Abstract
Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized by dryness and systemic involvement in more than a third of the patients. Patient management has suffered from the lack of effective treatments. However, progresses made in the understanding of pSS pathogenesis have allowed a move to a more targeted approach to therapeutic intervention. Given the key role of chronic B cell activation, B cell-targeted therapies were the first candidate. New pathways are currently investigated including costimulation and ectopic germinal centre formation. In this review, we have summarized the new tools available in clinical research in the field of pSS, the current evidence regarding B cell-targeted therapies and an overview of the promising drugs in the pipeline.
Introduction
Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized by lymphocytic infiltrates of salivary and lachrymal glands leading to xerostomia and xerophthalmia. Dryness is present in almost all the patients, associated with fatigue and pain. In addition, two-thirds of the patients present systemic involvement . Patient management has been hindered by the lack of effective treatments. Advancements in the understanding of pSS pathogenesis along with the development of targeted therapies in the rheumatologic field will probably allow moving into the era of biologics in pSS in the next future. B cell-targeted therapies have been the most promising avenue during the last decade. More recently, new targets have been identified and several trials are to commence in pSS patients. A more accurate definition of therapeutic objectives and the use of validated outcome measures will help better identify efficient drugs. This study aims to summarize the efficacy data of biologics used in pSS and also provide an overview of the promising drugs in the pipeline.
What are the therapeutic objectives in pSS?
Until now, the treatment of pSS has mostly relied 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 the case of severe systemic involvement, but the evidence-based medicine demonstrating the efficacy of these drugs is scarce .
Primary end points in the first trials assessing biologics in pSS (TNF (tumour necrosis factor) blockers, rituximab) mainly relied on symptoms such as visual analogue scale (VAS) for dryness, fatigue and pain . These common symptoms responsible for patients’ discomfort might not represent the only manifestations we want to improve with biologics, and improving systemic manifestations might be a valuable target.
Hence, new indexes have been developed to objectively assess systemic and symptomatic manifestations in pSS patients. The EULAR Sjögren’s syndrome disease activity index (ESSDAI) is a systemic disease activity index generated in 2009 by consensus of a large group of worldwide experts from European and North American countries . The ESSDAI includes 12 domains (i.e. organ systems: cutaneous, respiratory, renal, articular, muscular, peripheral nervous system (PNS), central nervous system (CNS), haematological, glandular, constitutional, lymphadenopathy and biological). Each domain is weighted and divided into three to four levels depending on their degree of activity. The final score, the sum of all domain scores, falls between 0 and, theoretically, 123, with 0 indicating no disease activity. ESSDAI is supposed to measure disease activity and avoid rating of damage. ESSDAI has been shown to have an excellent reliability and a large and accurate sensitivity to change to detect improvement . ESSDAI levels have been shown to correlate with B cell biomarkers and to predict lymphoma development . In order to help both physicians and researchers, disease activity levels and minimal clinically important improvement (MCII) have been determined within ESSDAI . Thus low, moderate and high activity levels were defined by an ESSDAI <5, between 5 and 13 and ≥14, respectively. In addition, MCII of ESSDAI has been defined as an improvement of ESSDAI by at least 3 points.
Likewise, the EULAR Sjögren’s syndrome patient-reported index (ESSPRI) has been developed in 2011 in a multicentre international cohort of 230 patients . The selection of domains was based on previous data that included patient’s interviews and also dryness, pain and fatigue. The ESSPRI uses 0–10 numerical scales, one for each domain. The final score is the mean score of the three domains. ESSPRI has been shown to have an excellent reliability, but a lower sensitivity to change than ESSDAI . As for ESSDAI, relevant thresholds have been determined with ESSPRI . Thus, the patient satisfactory symptom state (PASS) has been defined as an ESSPRI <5 and MCII as an improvement of ESSPRI at least by 1 point or 15% .
An alternative data-driven criterion has been recently suggested from a post hoc analysis of the TEARS trial (evaluating the efficacy of rituximab) . Five sensitive-to-change items were selected (oral dryness VAS, ocular dryness VAS, fatigue VAS, unstimulated whole salivary flow and erythrocyte sedimentation rate), and a Sjögren’s syndrome response index (SSRI)-30 response was defined as an at least 30% improvement from baseline of at least two among these five items. Nevertheless, the potential interest of this index to evaluate the effect of B cell and other targeted therapies need to be further evaluated. In addition, ultrasonographic assessment of salivary gland echostructure could be a promising tool .
In summary, we now have new tools that may help better define the inclusion criteria and primary outcomes in trials conducting in pSS. However, designing clinical trial is still challenging. Several constraints have to be taken into account. First, we have to select the population more likely to benefit from and respond to treatment. Inclusion criteria should select patients who are more likely to respond to treatment: patient with recent onset disease, moderate to high disease activity (i.e., systemic manifestations), B cell activation biomarkers and residual glandular function. However, recent studies have demonstrated that the more stringent the entrance criteria in a clinical study, the more challenging the recruitment . In addition, we have to consider that in randomized placebo-controlled trials, patients with more active forms of the disease cannot be included, as their exposure to the placebo is unethical. Finally, the choice of the primary outcome should be defined according to the biologic drug of choice and its potential target.
- –
Consensual indexes have been developed in recent years allowing assessment of disease activity and symptoms in pSS patients.
- –
Objectives are now for these indexes to be used as outcome criteria in randomized controlled trial, and Sjögren’s specialist to improve design of clinical trials.
What are the therapeutic objectives in pSS?
Until now, the treatment of pSS has mostly relied 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 the case of severe systemic involvement, but the evidence-based medicine demonstrating the efficacy of these drugs is scarce .
Primary end points in the first trials assessing biologics in pSS (TNF (tumour necrosis factor) blockers, rituximab) mainly relied on symptoms such as visual analogue scale (VAS) for dryness, fatigue and pain . These common symptoms responsible for patients’ discomfort might not represent the only manifestations we want to improve with biologics, and improving systemic manifestations might be a valuable target.
Hence, new indexes have been developed to objectively assess systemic and symptomatic manifestations in pSS patients. The EULAR Sjögren’s syndrome disease activity index (ESSDAI) is a systemic disease activity index generated in 2009 by consensus of a large group of worldwide experts from European and North American countries . The ESSDAI includes 12 domains (i.e. organ systems: cutaneous, respiratory, renal, articular, muscular, peripheral nervous system (PNS), central nervous system (CNS), haematological, glandular, constitutional, lymphadenopathy and biological). Each domain is weighted and divided into three to four levels depending on their degree of activity. The final score, the sum of all domain scores, falls between 0 and, theoretically, 123, with 0 indicating no disease activity. ESSDAI is supposed to measure disease activity and avoid rating of damage. ESSDAI has been shown to have an excellent reliability and a large and accurate sensitivity to change to detect improvement . ESSDAI levels have been shown to correlate with B cell biomarkers and to predict lymphoma development . In order to help both physicians and researchers, disease activity levels and minimal clinically important improvement (MCII) have been determined within ESSDAI . Thus low, moderate and high activity levels were defined by an ESSDAI <5, between 5 and 13 and ≥14, respectively. In addition, MCII of ESSDAI has been defined as an improvement of ESSDAI by at least 3 points.
Likewise, the EULAR Sjögren’s syndrome patient-reported index (ESSPRI) has been developed in 2011 in a multicentre international cohort of 230 patients . The selection of domains was based on previous data that included patient’s interviews and also dryness, pain and fatigue. The ESSPRI uses 0–10 numerical scales, one for each domain. The final score is the mean score of the three domains. ESSPRI has been shown to have an excellent reliability, but a lower sensitivity to change than ESSDAI . As for ESSDAI, relevant thresholds have been determined with ESSPRI . Thus, the patient satisfactory symptom state (PASS) has been defined as an ESSPRI <5 and MCII as an improvement of ESSPRI at least by 1 point or 15% .
