The management of patients suffering from primary Sjögren syndrome (pSS) has long been mainly symptomatic and demonstration of effectiveness of systemic drugs was lacking. However, progress made in the understanding of pSS pathogenesis has allowed moving into a more targeted approach to therapeutic intervention. Given the key role of chronic B-cell activation, B-cell target therapies were the first candidates. New pathways are currently being investigated, including costimulation and ectopic germinal center. In this review, we summarize the current evidence regarding B-cell targeted and anti-TNF therapies and provide an overview of promising drugs in the pipeline.
Key points
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Consensual indexes have been developed in recent years allowing assessment of disease activity and symptoms in patients with primary Sjögren syndrome (pSS) and thus setting-up of clinical trials.
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Given the key role of B cells in pSS pathogenesis, there was a great deal of hope for B-cell target therapies. But despite promising results from open trials and retrospective studies, rituximab failed to demonstrate efficacy in pSS in 2 randomized controlled studies.
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New pathways are currently being investigated, including specific pathways of B cells, germinal center formation, and costimulation of T cells and interleukin-6.
Introduction
The management of patients with primary Sjögren syndrome (pSS) has long suffered from the lack of effective treatments. Progress made in the understanding of pSS pathogenesis together with the development of targeted therapies in the rheumatologic field will probably allow moving into the era of biologics in pSS in the near future. B-cell targeted therapies have been the most promising avenue during the past decade. More recently, new targets have been identified and several trials are just about to begin in patients with pSS. A more accurate definition of therapeutic objectives and use of validated outcome measures will help to better identify efficient drugs. The aim of this article was to summarize efficacy data of biologics used in pSS and to give an overview of the promising drugs in the pipeline.
Introduction
The management of patients with primary Sjögren syndrome (pSS) has long suffered from the lack of effective treatments. Progress made in the understanding of pSS pathogenesis together with the development of targeted therapies in the rheumatologic field will probably allow moving into the era of biologics in pSS in the near future. B-cell targeted therapies have been the most promising avenue during the past decade. More recently, new targets have been identified and several trials are just about to begin in patients with pSS. A more accurate definition of therapeutic objectives and use of validated outcome measures will help to better identify efficient drugs. The aim of this article was to summarize efficacy data of biologics used in pSS and to give an overview of the promising drugs in the pipeline.
What are the therapeutic objectives in primary Sjögren syndrome?
Until now, the treatment of pSS mostly relies on symptomatic agents to relieve the main symptoms (tears and saliva substitutes, saliva-stimulating agents such as pilocarpine or cevimeline, and analgesics) and steroids with immunosuppressants in case of severe systemic involvement, but the evidence-based medicine demonstrating the efficacy of these drugs is scarce.
Primary endpoints in the first trials assessing biologics in pSS (tumor necrosis factor [TNF] blockers, rituximab) mainly relied on symptoms, such as the visual analog scale (VAS) for dryness, fatigue, and pain. Even if these manifestations are the most frequent and are responsible for patients’ discomfort, they might not represent the only manifestations we want to improve with biologics, and improving systemic manifestations might be a valuable target.
For that purpose, new indexes have been developed to objectively assess systemic and symptomatic manifestations in patients with pSS. The European League Against Rheumatism (EULAR) Sjögren’s syndrome disease activity index (ESSDAI) is a systemic disease activity index that was generated in 2009 by consensus of a large group of worldwide experts from European and North American countries. The ESSDAI includes 12 domains (ie, organ systems: cutaneous, respiratory, renal, articular, muscular, peripheral nervous system, central nervous system, hematological, glandular, constitutional, lymphadenopathy, biological). Moderate activity has been defined as an ESSDAI greater than or equal to 5.
Likewise, the EULAR Sjögren’s syndrome patient-reported index (ESSPRI) was developed in 2011 in a multicenter international cohort of 230 patients. The selection of domains was based on previous data that included patient interviews, and included dryness, pain, and fatigue. The ESSPRI uses 0 to 10 numerical scales, 1 for each domain. The final score is the mean score of the 3 domains.
