How to Diagnose Sjögren’s Disease

This image demonstrates the Schirmer test, which is used to detect deficient tear production of Sjögren’s disease. The filter paper strip is placed at the junction of the eyelid margins. After five minutes, 15 mm of paper should be moistened if tear production is normal, as shown here. If someone is older than 40, they may moisten between 10 mm and 15 mm. (Click to enlarge.)

Sjögren’s disease (SjD) is a systemic autoimmune disorder with clinical heterogeneity that challenges even the most experienced rheumatologists. SjD is an alternative name for Sjögren’s syndrome.¹ The Sjögren’s Foundation, as well as many SjD experts, has advocated for this name change to underscore the fact that SjD is not just about dryness, but a distinct autoimmune disease with potentially serious outcomes. SjD includes both glandular and extra-glandular manifestations, such as interstitial lung disease (ILD), peripheral neuropathy and an increased risk of lymphoma. Despite the fact that it affects an estimated 0.1–0.6% of the population, SjD remains under­diagnosed and frequently mischaracterized, in part due to its insidious onset and overlapping symptomatology with other rheumatic diseases.

In this article, we explore prac­tical approaches to the diagnosis and management of Sjögren’s disease with two experts at the Penn Sjögren’s Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia: Chadwick R. Johr, MD, associate professor of medicine, and Dana DiRenzo, MD, MHS, assistant professor of medicine. Their perspectives provide a focused, practice-oriented lens for navigating the diagnosis and monitoring of SjD in the clinical setting.

Interview with the Experts

TR: What aspect(s) of SjD interest you?

Dr. DiRenzo (DD): SjD is an under-recognized disease, and it’s very rewarding when you make the diagnosis and start someone on treatment that’s very impactful. Highly active SjD is also difficult to think about, hard to treat and collaborative because you need to talk to a lot of other specialists to co-manage it well. You get to get creative with immunosuppressants because there are currently no therapies [for the condition approved by the U.S. Food & Drug Administration (FDA)].

TR: What symptoms really get your attention for a possible diagnosis of SjD?

Dr. DiRenzo

DD: I love to ask about salivary gland swelling and pain. When a patient responds with something like, ‘Oh yeah, I had to go to urgent care for a swollen parotid gland,’ or ‘swelling has been going on since my 20s,’ or ‘I had a salivary stone,’ or ‘the dentist said my glands are swollen’ … this clues me in to more of a glandular phenotype. It also gets my attention when a patient says they have been repeatedly diagnosed with mononucleosis or mumps without necessarily [being tested] for it.

I also ask patients if their contacts fall out by the end of the day. If the answer is yes, I’ll want to do objective dry eye testing. It’s a good way to screen for dry eye in patients who may not be aware of it.

Dr. Johr (CJ): When it comes to dry mouth, I get suspicious when patients tell me they have surprising and severe dental disease. For example, someone [who] used to never get any cavities and now finds three or four at each dental visit for no reason whatsoever; or the other day they cracked a tooth just by eating steamed broccoli. As for dry eye, when the patient’s ophthalmologist has gone beyond the usual conservative measures of artificial tears and warm compresses by prescribing topical cyclosporin, placing tear duct plugs, etc., it gets my attention.

I also get concerned for SjD when you couple fibromyalgia symptoms, such as chronic widespread musculoskeletal pain and fatigue, with more objective findings, such as a positive anti-nuclear antibody (ANA) or rheumatoid factor, history of ILD or even a family history of systemic autoimmune disease. If you add objective findings to a subset of the more typical subjective symptoms, that raises my concern.

TR: Is it possible to diagnose SjD in the absence of sicca symptoms?

DD: Yes, because not all patients realize they’re dry. Dryness is relative. You only know what your own eyes and your own mouth feel like, so some people have no idea that they’re dry, especially if it started when they were super young. I have patients where I’ve looked in their mouths, and it’s like a desert in there, but they have no idea.

CJ: I have seen many patients who don’t complain of dryness, but when tested, are in fact very dry. The subjective symptoms often don’t match the objective signs, and this is well documented in the literature.

Dr. Johr

So look for objective measurements of dryness when you suspect SjD. A Schirmer’s test and whole mouth unstimulated sialometry (salivary flow rate) can be done in the office and take five minutes to complete. The latter involves spitting into a specimen cup that has been pre-weighed on a scientific scale and then weighing the cup again afterwards. I think every rheumatology office should have a scientific scale. They are inexpensive and you can easily train your staff to do the testing.

