Diagnosing and treating Sjögren's syndrome

August 14, 2016

Sjögren’s syndrome is underdiagnosed and seriously impacts the ocular surface and quality of life and places the patient at risk for multisystem involvement. Optometry’s role in identification, diagnosis and collaborative long-term management is an important one. Earlier attention to symptoms leading to diagnosis and collaboration with other health professionals will ensure better quality of life for our patients.


Sjögren’s syndrome is a chronic inflammatory disorder that affects 0.1 percent to 0.6 percent of the population and is estimated to affect as many as four million people in the United States. This is roughly equivalent to the same number of patients with rheumatoid arthritis.

However, only just over one million individuals have been diagnosed with Sjögren’s syndrome.1

 

 

This gap alludes to the difficulty in identifying the disease because it has an incipient course and initially presents with non-specificsymptoms. Many of the symptoms present early in the disease may be confused with other matters common to such items as menopause, medication side effects, and non-specific aging changes.

As a result, the time between initiation of symptoms associated with the disease and a confirmatory diagnosis is often 3.5 years or longer.1

Sjogren's patient with punctate epithelial keratopathy.

 

Related: Understanding Sjögren's syndrome

Sjögren’s syndrome may also present as a primary disease, meaning it occurs alone, or as a secondary disorder, occurring along with other chronic inflammatory disorders-most commonly rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), scleroderma, or polymyositis.2

The disease is found in both sexes, affects females roughly nine times more than males, and occurs in virtually any age range. The “typical” patient is female, Caucasian, and of middle to older age.3

Sjögren pathophysiology

The key factor of the disease is exocrine gland dysfunction where the body’s immune system begins to attack several key secretory glands, including the lacrimal and salivary glands. As such, two of the primary clinical features are keratoconjunctivitis sicca and xerostomia, which are hallmark of the clinical diagnosis. 

Related: Identify Sjögren's patients with Sjö test

However, this is only the tip of the iceberg. The disease often also affects other organ systems, including the nervous system, skin, lungs, and kidneys. In primary Sjögren’s syndrome, up to 75 percent of patients manifest with extraglandular disease.4

As such, the list of other symptoms associated with Sjögren’s syndrome involves dental decay, debilitating fatigue, dry skin, peripheral neuropathy, arthropathy, and gastrointestinal problems.

The cumulative risk of a Sjögren’s patient to develop non-Hodgkin’s B-cell lymphoma within 15 years of her diagnosis is 9.8 percent-significantly higher than that of the general population.5 In addition, 20 to 30 percent of patients with primary Sjögren’s syndrome have clinical pulmonary involvement, which is associated with lower quality of life and increased 10-year mortality.6

 

Pathogenesis

Sjögren’s syndrome is a complex and poorly understood mechanism, which appears to be directed by both genetic and epigenetic controls7,8 and involves several different key aspects of the immune system. Animal models suggest that the disorder begins in the lacrimal and submandibular salivary glands, then progresses to include involvement of other secretory glands. 

Related: Sjögren's requires an understanding beyond traditional symptoms

Sjögren’s is characterized by B-cell hyperactivity, manifested by hypergammaglobulinemia and the presence of multiple serum autoantibodies,9 the production of which is mediated via an antigen-driven process. It has been observed that the epithelial cells within labial salivary glands of Sjögren’s patients bear the characteristics of antigen-presenting cells.

This may lead to a breakdown in the negative feedback regulation of inflammation, with increased expression and production of autoantigens,9 with autoimmunogenic activity being propagated in lymphoid germinal centers.10

Studies examining genetics have identified several targets, including those involved in B-cell activation and activated B-cell Nf-kB signaling, which emphasize the role of B cells in the process of disease development.

In addition, T follicular helper cells (TFH), which mediate the selection and survival of B-cells and differentiation into plasma cells and memory B cells, may have a significant role-TFH cells have been discovered in the structural components of labial salivary gland tissue.11

Diagnosing Sjögren’s

The diagnosis of Sjögren’s syndrome has undergone attempts at simplification over time. The American-European Consensus Classification Criteria guidelines were published in 2002.11 They incorporate different aspects of clinical presentation, serology, and histopathology.

Clinical diagnostic guidelines consist of the following:

• At least one ocular symptom of the following:

o   Dry eyes > 3 mo

o   Foreign body sensation

o   Use of artificial tears > TID

• At least one oral symptom of the following:

o   Dry mouth > 3 mo

o   Recurrent or persistently swollen salivary glands

o   Need liquids to swallow dry foods

• At least one ocular sign of the following:

o   Shirmer’s I test (without anesthesia) <= 5mm/5min

o   Positive vital dye stain (van Bijsterveld >= 4)

Histopathology of lip biopsy showing focal lymphocytic sialodenitis

o   (focus score >= 1 per 4 mm2)

• At least one oral sign of the following:

o   Unstimulated whole salivary flow (+ 1.5mL in 15 minutes)

o   Abnormal parotid sialography

o   Abnormal salivary scintigraphy

Positive autoantibodies for Anti-SSA (Ro) or Anti-SSB (La)

Related: 4 biomarkers may improve Sjögren's syndrome treatment

 

 

The American College of Rheumatology proposed the following classification criteria 10 years later in 2012,12 which will be met if patients have at least two of the following three objective features:

• Positive serum anti-SS-A/Ro and/or anti-SS-B/La or (positive rheumatoid factor and ANA>=1:320)

• Labial salivary gland biopsy exhibiting focal lymphocytic sialadenitis with a focus score >= 1 focus/4 mm2

• Keratoconjunctivitis sicca with ocular staining score >= 3 (assuming the patient is not currently using daily eye drops for glaucoma and has not had corneal surgery or cosmetic eyelid surgery in the previous five years)

Serological studies may detect the presence of autoantibodies SS-A and SS-B, and are commonly tested along with complete blood count with differential, ANA, rheumatoid (Rh) factor, ESR, and CRP.

Biomarkers present in early stages of Sjögren’s syndrome may allow for earlier detection of the disease.

The presence of anti-salivary protein-1 (SP1), anti-carbonic anhydrase 6 (CA6), and parotid secretory protein (PSP) have been linked to an earlier stage of disease than the presence of SSA and SSB.14

These biomarkers are utilized as part of the testing in the Sjö test (Bausch + Lomb) in which a simple finger prick test can be performed within a few minutes in a clinical setting.

Biopsy of the salivary glands has been considered the gold standard for confirming the diagnosis of Sjögren’s syndrome;15 however, salivary gland imaging via ultrasonography may also be useful in earlier stage detection and improving the diagnostic performance of the American classification criteria.16

Studies of human saliva show elevations in the levels of TH1, TH2, and TH17 cytokines,17 in addition to significantly altered protein signatures in Sjögren’s patients.18 This approach may eventually shift diagnosis to include saliva analysis versus serology or the more invasive biopsy methods.

Related: How pregnancy can affect Sjögren's ectopic lymphoid structures

Managing Sjögren’s patients

Patients with Sjögren’s syndrome require a collaborative effort by several subspecialists to appropriately manage the different aspects of the disease. Rheumatology, optometry, ophthalmology, and dentistry are important contributors to disease management.19

Because there is no cure for Sjögren’s syndrome, primary goals for these providers are to reduce symptoms of exocrinopathy and to minimize damage to the organ systems supported by the secretory glands as well as those affected by extraglandular disease.

Rheumatologists employ several different systemic medications with varying effects, guided by the organ system involved as well as the severity of disease. Hydroxychloroquine and methotrexate are two of the more common medications utilized for pain management, along with prednisone.19

Management of fatigue and other aspects of organ system involvement are also addressed by rheumatology.

 

Ophthalmic care involves aggressive management of dry eye, a hallmark symptom due to the primary involvement of the lacrimal gland. A workup involving examination and quantification of symptoms with a standardized dry eye symptoms questionnaire such as the Ocular Surface Disease Index (OSDI)20 may be combined with objective findings and measurement of the components of the tears and ocular surface.

Standard diagnostic techniques involve quantification of tear production as a means of assessing lacrimal gland function via Schirmer’s tests, as well as monitoring integrity of the cornea and conjunctival epithelium via vital dye staining.

Treatment varies depending on severity, but consists of artificial tears and more viscous lubricants.

As an autoimmune disorder, the impact of inflammation and its elevated role in progressive ocular surface disease stresses the importance of anti-inflammatory agents such as cyclosporine-A and topical steroids in long term management strategies.

Also, with advancing disease, nutritional support such as autologous serum to maintain ocular surface health becomes increasingly likely. Punctual occlusion or cautery may also be performed as secretory capacity diminishes.

Oral care significantly helps Sjögren’s syndrome patients. Sjögren’s syndrome patients have increased dental caries, tooth extractions, and dental costs.21 The use of secretogogues such as pilocarpine and cevimeline and salivary stimulation via gum-chewing and lozenges are often employed by dental care providers in an attempt to improve salivary function, and potentially reduce the chances of tooth decay. 

More from Dr. Hauswirth

References

1. Sjögren’s Syndrome Foundation. Available at: www.sjogrens.org. Accessed 07/09/16.

2. Beckman KA, Luchs J, Milner MS. Making the diagnosis of Sjogren’s syndrome in patients with dry eye. Clin Ophthalmol. 2015 Dec 24;10:43-53.

3. Patel R, Shahane A. The epidemiology of Sjögren’s syndrome. Clin Epidemiol. 2014 Jul 30;6:247-55

4. Baldini C, Pepe P, Quartuccio L, Priori R, Bartoloni E, Alunno A, Gattamelata A, Maset M, Modesti M, Tavoni A, De Vita S, Gerli R, Valesini G, Bombardieri S.. Primary Sjogren’s syndrome as a multi-organ disease: impact of the serological profile on the clinical presentation of the disease in a large cohort of Italian patients. Rheumatology (Oxford). 2014 May;53(5):839-44.

5. Solans-Laque R, Lopez-Hernandez A, Bosch-Gil JA, Palacios A, Campillo M, Vilardell-Tarres M. Risk, predictors, and clinical characteristics of lymphoma development in primary Sjogren’s syndrome. Semin Arthritis Rheum. 2011 Dec;41(3):415-23.

6. Palm O, Garen T, Berge Enger T, Jensen JL, Lund MB, Aaløkken TM, Gran JT. Clinical pulmonary involvement in primary Sjogren’s syndrome: prevalence, quality of life and mortality – a retrospective study based on registry data. Rheumatology (Oxford). 2013 Jan;52(1):173-9.

7. Lessard CJ, Li H, Adrianto I, et al. Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjogren’s syndrome. Nat Genet. 2013 Nov;45(11):1284-92.

8. Li Y, Zhang K, Chen H, et al. A genome-wide association study in Han Chinese identifies a susceptibility locus for primary Sjogren’s syndrome at 7q11.23. Nat Genet. 2013 Nov;45(11):1361-5.

9. Routsias JG, Tzioufas AG.  Autoimmune response and target autoantigens in Sjogren’s syndrome. Eur J Clin Invest. 2010 Nov;40(11):1026-36.

10. Salomonsson S, Jonsson MV, Skarstein K, Brokstad KA, Hjelmstrom P, Wahren-Herlenius M, Jonsson R.  Cellular basis of ectopic germinal center formation and autoantibody production in the target organ of patients with Sjogren’s syndrome.  Arthritis Rheum. 2003 Nov;48(11):3187-201.

11. Szabo K, Papp G, Dezso B, Zeher M. The histopathology of labial salivary glands in primary Sjogren’s syndrome: focusing on helper T cells in the inflammatory infiltrates. Mediators Inflamm. 2014;2014:631787.

12. Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, Daniels TE, Fox PC, Fox RI, Kassan SS, Pillemer SR, Talal N, Weisman MH; European Study Group on Classification Criteria for Sjögren's Syndrome. Classification criteria for Sjogren’s syndrome: a revised version of the European criteria proposed by the American-European consensus group. Ann Rheum Dis. 2002 Jun;61(6):554-8.

13. Shiboski SC, Shiboski CH, