Recent advances in primary Sjogren's syndrome

Introduction

Despite its prevalence among the rheumatologic diseases, primary Sjögren’s syndrome has attracted less attention from researchers compared to rheumatoid arthritis (RA) and systemic lupus erythematous (SLE), partly owing to a previous misconception that the disease was mostly a nuisance without recognizing that it can threaten the function of vital organ systems. The clinical hallmarks of Sjögren’s syndrome have been well known for many decades and include keratoconjunctivitis sicca, or dry eyes, and xerostomia, or dry mouth. Sjögren’s syndrome is termed secondary when the sicca symptoms occur in association with RA, SLE, or other chronic inflammatory disease. Otherwise, it is termed primary Sjögren’s syndrome. The clinical diagnosis of primary Sjögren’s syndrome is based on the presence of symptoms of dry eyes and dry mouth, often with objective evidence of keratoconjunctivitis sicca and/or decreased salivary flow, and a positive test for serum anti-Ro antibodies or rheumatoid factor or, in the absence of these autoantibodies, a labial salivary gland biopsy showing focal lymphocytic infiltrates¹. Reversal of glandular dysfunction and management of extraglandular disease has been hampered by the lack of a proven disease-modifying therapy. Herein, we describe some of the exciting new research about the genetic and immunologic mechanisms of primary Sjögren’s syndrome and the recent progress towards finding a disease-modifying therapy.

Primary Sjögren’s syndrome is among the most common of the systemic autoimmune diseases, ranging in prevalence from 0.1 to 0.6%; it is much more common in women than in men². The disease is termed an “exocrinopathy” because of its predominant effects on the lacrimal and salivary glands, as well as other exocrine glands in the larynx (hoarseness), trachea (cough), skin (pruritus), and vagina (dyspareunia). In addition to the exocrinopathy, up to 75% of patients with primary Sjögren’s syndrome suffer from extraglandular disease manifestations, and up to 25% develop moderate or severe extraglandular disease³. Extraglandular manifestations range from the less serious complications of purpura, urticaria, inflammatory arthritis, and Raynaud’s syndrome to the more severe end of the spectrum exemplified by renal disease, lung disease, and peripheral neuropathy. Notably, patients with primary Sjögren’s syndrome have an increased risk of developing non-Hodgkin B cell lymphoma, with a recent study showing a cumulative risk at 15 years after diagnosis of 9.8%; this risk is higher than that of patients with RA and SLE who also have an increased risk of developing non-Hodgkin lymphoma^4,5. Interestingly, most non-Hodgkin B cell lymphomas that develop in patients with primary Sjögren’s syndrome belong to the marginal zone histological type and localize to the mucosa-associated lymphoid tissue (MALT), where the underlying disease is most active. The presence of parotid gland enlargement, rheumatoid factor, low C4, cryoglobulinemia, lymphopenia, and higher levels of disease activity as measured by the EULAR Sjögren’s syndrome disease activity index (ESSDAI) predicts a higher lymphoma risk⁶.

Current management

In primary Sjögren’s syndrome, the current treatments aim to reduce symptoms of the exocrinopathy as well as control the extraglandular features of the disease. Symptomatic therapies include topical therapies, such as artificial tears, artificial saliva, nasal saline spray, vaginal estrogen cream, and moisturizing skin lotions. Secretagogues, such as sugarless candy and chewing gum, as well as the muscarinic receptor agonists cevimeline and pilocarpine may be used to stimulate tear and saliva production. Topical cyclosporine eye drops are efficacious for improving the signs and symptoms of dry eyes.

At this stage, no disease-modifying drugs have been shown in randomized, placebo-controlled trials to be effective for the treatment of primary Sjögren’s syndrome. While hydroxychloroquine has been employed for reducing the symptoms of fatigue and joint pain in primary Sjögren’s syndrome, it failed in a randomized controlled trial to significantly reduce symptoms of dryness, pain, and fatigue over placebo⁷. Methotrexate has not been well studied for the treatment of primary Sjögren’s syndrome. In a small open study published 20 years ago, oral weekly methotrexate was not effective in increasing tear or saliva production⁸. More recently, the tumor necrosis factor (TNF)-α inhibitors infliximab and etanercept have been investigated for their efficacy and safety in patients with primary Sjögren’s syndrome and neither was found to be effective for improving disease outcomes^9,10.

The dearth of proven effective therapies for primary Sjögren’s syndrome has forced clinicians to take an empiric approach to the systemic treatment of extraglandular disease, guided by the severity of organ system involvement. Mild sensory neuropathies, common in patients with primary Sjögren’s syndrome, are generally treated symptomatically with, for example, gabapentin or pregabalin. Recurrent lower extremity purpura caused by a leukocytoclastic vasculitis may usually be managed with support stockings and non-steroidal anti-inflammatory drugs. Systemic corticosteroids may be prescribed for the treatment of organ-threatening vasculitis, non-specific interstitial pneumonitis (NSIP), interstitial nephritis, glomerulonephritis, and motor neuropathies. Other immunosuppressive agents, such as azathioprine, mycophenolate mofetil, and cyclophosphamide, are usually reserved for the treatment of serious or life-threatening extraglandular disease, such as NSIP and glomerulonephritis.