TR: So would you recommend objective dryness testing in patients with an ANA of 1:160 and fibromyalgia symptoms but no dryness?

CJ: Yes, I absolutely would. If there is a reasonable chance that a patient could have SjD, I wouldn’t want to miss it. I would do a Schirmer’s test and sialometry in the office and then consider sending the patient to one of our cornea specialists for further testing. Using a slit lamp, fluorescence and lissamine green, they are able to report an ocular staining score (OSS), which is more sensitive for early dry eye changes than Schirmer testing.

TR: How do you diagnose seronegative SjD?

DD: Diagnosing seronegative SjD requires a minor salivary gland biopsy (lip biopsy).²

TR: How is seronegative SjD different than seropositive SjD?

DD: Seropositive SjD is associated with more inflammation on labs. These are the patients with very high immunoglobulins, high inflammatory markers, hypocomp-lementemia and a positive rheumatoid factor. They have a lot of glandular swelling. They have high-grade inflammatory lesions on salivary gland ultrasound and an increased risk of lymphoma.

On the other hand, seronegative SjD patients tend to have normal labs and less organ involvement, but more neurologic findings like small fiber neuropathy and postural orthostatic tachycardia syndrome (POTS) symptoms.

I think in 10 years, we’re going to understand these entities much better with possibly even two different underlying mechanisms. It may be that they are two different pathophysiologic processes, and that’s what’s making the clinical trials hard. There are various mechanisms of action that could be coming into play. For example, dysautonomia could be part of the pathogenesis that is part of the dryness seen in patients without positive serologies.

CJ: In my mind, seropositivity is associated with more badness—significant organ manifestations, like ILD [interstitial lung disease], kidney disease and lymphoma. But seronegative patients can still develop any of these things. In this regard, you can think of it like rheumatoid arthritis (RA). Seropositive RA patients have a greater risk of developing extra-articular manifestations, but the seronegative patients can get these too.

TR: As you know, not all patients referred to us for dryness have SjD. What else is on your differential in these cases?

DD: Medications are the most common cause of dryness overall. Common culprits include tricyclic anti-depressants, over­active bladder medications, diuretics, antihistamines … the list goes on. There’s a great UpToDate article on this.

Otherwise, vitamin B12 deficiency can cause burning and tingling in the mouth, and vitamin C deficiency can cause mucosal irritation, so it’s worth checking levels. Viral infections, like COVID-19, can trigger a dysautonomia that leads to dry mouth or a dysbiosis with a reset of oral flora that leads to dryness with chronic indolent infection. Certain tongue coatings can suggest dysbiosis, so look at the patient’s tongue and work with their dentist to reset that.

CJ: When it comes to sicca symptoms, the most important don’t miss diagnosis on the differential is hepatitis C viral (HCV) infection. It is more common than SjD and can look identical to it, with fatigue, arthralgia, dryness and gland swelling. Although guidelines recommend that all adults undergo HCV screening at least once in their lifetime, many have not. Another common, and sometimes overlooked, consideration is thyroid disease.

TR: How do you screen patients with SjD for lung involvement?

DD: There’s a great guideline article that recommends high-resolution computed tomography (HRCT) chest without contrast and complete pulmonary function tests (PFTs) in all SjD patients with pulmonary symptoms, and this is how I practice because ILD is so prevalent in SjD.³

CJ: A recent systematic review and meta-analysis showed that the prevalence of ILD in SjD is actually about 20%, which is higher than previously reported.⁴ The authors note this increased prevalence can be explained by the subset of studies that mandated the use of HRCT in addition to PFTs when screening for ILD. So, you may miss up to half of the ILD in your SjD patients who have cough and/or dyspnea if you use PFTs alone to look for it.

TR: What’s your approach to cancer screening in patients with SjD?

DD: If the patient is seropositive, there is an increased risk of glandular lymphoma. In these patients, I like to check parotid and submandibular ultrasound, as well serum protein electrophoresis with immunofixation (SPEP with IFE), urine protein electrophoresis with immunofixation (UPEP with IFE), and serum free light chains at baseline and at least once a year. I screen more often if they have symptoms like glandular swelling.

TR: Anything to add, Dr. Johr?

CJ: I also ask about salivary gland swelling and have a low threshold to look at the tissue with ultrasound, even if swelling is only intermittent. I ask about B-symptoms (e.g., fever, weight loss, night sweats), but they are only present in about 10% of patients with SjD who have lymphoma. That’s why using the lack of B-symptoms as a way to rule out lymphoma in this population is a mistake.