B-cell Target Therapies
B cell as a central actor of primary Sjögren syndrome pathogeny
Increasing evidence that B cells play a leading role in the disease justified targeting this immune subset in treatment of pSS. In patients with pSS, hypergammaglobulinemia and presence of autoantibodies (rheumatoid factor [RF], anti-SSA/Ro, and anti-SSB/La) support the primary role of B cells. Moreover, B-cell biomarkers have been shown to be increased in patients with pSS. Last, pSS is the autoimmune disease with the higher risk of B-cell non-Hodgkin lymphoma, which represents the ultimate stage of chronic B-cell activation. B-cell activating factor of the TNF family (BAFF) plays a key role in the overstimulation of B cells in pSS. BAFF promotes B-cell maturation, proliferation, and survival, and excess BAFF levels are likely to mediate autoreactive B-cell accumulation. In the past few years, several studies have focused on the role of BAFF in pSS, increased both in the serum and in salivary glands with a correlation between serum BAFF levels with levels of RF and presence of anti-SSA/Ro in patients with pSS. Altogether, these results supported the use of B-cell target therapies in patients with pSS.
Rituximab
Registries and open-labeled studies
Rituximab is a chimeric monoclonal antibody targeting CD20, a B-cell–specific membrane protein, that acts through a depletion of mature B cells during 4 to 12 months. Several open-labeled studies including 15 to 30 patients have been conducted to evaluate the efficacy of rituximab in patients with pSS. Some of these studies reported an improvement of main pSS symptoms (fatigue, dryness, and pain), as well as quality of life during 6 months following 2 infusions. Longer follow-up suggested that this clinical efficacy was transient. A recent study reported the effects of a much longer and intense exposure to rituximab (5 courses over 2.5 years), and suggested that repeated courses could have a prolonged efficacy.
Other studies reported that rituximab induced a clinically significant improvement in the vast majority of patients with low-grade lymphoma or systemic inflammatory manifestations. The analysis of the French nationwide “AutoImmunité et Rituximab” (AIR) registry reported that rituximab treatment improved systemic manifestations of the disease in 69% of the patients and allowed a decrease of steroid use, especially in case of peripheral nerve involvement associated with cryoglobulinemia or vasculitis. Of note, many of these patients had a severe presentation, and could probably not have been included in a placebo-controlled trial due to the risk of organ damage or even mortality. Thus, these data support the efficacy of rituximab at least in some systemic inflammatory manifestations of pSS-like parotid swelling or cryoglobulinemia-associated vasculitis.
Randomized controlled studies
To confirm these findings, 4 randomized controlled studies have been conducted ( Table 1 ). The first published trial, performed in the United Kingdom, included only 17 patients and suggested that, among the various symptoms, fatigue was the most likely to be improved by rituximab, even if the primary endpoint was not met. The second study, performed in The Netherlands, included 30 patients (10 assigned to placebo and 20 to rituximab) and reported that stimulated and nonstimulated salivary flow rate was improved 6 months after 2 infusions of 1000 mg in the rituximab arm but not in placebo-treated patients. Two larger multicenter trials were then conducted, the TEARS trial in France and the TRACTISS trial in United Kingsom. The TEARS study included 120 patients with either recent active disease (less than 10 years from disease onset) and biological markers of B-cell hyperactivity, or systemic involvement. Patients received either 2 infusions of 1 g rituximab or a placebo. The primary endpoint (at least 30 mm improvement of at least 2 among 4 VASs assessing global activity by the patient, dryness, fatigue, and pain) was not met at the study completion (week 24), but only at an earlier time point (week 6). However, several other secondary outcome measures were improved, notably salivary flow and salivary gland ultrasonographic abnormalities, raising the possibility that the predefined primary endpoint was not able to measure a positive effect of the treatment. The TRACTISS trial included 133 patients with pSS: 66 were assigned to receive placebo and 67 to rituximab (1000 mg) at weeks 0, 2, 24, and 26. Primary endpoint was the proportion of patients achieving 30% reduction in either fatigue or oral dryness at 48 weeks, measured by VAS. Preliminary results were presented at the 2015 American College of Rheumatology (ACR) meeting in San Francisco: this trial failed to demonstrate any efficacy of rituximab on its primary endpoint: dryness or fatigue VAS, but showed a modest effect of rituximab on salivary flow.
