more immunosuppressive than TNF-{alpha} blockers. The combination of abatacept and a TNF-{alpha} blocking agent does not seem to be more effective than either agent alone. Because abatacept has the ability to suppress T-cell function, it is a potential treatment for psoriasis and other autoimmune conditions involving T-cell driven pathological processes. However, a recent controlled trial in patients with RA showed an increased rate of serious adverse events in patients receiving abatacept in combination with other biological therapies [62], including a trend to a higher incidence of neoplasms (7% vs 2%).

The few studies of T-cell dysfunction in primary SS have centred on the role of the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and possible alterations in the T-cell receptor (TCR) [63]. Recent evidence suggests that CTLA-4, an immune attenuator, contributes significantly to homoeostatic control of T-helper-cell proliferation, and has a critical immunoregulatory role in the down-regulation of T-cell activation. Only two studies have been carried out in patients with primary SS. The first found no significant differences in the CTLA-4 polymorphisms of Tunisian patients with SS compared with the control group [64], while a recent study by Downie-Doyle et al. [65] described significant differences in haplotype frequencies of Australian SS patients compared with controls. Controlled trials would be necessary to evaluate the possible effect of abatacept in primary SS.


   Cytokine targeted therapies
Top
 Abstract
 Introduction
 B-cell targeted therapies
 T-cell targeted therapies
 Cytokine targeted therapies
Concluding remarks
 Acknowledgements
 References
 
A possible role of cytokines in the aetiopathogenesis of primary SS has been suggested by several studies [66, 67]. In the hope of achieving new therapeutic agents, attempts to develop anti-cytokine agents are not surprising. However, recent data have demonstrated that the excellent results obtained in rheumatic diseases using agents blocking some cytokines (such as anti-TNF agents for RA and spondyloarthropathies) have not been confirmed in systemic autoimmune diseases such as SLE or primary SS.

Infliximab
Recent studies have analysed the role of infliximab for the treatment of primary SS (Table 2). In a single-centre, open-label pilot study, Steinfeld et al. [68] found an improvement in clinical and functional parameters in 16 patients with primary SS treated with three infusions of infliximab (3 mg/kg) at 0, 2 and 6 weeks. In 1-yr follow-up study including 10 of these 16 patients, the same authors found a significant decrease in global and local disease manifestations in all 10 patients [69]. Although treatment was generally well tolerated, the main side effect was a mild, self-limiting infusion reaction in four (40%) patients (one of them presenting with generalized rash, fever and arthralgia), while two (20%) developed infectious processes (enteritis and tonsillitis). In addition, the main improvement was only observed in subjective symptomatology, with no changes in the erythrocyte sedimentation rate (ESR) or IgG levels. The same authors have evaluated the safety and efficacy of a maintenance regimen of infliximab in 10 of the 16 patients with primary SS who received additional infusions of infliximab for 1 yr. A statistically significant decrease in global and local disease manifestations was observed in all 10 patients. Treatment was generally well tolerated, with the main side effect being a mild, self-limited infusion reaction.

Other authors have reported successful responses in some patients with extraglandular features. Caroyer et al. [70] recently reported the successful treatment of a severe sensory neuropathy with infliximab, while Pessler et al. [71] reported a successful response to infliximab in a 11-yr-old girl with polyarthritis, suggesting that TNF-{alpha} blockers may have a role in the treatment of arthritis in paediatric SS.

However, the key study for evaluating the therapeutic effect of infliximab in primary SS has been recently published by Mariette et al. [72]. These authors conducted a multicentre, randomized, double-blind, placebo-controlled trial including a total of 103 patients with primary SS, who were randomly assigned to receive infliximab infusions (5 mg/kg) or placebo at Weeks 0, 2 and 6 and were followed up for 22 weeks. At week 10, 26.5% of patients receiving placebo and 27.8% of patients treated with infliximab had a favourable overall response (P = 0.89), and at week 22, 20.4% of the placebo group and 16.7% of the infliximab group had a favourable response. In addition, the two groups did not differ in any of the secondary end points over the 22 weeks of the trial. This randomized, double-blind, placebo-controlled study of an anti-TNF agent did not show any evidence of efficacy of infliximab in primary SS [72]. Although infliximab might play a role in the treatment of specific severe refractory extraglandular features, in the light of this controlled study, anti-TNF agents should not be considered as a first-line option for the treatment of primary SS.