TR: When and how do you incorporate dentists and ophthalmologists into your patients’ care teams?

DD: Everyone with SjD needs to be seen by an ophthalmologist, and you can use the 2016 ACR-EULAR classification criteria for SjD to remember what dryness measures are important.⁵ Look for an OSS in the ophthalmology notes. It’s the most useful and tells you if dryness is inflammatory or not. A Schirmer’s test tells you if the patient isn’t making tears, but it’s nonspecific. For example, a patient with dysautonomia isn’t making tears, but the dryness isn’t due to inflammation.

The OSS is helpful for management, too. Dry eye should be treated aggressively, with no visible surface dry patches, keratoconjunctivitis or keratitis. Start with over-the-counter eye drops, but if persistent, step up to prescription eye drops like topical cyclosporine, and/or procedural interventions if necessary. A patient could be scarring down the surface of their eyes if dryness isn’t well controlled, and ophthalmology can make sure this isn’t occurring with their fancy equipment.

CJ: Because patients with SjD are at increased risk of dental complications, it’s recommended they see their dentist more often than the average person, typically three or even four times per year. However, dental insurance often refuses to cover the cost of the extra visits. When this occurs, we should advocate for our patients by writing a letter of necessity to the insurance company, explaining that the extra visits are justified by an underlying medical illness. You can find a letter template for this on the Sjögren’s Foundation website (www.sjogrens.org).

I’d also like to add that clinical practice guidelines for the oral management of SjD strongly recommend the use of topical fluoride in SjD patients with dry mouth to help prevent cavities, yet many are not on this important preventive treatment despite frequent dental visits. I typically prescribe sodium fluoride products with 5,000 ppm (hint: they have ‘5000’ in the name).

I instruct patients to brush their teeth with their usual toothpaste, floss, then rinse like they normally do each evening. Then afterward, brush their teeth with the prescription fluoride paste just to coat the teeth, spit out the excess and go to bed. If they want to rinse the fluoride, wait 30 minutes before doing so to give it time to work.

TR: Any other favorite SjD pearls to share with our readers?

CJ: Using sicca symptoms as the sole method of screening for SjD is a mistake. Look for objective evidence of dryness whenever you suspect SjD. A lot of patients with SjD are misdiagnosed as ‘just having fibromyalgia,’ when five minutes of objective testing (e.g., sialometry or Schirmer’s testing) could lead to a bona fide autoimmune diagnosis, potentially changing that person’s life.

Also, autonomic neuropathy is frequently overlooked in patients with SjD, although the literature suggests that up to half [of patients] may have it. Autonomic symptoms, like dizziness, are often attributed to ‘just fibromyalgia’ though they have distinct treatments that can really help. To screen for autonomic neuropathy, I like to ask about unusual sweating patterns (e.g., ‘My head sweats a lot, but my body doesn’t sweat at all’) in addition to asking questions that get at orthostasis (e.g., ‘Do you have difficulty standing in line at the grocery?’)

DD: I find salivary gland ultrasound really useful. A picture is worth a thousand words. In a patient whom you aren’t quite sure how active their glands are (e.g., Is there lymphoma in there or not?), I use imaging to be more objective. The ultrasound grading systems are really easy to understand, and you can follow imaging findings over time that could give you a reason to treat with something like rituximab if necessary.

If you don’t have access to a rheumatologist who is trained in musculoskeletal ultrasound, that’s okay. Just call your local radiologist, and ask for a head and neck ultrasound that focuses on the glands. Ask them to describe the glands and surrounding lymph nodes.

Conclusion

We will all take something different away from the wisdom shared by these SjD experts. Personally, I’ve already started recommending objective dryness testing more often for patients I would’ve previously diagnosed as just having fibromyalgia. It’s interviews and advice like this that really move the needle for me and my patients clinically, and I’m grateful for the opportunity that rheumatology affords me to keep learning.

Samantha C. Shapiro, MD, is a clinician educator who is passionate about the care and education of rheumatology patients. She writes for both medical and lay audiences and practices telerheumatology.

References

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3. Lee AS, Scofield RH, Hammitt KM, et al. Consensus guidelines for evaluation and management of pulmonary disease in Sjögren’s. Chest. 2021 Feb;159(2):683–698. https://journal.chestnet.org/article/S0012-3692(20)34902-3/fulltext.
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