Advances in understanding of disease pathogenesis

Primary Sjögren’s syndrome results from a complex interplay of several factors, including genetic and epigenetic controls of immune homeostasis and gene expression, age and gender, and environmental insults. It follows a typical multistep model of human autoimmune diseases characterized by loss of immunologic tolerance to self-antigens, the permissive production of autoantibodies, and the subsequent emergence of disease^11,12. Studies of labial salivary glands reveal the contribution of a panoply of cell types, including T cells, B cells, macrophages, dendritic cells, and epithelial cells, that combine to orchestrate a persistent chronic inflammatory response.

The basis for the exocrine gland dysfunction is poorly understood and may result from effects related to the pro-inflammatory cytokine/chemokine milieu, autoantibody-mediated blockade of muscarinic acetylcholine receptors (e.g. anti-muscarinic receptor 3 antibodies), neurotransmitter imbalances, or the destruction of glands. The potential reversibility of glandular dysfunction is unclear and must necessarily await the discovery of a disease-modifying drug that can ameliorate the loss of lacrimal and salivary secretory flow.

Investigational systemic therapies

The pipeline of investigational therapies for primary Sjögren’s syndrome has grown substantially over the past 5 years (Table 1). Despite the initial promise of rituximab therapy for this disease, the results of two randomized, placebo-controlled trials from France and the United Kingdom recently failed to demonstrate significant improvement in the endpoints of dryness, pain, and fatigue^49,50. Other targeted approaches are in much earlier phases of development and have not been adequately studied in randomized, controlled trials. Open treatment with belimumab, a monoclonal antibody that inhibits BAFF, led to some improvement in physician assessment of systemic disease activity and serologic markers of B cell function but failed to show any significant benefit in terms of reducing symptoms of fatigue, pain, and dryness⁵¹.

A clinical trial has been initiated in patients with primary Sjögren’s syndrome that combines treatment with both rituximab and belimumab. It is based on the rationale that BAFF levels increase following rituximab-induced CD20 B cell depletion⁵², which in turn may promote the survival of self-reactive B cells and perpetuate the breach in B cell tolerance. In theory, combining belimumab with a B-cell-depleting agent would neutralize the excessive BAFF and allow for reconstitution of a non-self-reactive B cell repertoire. Other inhibitors of the BAFF/BR3 pathway are under development as well. Since PI3kδ is a signaling molecule crucial for BR3 function²⁸, studies are also now underway in patients with primary Sjögren’s syndrome to investigate the potential benefits of a small molecule PI3kδ inhibitor.

Bruton’s tyrosine kinase (Btk) inhibitors, which are approved for the treatment of certain B cell malignancies, are also in early stage clinical trials for the treatment of primary Sjögren’s syndrome. These small molecule Btk inhibitors can not only inhibit B cell receptor-dependent B cell proliferation and activation but also impact FcR-dependent proinflammatory cytokine production by myeloid cells⁵³.

The use of co-stimulatory blockade with abatacept is a well-reasoned therapeutic intervention for primary Sjögren’s syndrome owing to the important role of T cell activation in the pathogenesis of this disease. In an open-label study, treatment with abatacept was shown to significantly decrease the scores for the ESSDAI and EULAR Sjögren’s syndrome patient-reported index (ESSPRI) and the serum levels of rheumatoid factor and IgG⁵⁴. However, measures of salivary and lacrimal gland function did not change during treatment⁵². Larger controlled studies of abatacept therapy for primary Sjögren’s syndrome are in progress.

Several biologics are under development for the treatment of primary Sjögren’s syndrome that inhibit the activation of T cells. A non-depleting, Fc-silent, anti-CD40 monoclonal antibody (CFZ533) blocks the binding of CD40 to CD154 and thereby inhibits T cell activation. CD154 is particularly important in the activation of TFH cells. TFH cells are also being targeted by a monoclonal antibody to B7RP1 (ICOS-L), or AMG557. Blocking the B7RP1/ICOS-L pathway has been shown to decrease the differentiation of CD4⁺ naïve T cells into TFH cells and inhibit germinal center formation⁵⁵ and thus could decrease B cell activation and ectopic lymphoid tissue formation in the target organs of primary Sjögren’s syndrome.

Tocilizumab, an IL-6 receptor-blocking antibody, has been approved for the treatment of RA and juvenile idiopathic arthritis and is currently in a phase II study investigating its efficacy and safety in primary Sjögren’s syndrome. The IL-6/IL-6 receptor pathway is important in promoting the differentiation and maintenance of TH17 and TFH cells. Low-dose IL-2 therapy is also being considered as a possible therapy for primary Sjögren’s syndrome because of its capacity to expand the T regulatory cell population^56,57; however, IL-2 can also have the undesirable effect of activating T cells and perpetuating the effector arm of a T-cell-driven response. Whether the dose of IL-2 can be adjusted to favor the expansion of T regulatory cells over the activation of pathogenic effector T cells will require further study.

IFN-α is an intriguing therapeutic target in primary Sjögren’s syndrome for the reasons described above. Sifalimumab and rontalizumab, anti-IFN-α monoclonal antibodies under development for the treatment for SLE, would also have a strong rationale for testing in primary Sjögren’s syndrome. In addition, anti-retroviral therapies might have some therapeutic appeal in the future considering the emerging evidence that expression of endogenous retroelements in the target tissue may engage nucleic acid sensors and augment chronic inflammatory responses.

Looking forward

Drug developers are gradually shifting their attention towards primary Sjögren’s syndrome as a possible indication for new targeted therapies. The prevalence of primary Sjögren’s syndrome and the ready access to the target tissue through labial salivary gland biopsy provides unique advantages for investigation. Moreover, the lack of an approved disease-modifying therapy affords appropriate equipoise for conducting placebo-controlled trials of experimental therapies without the concomitant use of background immunosuppressive agents.

There are also challenges ahead in bringing a new drug through the development process owing to the lack of a roadmap for success. Many failed drug trials in primary Sjögren’s syndrome have raised questions about the optimal approach for investigating new therapeutics in the future. Thus far, the focus has been on interventions that are immunomodulatory and that down-regulate chronic inflammatory responses. Other mechanisms may be at play, such as neuroendocrine abnormalities, that affect some of the disease manifestations, such as fatigue. There is uncertainty about the most appropriate selection of subjects for clinical trials. Some authorities have advocated for the inclusion of patients with early disease only (e.g. < 4 years from diagnosis) with a minimum cut-off for stimulated whole salivary flow to ensure participants have sufficient glandular secretory capacity to detect a treatment response. This approach is logical if the experimental treatment is aimed at improving glandular function. Other trials may be designed to focus on the subset of patients with moderate-to-high levels of systemic disease activity if the investigational drug is hypothesized to benefit patients with extraglandular manifestations of disease.

What is the appropriate primary endpoint for evaluating the clinical efficacy of a targeted therapy? Is it unstimulated or stimulated salivary flow? The answer is probably “yes” if increasing tear and salivary flow is the postulated action of the experimental agent. If the therapy is aimed at other disease manifestations, then two composite indices, the ESSPRI and ESSDAI, have been developed that broadly quantify disease activity. ESSPRI is an instrument that measures patient-oriented outcomes such as dryness, fatigue and pain symptoms, while the ESSDAI is a validated index of systemic disease activity. Recent work has set thresholds for clinically meaningful improvement in the ESSPRI (decrease in one point or 15%) and ESSDAI (≥ three points)⁵⁸. It has been proposed that an ESSDAI of five points or more (moderate disease activity) should be an eligibility requirement for evaluating new therapies directed at systemic manifestations of primary Sjögren’s syndrome⁵⁸. However, applying these restricted inclusion criteria significantly reduces the proportion of patients with primary Sjögren’s syndrome that would be eligible for a clinical trial^59,60. Regardless, a more focused approach of testing new drugs in selected study populations with outcomes based on the mechanistic rationale of the experimental drug may improve the success rate of clinical trials in this disease.

The accelerated pace of discovery in primary Sjögren’s syndrome promises to illuminate the genetic, epigenetic, and environmental factors that are responsible for triggering and perpetuating the disease process. This new knowledge will inform the development of novel therapies that in the future will positively impact the care of patients who suffer from this chronic illness.

Abbreviations

AID, activation-induced cytidine deaminase; BAFF, B-cell-activating factor; BAFF-R, B-cell-activating factor receptor; BCMA, B cell maturation antigen; Btk, Bruton’s tyrosine kinase; EBV, Epstein-Barr virus; EBER, EBV encoded small RNA; ESSDAI, EULAR Sjögren’s syndrome disease activity index; ESSPRI, EULAR Sjögren’s syndrome patient-reported index; HEVs, high endothelial venules; ICOS, inducible T cell co-stimulator; ICOS-L, ICOS ligand; IFN, interferon; IL, interleukin; ILC, innate lymphoid cell; KIR, killer-like receptor; LINE-1/L1, long interspersed nuclear element 1; LTβR, lymphotoxin β receptor; LTRs, long-terminal repeats; MALT, mucosa-associated lymphoid tissue; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells; NK, natural killer; NSIP, non-specific interstitial pneumonitis; PI3kδ, phosphatidylinositol 3-kinase delta; RA, rheumatoid arthritis; RIG-1, retinoic acid-inducible gene 1; SINEs, short interspersed nuclear elements; SLE, systemic lupus erythematous; TACI, transmembrane activator and calcium-modulator and cyclophilin ligand interactor; TFH, T follicular helper; TH, T helper; TNF, tumor necrosis factor; TLR, Toll-like receptor.