Etanercept
Two recent studies performed in small series of patients have demonstrated a limited beneficial effect of etanercept in primary SS (Table 2). Sankar et al. [73] conducted a 12-week randomized, double-blind, placebo-controlled trial of etanercept. Twenty-eight patients received 25 mg of etanercept or placebo (vehicle) by twice-weekly subcutaneous injection. Of the 14 patients taking etanercept, 11 had primary SS and three had SS secondary to RA. Baseline measures did not differ between the two groups. Three etanercept-treated patients and one placebo-treated patient did not complete the trial. Five etanercept-treated patients and three placebo-treated patients showed improvement from baseline in the primary outcome variable at 12 weeks, but the difference was not statistically significant. There were no significant differences between the groups for changes in subjective measures of oral or ocular symptoms (by visual analogue scale), the IgG level, Schirmer I test result, van Bijsterveld score, or salivary flow. However, the ESR had decreased in the etanercept group compared with baseline [73].

Zandbelt et al. [74] evaluated the effect of etanercept on sicca, systemic and histological signs of 15 patients with primary SS who were treated with 25 mg etanercept subcutaneously twice per week during 12 weeks, with follow-up visits at Weeks 18 and 24. No increase of salivary or lachrymal gland function was observed in any patient. In four patients, a decrease of fatigue complaints was noted, which was also reflected by decreased scores in the Multidimensional Fatigue Instrument (MFI) questionnaire. A repeated treatment up to 26 weeks showed the same results. The authors concluded that etanercept 25 mg twice weekly did not appear to reduce sicca symptoms and signs in SS and did not affect minor salivary gland biopsy results.

These two studies showed no evidence to suggest that treatment with etanercept at a dosage of 25 mg twice weekly was clinically efficacious in SS.

Emerging anticytokine therapies
Recent studies have analysed the blockade of other cytokines as a possible therapeutic option in patients with RA or SLE, including monoclonal antibodies against IL-6, IL-10, IL-17 or IFN-{alpha} [75–78]. A recent double-blind randomized controlled trial of the IL-6R antagonist, tocilizumab, demonstrated a significant improvement of RA in 359 patients, although some analytical adverse events were observed, including elevation of transaminases and lipid levels [79]. The aetiopathogenic similarities between SLE and primary SS suggest that these anti-cytokine therapies might also be tested in primary SS in the future.


   Concluding remarks
Top
 Abstract
 Introduction
 B-cell targeted therapies
 T-cell targeted therapies
 Cytokine targeted therapies
 Concluding remarks
Acknowledgements
 References
 
Weighing the risks and benefits of biological therapies
Biological agents, particularly B-cell targeted therapies, constitute a major advance in the therapeutic armamentarium for patients with primary SS, even though they are not yet licensed for this use by the FDA and the EMEA. This off-label use should be centred on treating patients with either life-threatening situations or severe involvement refractory or intolerant to standard therapy (corticosteroids plus immunosuppressive agents). The initiation of biological therapy should be preceded by recording a detailed history and a complete physical examination in order to consider possible contraindications. The overall and long-term risks of biological agents in patients with primary SS is unknown, and the decision to use these agents should be governed by the clinical manifestations. Patients should be counselled about the potential risks of using biological therapies. The two cases of PML reported in patients with SLE treated with rituximab [35], together with the recent communication of an additional case of PML in a patient with RA treated with etanercept [80], only strengthen the need for careful evaluation of the risk/benefit profile of using biological agents in patients with rheumatic and systemic autoimmune diseases.