An alternative data-driven criterion has been recently suggested from a post hoc analysis of the TEARS trial (evaluating the efficacy of rituximab) . Five sensitive-to-change items were selected (oral dryness VAS, ocular dryness VAS, fatigue VAS, unstimulated whole salivary flow and erythrocyte sedimentation rate), and a Sjögren’s syndrome response index (SSRI)-30 response was defined as an at least 30% improvement from baseline of at least two among these five items. Nevertheless, the potential interest of this index to evaluate the effect of B cell and other targeted therapies need to be further evaluated. In addition, ultrasonographic assessment of salivary gland echostructure could be a promising tool .
In summary, we now have new tools that may help better define the inclusion criteria and primary outcomes in trials conducting in pSS. However, designing clinical trial is still challenging. Several constraints have to be taken into account. First, we have to select the population more likely to benefit from and respond to treatment. Inclusion criteria should select patients who are more likely to respond to treatment: patient with recent onset disease, moderate to high disease activity (i.e., systemic manifestations), B cell activation biomarkers and residual glandular function. However, recent studies have demonstrated that the more stringent the entrance criteria in a clinical study, the more challenging the recruitment . In addition, we have to consider that in randomized placebo-controlled trials, patients with more active forms of the disease cannot be included, as their exposure to the placebo is unethical. Finally, the choice of the primary outcome should be defined according to the biologic drug of choice and its potential target.
- –
Consensual indexes have been developed in recent years allowing assessment of disease activity and symptoms in pSS patients.
- –
Objectives are now for these indexes to be used as outcome criteria in randomized controlled trial, and Sjögren’s specialist to improve design of clinical trials.
B cell-targeted therapies
B cell as a central actor of pSS pathogeny
Increased evidence that B cells play a leading role in the disease justified targeting this immune subset in the treatment of pSS. In pSS patients, hypergammaglobulinaemia and the 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 pSS patients . Finally, pSS is the autoimmune disease with the higher risk of B cell non-Hodgkin’s 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 the excess BAFF levels are likely to mediate the accumulation of autoreactive B cells . In the last few years, several studies have focused on the role of BAFF in pSS. It has been first demonstrated that the serum BAFF levels were increased and correlate with the levels of RF and the presence of anti-SSA/Ro in pSS patients . Second, increased levels of BAFF have been found in the salivary glands. Very interestingly, it has been shown that BAFF was secreted not only by usual professional BAFF-producing cells such as monocyte-macrophages and dendritic cells (DCs) but also by T and B cells and by the target cells of autoimmunity in pSS: salivary epithelial cells . Altogether, these results supported the use of B cell-targeted therapies in pSS patients.
Rituximab
Registries and open-labelled studies
Rituximab is a chimeric monoclonal antibody targeting CD20, a B cell-specific membrane protein, which acts through the depletion of mature B cells during 4–12 months . Several open-labelled studies including 15–30 patients have been conducted to evaluate the efficacy of rituximab in pSS patients . Some of these studies reported an improvement of main pSS symptoms (fatigue, dryness and pain) and quality of life in the first 6 months following the two 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 (five 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 the case of peripheral nerve involvement associated with cryoglobulinaemia or vasculitis . Of note, many of these patients had a severe presentation, which would have prevented their inclusion in placebo-controlled trials due to an increased risk of organ damage or death. Thus, these data support the efficacy of rituximab at least in some systemic inflammatory manifestations of pSS such as parotid swelling or cryoglobulinaemia-associated vasculitis.
