Sjogren's is Complex

KEY POINTS:

  1. Disease features vary widely among Sjogren's patients.

  2. Sjogren's appears to have a number of subtypes. These subtypes may be associated with different symptom clusters, prognostic factors and responses to treatment.

  3. Studies that reveal the underlying biology of Sjogren's have the potential to support the discovery of new and targeted treatments.   

Each patient is unique

“Primary SS is a multisystem disorder that does not behave as a single disease.”     

 ~ G. Cafaro, C. Coria et al. in their article, One Year in review 2019: Sjogren’s syndrome (96).

 

Sjogren’s symptoms vary greatly from patient to patient. While most, but not all, have significant sicca (dryness) symptoms, even this ranges from mild to severe. Interestingly, sicca severity does not correlate well with current measurements used to assess dryness (78). An estimated 20 % of Sjogren’s patients do not have significant dry eyes or dry mouth at the time of presentation (2). This non-sicca subset includes many of the patients who present with organ system or neurologic involvement. Because the Sjogren’s Classification Criteria are heavily weighted toward sicca measurements (4, 36), these patients often experience especially long delays to diagnosis.

 

Many rheumatologists stick rigidly to the Classification Criteria, not recognizing the important distinction between diagnostic criteria (which do not exist for Sjogren’s) and Classification Criteria (77). Finding new specific biomarkers that identify the disease early and accurately could be a game-changer.

Despite being common, Sjogren’s is rarely a front burner diagnosis. Due to inadequate diagnostic tests, diverse presentations, and a lack of clinician awareness, some patients probably go a lifetime without a proper diagnosis. Common misdiagnoses include fibromyalgia, chronic fatigue syndrome, depression, undifferentiated connective tissue disease, seronegative rheumatoid arthritis and others.

Even for patients with an established diagnosis of Sjogren’s, systemic manifestations are often overlooked. Common neglected areas include general systemic features such as fatigue, pain, and brain fog, which are now understood to have a biologic basis (26, 88, 91). These disabling and sometimes debilitating symptoms are what destroys the quality of life for many patients (98).  Other common manifestations that are frequently overlooked include painful neuropathies, dysautonomias, and GI symptoms (2, 112).

 

An alarming number of patients report that they have never been screened or monitored for serious organ system complications, lymphoma risk, or comorbidities. This is an important part of comprehensive Sjogren’s care.  

Patient Story

Some of these symptoms come on gradually over time and cause us to adapt and modify activities, often without even realizing we are doing so. And that unless things get really bad pretty quickly they aren't well recognized by those we seek help from, or even by ourselves.

 

I don't think we are drama-laden, attention-seeking people. We are just people doing our best to live under dramatic and constantly fluctuating bizarre symptoms that are invisible to others. So to them our responses can seem dramatic.

 

~ Sjogren’s patient seeking a diagnosis for dysautonomia symptoms.

Why Sjogren's is hard to treat

 

1. Sjogren’s tends to be diagnosed late, after the disease has far progressed.
 

Numerous studies of rheumatoid arthritis and systemic lupus erythematosus have demonstrated lower rates of progression, complications and comorbidities with timely medical intervention. These diseases are closely related to Sjogren’s, and much better studied. Early treatment almost never happens with Sjogren’s. So far, there are no long-term prospective studies that look at the impact of treatment on the clinical course of Sjogren’s.
 

Because early Sjogren’s symptoms are often scattered or subtle, little is known about progression from early stages to diagnosis. Notably, about 30 % of patients report childhood symptoms that they now attribute to Sjogren’s (115). Yet, Sjogren’s diagnosis tends to occur in middle age, after much damage has already occurred.

 

Patients tend to accumulate various Sjogren’s features over many decades. Few clinicians connect the dots, or even think about the possibility of systemic disease, until the patient becomes too ill to live a normal life. Even then, the diagnosis is often delayed for several more years. Patients tend to bounce between specialists, who typically focus on their area of practice without considering the possibility of Sjogren’s. After longstanding and worsening symptoms, many people with Sjogren’s figure out on their own that they might have the disease, and request a diagnostic evaluation.

Many patients figure out on their own that they might have Sjogren's


Clinicians should never berate a person with possible Sjogren’s features for requesting that the diagnosis be considered. The current medical system fails to diagnose Sjogren's in a timely manner. Many clinicians, and even some rheumatologists, remain unfamiliar with common systemic features. Patients often need to become very knowledgeable to get comprehensive Sjogren's care.

This website and the website of the Sjogren’s Foundation are reliable up-to-date resources for patients and clinicians. Many other websites fail to adequately reflect the serious systemic nature of the disease.

2. Sjogren's subtypes

The remarkable diversity of Sjogren’s presents a great challenge for diagnosis and treatment. Two Sjogren’s patients may share similar symptoms, but respond quite differently to the same treatment.
 

While no autoimmune disease is fully understood, Sjogren’s research lags far behind similar diseases. Some areas are becoming clearer, such as risk factors for progression to lymphoma. However, we still know little about how to customize the management of individual patients. Different treatments probably work better for different Sjogren’s subtypes. These subtypes need to be defined in order to test current treatments, discover new treatments and guide individual management. This work has started, but is yet to be developed in great detail (96).

Two versions of subtypes:  Phenotypes and Endotypes    

        

Phenotypes are the obvious clinical manifestations of a disease. This is how most clinicians and patients think about Sjogren’s. For example, dryness, fatigue, lung disease and neuropathy are examples of Sjogren’s phenotypes. So are lip biopsies and blood tests such as SSA, RF, cryoglobulins, or lymphocyte counts.  The current Classification Criteria are based on measurements of phenotype.
 

There is no one phenotypic feature, including any diagnostic test, that is shared by every Sjogren’s patient. Some data show that certain Sjogren’s phenotypes can be made into subgroups that have higher frequencies of particular complications and comorbidities (113, 137). At this time, all subgroups are considered to be at some level of risk for most of the serious outcomes, including organ system involvement and lymphoma.

 

Endotypes describe the unique underlying biologic processes that produce the symptoms and damage of Sjogren’s. This invisible web of events is at the core of what actually causes Sjogren’s. These molecular events and pathways probably vary among subgroups of Sjogren’s patients, creating a number of endotypes.

 

Some endotypes might turn out to correlate with symptom clusters (phenotype groups), although there is not enough research to determine this in any detail. Defining distinct endotypes within Sjogren’s will help lead the discovery of targeted systemic treatments based on the patient’s molecular profile. This is the new frontier in Sjogren’s research (47, 67, 96, 114).

“The discovery of new biomarkers mirroring the diverse endotypes of the disease will offer the opportunity for early diagnosis, more effective patient stratification, as well as an estimation of response to specific treatments. New biologic therapies are expected not only to control the clinical manifestations of the disease and improve quality of life, but also modify the disease course and adverse outcomes including lymphoma.”

 

~ A.G. Tzioufas and A.V. Goules in their article: Limited efficacy of targeted treatments in Sjogren’s syndrome: why? (114)

Updated 4-12-20