Consensus on the definition of outcome measures in primary SS
The development of a standardized measurement of disease activity and outcomes should be considered critical for the design of controlled clinical trials using biological agents in primary SS, as occurs in other autoimmune diseases such as RA or SLE. Consideration of the therapeutic response in patients with primary SS should be multidimensional, including the evaluation of sicca syndrome, general features, extraglandular involvement, biological markers and B-cell lymphoproliferative processes. Table 5 summarizes the main outcome measures proposed for clinical trials in SS, centred on the measurement of sicca manifestations (using subjective and objective measures), general features (mainly fatigue), health-related quality of life (using subjective measures), predictive biomarkers (gammaglobulin/IgG levels, C-reactive protein, beta-2 microglobulin, C3 and C4 levels, cryoglobulins, anti-La antibodies, RF and BAFF levels) and evaluation of SS activity and chonicity [18, 81–84]. International efforts to develop specific SS indexes for activity and damage should be encouraged: some recent multicentre studies from Italy, the UK and Sweden [82–84] have initiated this line of work.


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  		TABLE 5. Main outcome measures proposed for clinical trials in SS [18, 81–84]

 
Five-year view
Advances in our knowledge of the molecular mechanisms involved in the aetiopathogenesis of primary SS will allow the development of new treatments for this disease. New therapeutic approaches in primary SS using biological agents are centred on correcting lymphocytic dysfunction, with agents directed at modifying T-cell dysfunction or diminishing B-cell hyperactivity. B-cell targeted therapies seem to be the most promising agents in primary SS, especially rituximab (anti-CD20), which has been used in more than 50 reported cases. Rituximab has demonstrated therapeutic efficacy in the treatment of associated extraglandular and lymphoproliferative processes, although data from randomized, double-blind, placebo-controlled studies are not yet available. Other promising B-cell targeted therapies include agents against CD22+ cells (epratuzumab) and therapies antagonizing Blys/BAFF (belimumab). It seems logical that these agents may play a role in modifying the aetiopathogenic events of patients with primary SS, a disease characterized by B-cell hyperactivity. However, the promising results obtained in open-label studies of the use of B-cell targeted agents in primary SS should be confirmed in controlled studies. Further data are necessary on the optimal dose, the interval between treatment courses and safety issues. In addition, consensual end-points, outcome measures and biomarkers of response for clinical trials in SS remain to be defined.

The excellent results of TNF-targeted therapies in RA led to these agents being tested in patients with primary SS. However, recent controlled studies have showed a lack of efficacy of anti-TNF agents (infliximab, etanercept) in primary SS. Strategies based on T-cell targeted therapies (efalizumab, abatacept, alefacept) should currently be considered as possible future therapeutic options, although the poor response obtained with anti-TNF agents (which may be considered as partially directed against T cells) might suggest a similar lack of response.

In spite of its frequency and clinical relevance, primary SS has traditionally been considered as a ‘second line’ autoimmune disease, with a significant lack of interest in developing new research or therapeutic strategies. This has often led to pessimism in both patients and physicians. The recent emergence of biological therapies suggests new possibilities for the therapeutic management of this disease, offering a more optimistic point of view of the treatment of primary SS, which, at present, is often considered to lack adequate specific therapy. In the near future, biological agents will play key roles in the treatment of severe involvement, broadening the therapeutic options in patients with primary SS. However, the possible risks and benefits of using these agents should be carefully balanced, and a reasonable assessment of the risk of serious adverse events versus the treatment benefit should be made on a patient-by-patient basis.


   Acknowledgements
Top
 Abstract
 Introduction
 B-cell targeted therapies
 T-cell targeted therapies
 Cytokine targeted therapies
 Concluding remarks
 Acknowledgements
References
 
We wish to thank David Buss for his Editorial assistance.

The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 B-cell targeted therapies
 T-cell targeted therapies
 Cytokine targeted therapies
 Concluding remarks
 Acknowledgements
 References
 

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Submitted 23 November 2006; revised version accepted 19 March 2007.
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