Sjögren syndrome (SS) comprises glandular and extraglandular manifestations. Double-blind prospective trials of traditional disease-modifying antirheumatic drugs and biologics have failed because they have not improved benign symptoms, the major cause of lowered quality of life. Rituximab has proven effective in SS patients with associated mixed cryoglobulinemia, parotid gland swelling, lymphocytic interstitial pneumonitis, thrombocytopenia, and other manifestations. There were few of these SS patients in the trials required for FDA approval. Most patients had benign symptoms and did not show benefit, leading to failure of the study. This article examines the reasons for these failures and proposes future directions.
Key points
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Failure of benign manifestations, such as fatigue or cognitive impairment, must be shown by current peripheral blood tests.
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Benign symptoms, including dry eye and dry mouth, correlate poorly with objective findings of tear flow and saliva flow.
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Many of Sjögren syndrome patients who have extraglandular manifestations are incorrectly labeled as systemic lupus erythematosus or rheumatoid arthritis patients.
Introduction
Symptoms of Sjögren syndrome (SS) include both benign and systemic manifestations.
The benign (glandular) symptoms include ocular and oral discomfort. The myalgias and arthralgias, as well as generalized fatigue and cognitive difficulties, are also included in the benign category. However, these features certainly are not benign to the patients.
Dry or painful eyes are now the most frequent reason for visits to ophthalmology clinic, and a leading cause of lost work efficiency.
Because patients increasingly sit at computer stations in low-humidity office buildings, tear film dysfunction is exacerbated by the 90% blink rate reduction that accompanies staring at the computer screen.
In the United Kingdom alone, the financial loss from dry eyes alone was estimated at more than £150,000,000.
Patients’ most commonly identified benign symptom limiting their daily function is the chronic fatigue and loss of ability to function at their previous cognitive level.
The patients equate this disability at the level of moderate angina, and state that they would be willing to exchange more than 2 years of life expectancy to not have this limitation.
The benign symptoms emphasized here are benign only in their nomenclature; these have been the symptoms that have not shown improvements in clinical trials with biologic agents.
Yet, rheumatologists and investigators have assumed that the next anticytokine therapy will have a different and better result than the numerous other anticytokine therapies that are buried in the graveyard of failed clinical trials over the past decade.
The future of therapy for SS is not that bleak but clinicians and investigators must stop and ask about the choice of targets, methods of biomarkers, and trial design.
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If extraglandular manifestations of SS are going to be targeted, suitable SS patients must be identified and more efficiently enrolled. This involves education of rheumatologists and other specialists about sick SS patients misclassified as systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA) patients.
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If benign symptoms are going to be targeted, neurochemists have much to teach about the pathways that mediate these symptoms. A broader understanding of the innate immune system and how it interacts with the central immune system is provided by murine sickness models after viral infection.
Introduction
Symptoms of Sjögren syndrome (SS) include both benign and systemic manifestations.
The benign (glandular) symptoms include ocular and oral discomfort. The myalgias and arthralgias, as well as generalized fatigue and cognitive difficulties, are also included in the benign category. However, these features certainly are not benign to the patients.
Dry or painful eyes are now the most frequent reason for visits to ophthalmology clinic, and a leading cause of lost work efficiency.
Because patients increasingly sit at computer stations in low-humidity office buildings, tear film dysfunction is exacerbated by the 90% blink rate reduction that accompanies staring at the computer screen.
In the United Kingdom alone, the financial loss from dry eyes alone was estimated at more than £150,000,000.
Patients’ most commonly identified benign symptom limiting their daily function is the chronic fatigue and loss of ability to function at their previous cognitive level.
The patients equate this disability at the level of moderate angina, and state that they would be willing to exchange more than 2 years of life expectancy to not have this limitation.
The benign symptoms emphasized here are benign only in their nomenclature; these have been the symptoms that have not shown improvements in clinical trials with biologic agents.
Yet, rheumatologists and investigators have assumed that the next anticytokine therapy will have a different and better result than the numerous other anticytokine therapies that are buried in the graveyard of failed clinical trials over the past decade.
The future of therapy for SS is not that bleak but clinicians and investigators must stop and ask about the choice of targets, methods of biomarkers, and trial design.
- •
If extraglandular manifestations of SS are going to be targeted, suitable SS patients must be identified and more efficiently enrolled. This involves education of rheumatologists and other specialists about sick SS patients misclassified as systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA) patients.