Randomized controlled studies
In order to confirm these findings, four randomized controlled studies have been conducted. The first published trial, performed in the UK, 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 end point 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 non-stimulated salivary flow rates improved 6 months after the two 1000-mg infusions in the rituximab arm but not in placebo-treated patients . Two larger multicentre trials were then conducted: the TEARS trial in France and the TRACTISS trial in UK . The TEARS study included 120 patients with either recent active disease (<10 years from disease onset) and biological markers of B cell hyperactivity, or systemic involvement. Patients received either two infusions of 1 g of rituximab or placebo. Its primary end point (at least 30-mm improvement of at least two among four VASs assessing the 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 , thereby raising the possibility that the predefined primary end point could not reflect the positive effect of the treatment. The TRACTISS trial included 133 pSS patients: 66 were assigned to receive placebo and 67 to rituximab (1000 mg) at weeks 0, 2, 24 and 26. The primary end point was the proportion of patients achieving 30% reduction in either fatigue or oral dryness at 48 weeks, measured by VAS. Preliminary results have been presented at the 2015 ACR meeting in San Francisco: this trial failed to demonstrate the efficacy of rituximab on its primary endpoint, dryness or fatigue VAS, but showed a modest effect of rituximab on salivary flow .
Epratuzumab
Epratuzumab is a humanized IgG 1 -kappa monoclonal antibody targeting CD22, a co-receptor of the B cell receptor (BCR). Different from rituximab, epratuzumab might not act via B cell depletion. Binding of this molecule to CD22 is likely to enhance its inhibitory functions on BCR and modulate B cell activation . Epratuzumab showed promising results in phase 2 in patients with moderate/severe active lupus . However, those results were not confirmed in a phase III study, and the data presented at the 2015 ACR meeting in San Francisco failed to demonstrate any efficacy of epratuzumab in lupus .
In pSS, an open-label study including 16 patients who received four monthly infusions with epratuzumab reported significant responses in half of the patients . Efficacy was assessed by a composite end point involving Schirmer’s test, unstimulated whole salivary flow, fatigue, erythrocyte sedimentation rate and immunoglobulin G. This study was published in 2006; however, a randomized trial is mandatory to confirm epratuzumab as a new therapeutic option in pSS.
BAFF inhibition
Belimumab is a monoclonal antibody targeting BAFF . It has demonstrated its efficacy in the treatment of Systemic Lupus Erythematosus (SLE) . The BELISS study is an open-labelled trial that evaluated the efficacy of belimumab in 30 patients with pSS and anti-SSA who presented either current systemic complications or salivary gland enlargement, or early disease (<5 years), or biomarkers of B cell activation . Belimumab was administered at the dose 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 two of five items: reduction in ≥30% in dryness score on a VAS, ≥30% in fatigue VAS score, ≥30% in VAS pain score, ≥30% in systemic activity VAS assessed by the physician and/or >25% improvement in any B cell activation biomarker values. The primary endpoint was achieved by 60% of the patients. Improvement in both patient symptoms (measured by ESSPRI) and systemic complications (measured by ESSDAI) was observed. No changes were observed in salivary flow and Schirmer’s test. These results are encouraging, but they need to be confirmed in a randomized controlled trial.
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Given the key role of B cells in pSS pathogenesis, the B cell-targeted therapies showed great promise.
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Despite promising results from open trials and retrospective studies, rituximab failed to demonstrate efficacy in pSS.
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New pathways to block B cells have been identified including BAFF.
TNF blockers
Inhibition of TNF-α failed to demonstrate the efficacy in pSS patients in two randomized controlled studies ( Table 1 ). In the first study, TRIPSS, 103 patients received infliximab (5 mg/kg) or placebo at weeks 0, 2 and 6 and were followed up for 22 weeks . Efficacy, defined as an improvement of two of three VASs 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 to placebo.
| Reference | Treatment | N | Primary end point | Significant difference for primary end point |
|---|---|---|---|---|
| (Sankar et al. 2004) | Etanercept | 14 | ≥20% improvement from baseline for two of three 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 two of three VASs measuring joint pain, fatigue and the most disturbing dryness. | No 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. Plos One 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 two of four VASs | No Modest effects on secondary end points |
| (Brown et al. ACR 2015) TRACTISS | Rituximab | 110 | At 48 weeks, 30% improvement in VAS fatigue or oral dryness score | No Modest effect on salivary flow |
| (St Clair et al. ACR 2015) | Baminercept, Lymphotoxin-beta Receptor Fusion Protein | 72 | At 24 weeks, change in stimulated whole salivary flow | No Modest effect on ESSDAI |
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