| Reference | Treatment | N | Primary Endpoint | Significant Difference for Primary Endpoint |
|---|---|---|---|---|
| Sankar et al, 2004 | Etanercept | 14 | ≥20% improvement from baseline for 2 of 3 domains: subjective or objective measures of dry mouth and dry eyes, and IgG level or ESR | No |
| Mariette et al, 2004 TRIPPS | Infliximab | 103 | At week 10 ≥30% improvement in 2 of 3 VASs measuring joint pain, fatigue, and the most disturbing dryness. | No and no differences for secondary outcomes |
| Dass et al, 2008 | Rituximab | 17 | At week 24 20% reduction in VAS fatigue score | No (/placebo) Yes (/baseline) |
| Meijer et al, 2010 | Rituximab | 30 | At weeks 5, 12, 24, and 48 Improvement in the stimulated whole saliva flow rate | Yes, significant improvement at weeks 5 and 12 |
| Norheim et al, 2012 | Anakinra | 26 | Change in Fatigue VAS at week 4 | No |
| Devauchelle-Pensec et al, 2014 TEARS | Rituximab | 122 | At week 24 30-mm improvement in 2 of 4 VASs | No, but modest effects on secondary endpoints |
| Bowman et al, ACR 2015 TRACTISS | Rituximab | 110 | At 48 wk 30% improvement in VAS fatigue or oral dryness score | No, but modest effect on salivary flow |
| St Clair et al, 2015 | Baminercept, lymphotoxin-beta receptor fusion protein | 72 | At 24 wk Change in stimulated whole salivary flow | No, but modest effect on ESSDAI |
Epratuzumab
Epratuzumab is a humanized immunoglobulin (Ig)G 1 -kappa monoclonal antibody targeting CD22, a coreceptor of the B-cell receptor (BCR). Conversely to rituximab, epratuzumab might not act via B-cell depletion. Binding of this molecule to CD22 is likely to enhance CD22 inhibitory functions on BCR and to modulate B-cell activation. Epratuzumab had shown promising results in phase II in patients with moderate/severe active lupus. However, results from a phase II randomized controlled trial presented at the 2015 ACR meeting in San Francisco failed to demonstrate any efficacy of epratuzumab in lupus. In pSS, one open-label study including 16 patients who received 4 monthly infusions with epratuzumab reported significant responses in half of the patients. Efficacy was assessed by a composite endpoint involving the Schirmer test, unstimulated whole salivary flow, fatigue, erythrocyte sedimentation rate, and IgG. However, this study was published in 2006, and a randomized trial is mandatory to confirm epratuzumab as a new therapeutic option in pSS.
B-cell activating factor of the tumor necrosis factor family inhibition
Belimumab is a monoclonal antibody targeting BAFF, which has demonstrated its efficacy in the treatment of systemic lupus erythematosus (SLE). The Efficacy and Safety of Belimumab in Subjects With Primary Sjögren’s Syndrome (BELISS) study is an open-labeled trial that evaluated efficacy of belimumab in 30 patients with pSS with anti-SSA/Ro and either current systemic complications or salivary gland enlargement, or early disease (<5 years), or biomarkers of B-cell activation. Belimumab was administered at the dosage of 10 mg/kg, at weeks 0, 2, and 4 and then every 4 weeks to week 24. The primary endpoint, assessed at week 28, was improvement in 2 of 5 items: reduction of 30% or more in dryness score on a VAS, 30% or more in fatigue VAS score, 30% or more in VAS pain score, 30% or more in systemic activity VAS assessed by the physician, and/or greater than 25% improvement in any B-cell activation biomarker values. The primary endpoint was achieved by 60% of the patients. Improvement of both patients’ symptoms (measured by ESSPRI) and systemic complications (measured by ESSDAI) was observed. Salivary flow and Schirmer test did not change. These results are encouraging, but need to be confirmed in a randomized controlled trial.
Tumor necrosis factor blockers
Inhibition of TNF has failed to demonstrate efficacy in patients with pSS in 2 randomized controlled studies. In the first one, the Trial of Remicade in Primary Sjögren’s Syndrome (TRIPSS) study, 103 patients received infliximab (5 mg/kg) or placebo at weeks 0, 2, and 6 and were followed for 22 weeks. Efficacy, defined as an improvement in 2 of 3 VAS that evaluated pain, fatigue, and dryness, was not achieved. Etanercept was assessed in a 12-week randomized, double-blind, placebo-controlled trial including 28 patients. Again, the primary objective was improvement of VAS for pain, fatigue, and dryness, and etanercept did not lead to a significant improvement of VAS compared with placebo. Blocking of another proinflammatory cytokine, interleukin (IL)-1, has been tested in pSS with the assessment of anakinra, the recombinant IL-1ra, but again, this treatment failed to demonstrate efficacy in patients with pSS.
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