- •
If benign symptoms are going to be targeted, neurochemists have much to teach about the pathways that mediate these symptoms. A broader understanding of the innate immune system and how it interacts with the central immune system is provided by murine sickness models after viral infection.
Background
To consider the future of therapy in SS, the concept of the danger hypothesis that gave rise to exploration of the innate immune system and its interactions with the central nervous system (CNS) is reviewed ( Box 1 ).
The initial development of development of disease-modifying antirheumatic drugs (DMARDs) and immunosuppressive drugs was based on the identification of autoantibodies in subjects and rejection of skin grafts in animals or humans. This led to recognition of human leukocyte antigens, T-cells, and B-cells. This led to the tolerance model.
To explain the ability of the immune system to distinguish self from modified self, the role of the thymus in removing self-reactive lymphocytes was recognized by Medawar. For those self-reactive lymphocytes that escaped thymic deletion, autoimmune disease was the consequence. The thymus was an organ in which almost all new lymphocytes underwent apoptosis and any lymphocytes reactive with these self-products were destined for self-death.
In Medawar’s tolerance model, a back-up system of peripheral immune suppression of lymphocytes was proposed to eliminate autoimmune cells that managed to sneak through thymic screening. Autoimmune disease was a failure of these mechanisms and therapy was directed to correcting these immune lapses. Therapy directed by this model led to great success in organ graft transplantation and certain autoimmune disorders.
Subsequently, it would be recognized that the tolerance mechanisms of the immune system (ie, acquired or adaptive immune system) evolved later than a more primitive innate immune system. However, this model guided immunologic studies and therapy for more than 2 decades.
Initial therapies, including steroids, DMARDs, and immune suppressive drugs, were developed using these models. However, the products of activation of the acquired immune system (eg, cytokine or autoantibody levels) remain the main sources of outcome markers in therapeutic trials.
Although elegant, the tolerance model did not explain many of the observed immediate responses of the immune system or the overall changes in behavior that accompanied immune challenge. A more general danger signal hypothesis was proposed by Gallucci and Matzinger, Janeway and Medzhitov, and Medzhitov and Janeway. The danger system model incorporated the adrenal hypothalamic axis and the role of prostaglandins, as well as the role of cortical (CNS) memory in the form of danger signals, in addition to immune responses of adaptive memory lymphocytes.
The key extension of the danger system model was the multiorgan responses needed to recognize and respond to infections. This predicted and incorporated the innate immune system in the periphery, including TLR receptors. It further predicted the CNS communication with the peripheral immune system. However, markers that correlate with the complex CNS changes that accompany response to foreign infections or autoimmune diseases that mimic these reactions have yet to be identified.
An understanding of the danger model and its markers will represent the therapeutic challenge of the next decade
Tolerance model (distinguish self from altered-self at thymic level) a
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Human leukocyte antigens
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T-cells and specific antigen driven responses
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Costimulatory factors
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B-cells and autoantibodies
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Memory at level of peripheral immune system
Danger signal model (distinguish self from infection) b
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Peripheral immune system communicates with CNS
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Innate toll-like receptors in periphery
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Unique toll-like receptors in CNS
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Cytokines, neurokines, neurotransmitters
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Prostaglandins and lipoproteins
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Hypothalamic, adrenal axis
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CNS and peripheral nervous system modulation of inflammation
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Memory at cortical level of danger signals
a Medawar
b Gallucci and Matzinger, Matzinger and Janeway, and Janeway and Matzinger
This hypothesis includes the traditional adaptive or acquired immune system of T-cell–mediated B-cell production of autoantibodies. However, it also includes the interactions of the innate immune system with elements of the CNS.
The adaptive (or acquired) immune system is based on Medewar’s failure of tolerance model, and has provided a family of drugs used to treat the extraglandular manifestations of SS, including disease-modifying antirheumatic drugs (DMARDs) and many biologic drugs.
However, it was recognized more than 25 years ago that the adaptive peripheral immune system did not adequately explain the interaction of the peripheral immune system with the CNS. A broader immune system was proposed to distinguish self from exogenous infections, as outlined by the danger model hypothesis of Gallucci and Matzinger and Janeway and Medzhitov (see Box 1 ).
