Sjogren's is Always Systemic

“Sjögren’s is a systemic autoimmune disease that affects the entire body.”

 

-The Sjogren’s Foundation

This page makes the case, backed by research, for why Sjogren’s is never just a sicca (dryness) disease.

Some level of systemic disease can be found in nearly every thoroughly evaluated Sjogren’s patient.

Sicca while common, is not seen in every patient. Systemic features often precede dryness.(3) An estimated 20% of Sjogren’s patients do not have obvious sicca when Sjogren’s first presents itself. (2)

Every Sjogren’s patient deserves to be monitored for complications and comorbidities. Recognizing the multiple systemic features of Sjogren’s is key to providing and receiving optimal care. 

Please note: A section about working with rheumatologists and other clinicians will follow at a later date.   

“Three recent multicenter studies including more than 2,500 European patients from France, Spain and Italy have confirmed that primary SS is, undeniably, a systemic autoimmune disease.” 

Flores-Chaves et al, 2018. (116)

KEY POINTS:

  • Evidence overwhelmingly supports that Sjogren’s is a complex, multisystemic, inflammatory disease. 

  • Many systemic (non-sicca) manifestations tend to be overlooked.

  • Life-threatening manifestations do occur. About 10% of Sjogren's patients die from direct disease complications. (24, 16, 42, 116

  • The systemic features of Sjogren’s fall into three principal categories. Even sicca-dominant patients usually display features in two or three categories.

  • Comorbidities also add to the disease burden and are an additional cause of early mortality.  (47, 61, 124)

Terminology

 

ESSDAI- This is the "EULAR Sjogren’s syndrome disease activity index." EULAR stands for the European League against rheumatism. The ESSDAI is a standardized scoring system that rates 12 specific “domains” of systemic manifestations.This is the primary tool that Sjogren’s researchers use to measure overall disease activity. See the discussion below about the limitations of using the ESSDAI alone to define systemic disease.  

EGM- Extraglandular Manifestations. Extraglandular refers to any feature that is not directly caused by sicca. This term is used inconsistently by rheumatologists. Some limit EGM to mean only those features included in the 12 ESSDAI domains. (Category 1). Other rheumatologists include ESSDAI and Out of ESSDAI features (Category 2) as part of EGM, but not general systemic features (Category 3). Still others use the term to include all three categories of systemic features.

Systemic Sjogren’s, like EGM, can be defined differently, even among Sjogren's experts. Adding to the confusion, some rheumatologists equate "systemic" with “organ involvement” even though some of the of ESSDAI features do not impact organs per se. 

Any time the terms "EGM," "systemic," or "organ involvement" are used, the meaning must be clarified. 

The three categories of systemic Sjogren's features

Category 1: ESSDAI features (“Classic” EGM) 

Many, but not all, researchers narrowly define EGM and systemic involvement to mean only the features included in the ESSDAI (listed below).

Yet even by this strict definition of systemic involvement, a large majority of Sjogren’s patients qualify as having systemic disease.

  • Studies show that 70-80% of Sjogren’s patients have at least one ESSDAI feature at the time of presentation. (61, 92)   

  • A large prospective study in Spain showed that less than 10% of patients had no ESSDAI score after being followed for 6 years. (38)

For more in depth information on ESSDAI systemic features click here.

A brief overview of the 12 ESSDAI domains

  1. Constitutional: fever, night sweats unexplained weight loss                   

  2. Lymphadenopathy and lymphoma: Enlarged lymph nodes or lymphoma 

  3. Glandular: swelling of the saliva glands or tear glands (this is not sicca!)

  4. Articular: joint  pain or inflammation, morning stiffness

  5. Cutaneous (skin): vasculitis, purpura, erythema multiforma

  6. Pulmonary (lung): multiple types of lung disease

  7. Renal (kidney)

  8. Muscular (myositis)

  9. Peripheral nervous system (PNS): neurologic complications outside the CNS

  10. Central nervous system(CNS): neurologic complications of the brain and spinal cord

  11. Hematological: “cytopenias” not due to another cause. Low red blood cells, low neutrophils, low lymphocytes, low platelets.

  12. Biological: low complement, high or low IgG, cryoglobulinemia

Using the ESSDAI alone to define systemic Sjogren’s is problematic because:

  1. The ESSDAI does not include “out of ESSDAI” EGM or general systemic features. Patients with non-ESSDAI systemic manifestations may be incorrectly considered to have sicca-only disease because their ESSDAI score is zero.

  2. The ESSDAI is a time-consuming, detailed research tool. Therefore, patients are rarely evaluated for an ESSDAI score, or if they are, the evaluation is often incomplete. 

  3. Researchers sometimes perform a review of medical records to determine ESSDAI scores. This retrospective approach leads to artificially lower ESSDAI scores because of incomplete assessment and documentation.

  4. The ESSDAI measures disease activity, not disease damage. It does not reflect past systemic involvement or even current stable symptoms caused by past disease damage. For example, a person could rate as “0/ no activity” in the pulmonary domain because of stable respiratory symptoms caused by old damage. Complicating matters further, it can be difficult to tell if long lasting features are stable, especially when no previous tests are available. (150)

  5. Several ESSDAI domains tend be to be greatly underestimated, resulting in untreated systemic disease and unchecked disease progression.  

    Commonly overlooked ESSDAI features:

     

Pulmonary (lung) disease is now understood to impact most Sjogren’s patients, including many without obvious pulmonary symptoms. While most studies estimate a lung disease prevalence of 9-24%, these percentages are generally based on studies of symptomatic patients. Moderate, or even severe, interstitial lung disease may be present in asymptomatic patients (89). CT scan abnormalities are found in 30-65% of asymptomatic patients, including many with no or mild symptoms. (47, 54, 102) These findings have led some experts to question the wisdom of only screening patients with symptoms, because early identification and treatment improves outcomes (54, 89, 150). 