In the danger model, the peripheral innate immune system still provides the first line of defense but subsequently interacts with the midbrain, the cerebral cortex, and the hypothalamic-adrenal axis by a series of danger-associated molecular patterns (DAMPs) leading to up regulation of toll-like receptors (TLRs) in activated astroglial cells. This activation results in up regulation of neurohormones, cytokines, neurokines, prostaglandins, and neurotransmitters. Morris and colleagues have recently summarized the interactions between activation of DAMPs and central mechanisms of fatigue that involve pathways of tumor necrosis factor (TNF), interferon (IFN)-1 and -2, and ultimately mitochondrial processing of ATP. This is shown schematically in Fig. 1 .
Reasons for failure of trials of biologics in Sjögren syndrome trials
It is important to point out that there has not been total failure of biologics in SS. Reasonable results in the control of extraglandular manifestations of SS have been achieved.
Indeed, the most widely used biologic agent for treatment of SS in Europe is rituximab, although it is not yet approved for SS in the United States by the Food and Drug Administration (FDA).
The failure for FDA approval of rituximab derives from the failure of biologic agents to improve SS benign symptoms and the relatively small proportion of SS patients with extraglandular symptoms in the pivotal double-blind trials.
A PubMed literature search reveals more than 5000 published studies (including many double-blind studies) on the use of rituximab and other biologic agents in extraglandular manifestations of SS.
However, rituximab was not given on a routine preventive schedule in these published studies but was given in response to particular manifestations such as vasculitis, mixed cryoglobulinemia, intractable rashes, or other organ involvement.
This is not a heretical suggestion because infections are not treated on a prophylactic basis but after the signs and symptoms are present.
Unfortunately, SS subjects with a high level of EULAR Sjögren Syndrome Disease Activity Index (ESSDAI) are not numerous enough or are often clinically unsuitable for the type of prospective randomized study required for approval in the United States by the FDA.
Among studies of other biologic agents, such as abatacept (Orencia) or belimumab (Benlysta), that have been presented in publication or abstract form, improvements of ESSDAI of 3.5 or more have been achieved.
However, the length of time to enroll and randomize an adequate number of these subjects with such active disease has been quite long, suggesting that the use of this drug in most SS patients would be impractical.
Further, the level of improvement in the patient’s quality of life assessment in most belimumab-treated patients was not improved sufficiently to consider these medications cost-effective or gain approval to formulary in Europe. In the United States, where the drug is approved for SLE, the enthusiasm for the drug by both patients and rheumatologists has been limited.
Major problem in enrolling Sjögren syndrome patients with extraglandular manifestations: many of the sickest Sjögren syndrome patients are misclassified as systemic lupus erythematosus, rheumatoid arthritis, or progressive systemic sclerosis
An important recent presentation at the 2015 American College of Rheumatology (ACR) conference by Rasmussen and colleagues pointed out that more than half of the sickest SS patients were incorrectly diagnosed as SLE or RA ( http://acrabstracts.org/abstract/previous-diagnosis-of-sjogrens-syndrome-as-rheumatoid-arthritis-or-systemic-lupus-erythematosus ).
Thus, even in rheumatology clinics with great expertise in diagnosing SS, the SS patients with extraglandular manifestations such as arthritis, lymphadenopathy, Idiopathic thrombocytopenic purpura (ITP), or mixed cryoglobulinemia who would be expected to benefit from biologic agents were not included in the cohort recruited for the clinical studies.
Thus, in general practice, it is not hard to imagine that the sickest SS patients are being seen in other clinics such as hematology (ITP, hemolytic anemia, lymphadenopathy), pulmonary (interstitial pneumonitis), neurology (transverse myelitis, peripheral neuropathy, mononeuritis multiplex), or renal (interstitial nephritis). These SS patients would not be correctly identified as eligible for treatment in the biologic drug trials.
Recent informal surveys among neurologists and hematologists at the authors’ institution found the following:
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It is rare that a previously diagnosed SLE or RA patient who is referred to one of these other clinics for treatment of significant extraglandular manifestation with a positive antinuclear antibody (ANA) is asked about the simplest manifestations of SS to make the correct diagnosis.
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To extend these somewhat surprising results, the authors were allowed to conduct a simple informal survey of hematologists attending the American Society of Hematology meetings held in San Diego last year.
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Over 80% of these board-certified hematologists were not aware that SS antigen-A (SS-A) or SS antigen-B were not criteria for diagnosis of SLE.
The authors doubt that other specialists, including many in rheumatology, would do much better.
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