 

Small fiber neuropathies (SFNs). 

Painful small fiber neuropathy is the most common type of neuropathy in autoimmune patients, including SS (Sjogren’s).”  ~ Vivino et al, (p.155) (151)

 

Painful SFNs typically cause burning, tingling, and numbness in the feet and legs, although other areas of the body can be affected. SFNs are often overlooked (87, 96, 138) because they are undetectable by the typical neurologic examination and by electrodiagnostic (EMG/ nerve conduction velocity) tests. Formal ESSDAI assessments are often limited to large fiber and motor neuropathies, which are verifiable by neurologic examination and electrodiagnostic tests.

 

Dysautonomias impact up to 50% of Sjogren’s patients (50, 53), yet dysautonomia is not mentioned by the ESSDAI. In many patients, dysautonomia symptoms (cardiovascular, GI, bladder control issues, abnormal sweating and others) are incorrectly attributed to anxiety or functional neurologic disorder. (32, 33)

Category 2: “Out of ESSDAI” systemic features

These are the numerous, distinct systemic manifestations that are not measured by the ESSDAI, including rare but important complications such as ocular EGM (e.g., uveitis and scleritis). (69)  

 

More common features in this category include gastrointestinal (GI) manifestations which are nearly ubiquitous, (112, 148) and Raynaud’s phenomenon, which impacts 10-30% of individuals with Sjogren’s. (3, 81)

 

Almost every Sjogren’s patient has at least one “out of ESSDAI” EGM. These are often overlooked by both researchers and clinicians.

 

For more in depth information on "Out of ESSDAI" systemic features click here.

Category 3:  General systemic features

 

Some combination of flu-like fatigue, malaise, widespread muscle pain, stiffness, and cognitive dysfunction (brain fog), occurs in a large majority of Sjogren’s patients.

These poorly understood features tend to be the most debilitating aspect of Sjogren’s, often causing a profound reduction in health related quality of life.(22, 26, 86) The degree of functional disability is high in Sjogren’s and is largely determined by these general systemic features, especially physical fatigue. (27, 42, 43)

General systemic symptoms tend to be ignored, dismissed, or even psychologized. Although these features are sometimes accompanied by depression, this does not mean that depression is the main cause of fatigue or pain. Evidence is mounting that there is a biologic basis for many general systemic features. (88, 152)

“Although fatigue is associated with depression, depression is not the primary cause of fatigue in primary Sjogren’s syndrome.”  ~ Segal et al, 2008 (100)

For more in depth information on General systemic features click here.

 

Comorbidities -  Indirect systemic complications

Sjogren’s patients are at increased risk of developing additional chronic diseases or conditions.  

These diseases, called comorbidities, are associated with worsened health outcomes, and in some cases, with shorter lifespans. Comorbidities may be related to the underlying disease process but are generally not considered to be direct disease features. 

 

1. General comorbidities

Numerous comorbidities seen in Sjogren’s are also seen in other systemic inflammatory diseases. Cardiovascular disease (103), venous thromboembolism (105) and severe infections, especially respiratory (124), contribute to increased hospitalizations and early mortality in some Sjogren’s patients. (16, 42)

 

2. Autoimmune and autoinflammatory comorbidities

Fifty percent of Sjogren’s patients experience polyautoimmunity (having more than one autoimmune disease). (122, 123) The most commonly associated diseases in this category include rheumatoid arthritis (RA), systemic lupus erythematosus, and autoimmune thyroid disease, but there are many others. Associated autoimmune and autoinflammatory diseases may predate, coincide with, or follow a Sjogren’s diagnosis. 

Don’t call it “secondary Sjogren’s”! 
The term “secondary Sjogren’s” is confusing and obsolete. If a patient has both Sjogren’s and RA, it should be referred to as “Sjogren’s associated with RA.” Each disease deserves specific management. (122, 123, 153)

For more in depth information on Comorbidities click here.

IN SUMMARY:

  • Nearly all Sjogren’s patients experience well-characterized systemic Sjogren’s features, usually some combination of “classic” EGMs and “out of ESSDAI” EGMs (Categories 1 and 2).
  • In addition, most Sjogren’s patients experience general systemic features (Category 3). These often have a devastating impact on function and quality of life.
  • Comorbidities such as cardiovascular disease and severe infections are similar to those seen in other systemic inflammatory diseases.These similarities provide additional supporting evidence that Sjogren’s is a systemic disease. ​
  • Early diagnosis and treatment is a core principle of rheumatology, emphasized in the management of nearly every major rheumatologic disease. Recognizing the multisystemic nature of Sjogren’s is key to providing optimal care. Monitoring for complications and comorbidities allows for timely intervention, which in turn may reduce serious outcomes. (3, 54, 79, 89)

Practical Considerations:

The Sjogren’s is Systemic section provides background information, not guidance about ongoing care or communicating with rheumatologists.

General principles for working with clinicians can be found in this blog post. There is no “one-size-fits-all” management strategy for Sjogren’s. Sjogren’s is extremely complex. It requires deep knowledge, patience (by clinicians and patients), and creativity to provide comprehensive, multi-disciplinary care. 

Patients are encouraged to share with their clinicians pertinent research articles cited on Sjogren’s Advocate and Clinical Practice Guidelines (CPGs) published by the Sjogren’s Foundation.

CPGs are currently available for oral, ocular, and general systemic manifestations, including joint and musculoskeletal pain. A detailed set of guidelines for pulmonary disease are expected to be published by Fall 2020.

 

CPGs for other systemic features are in the pipeline.

Updated 8-23-20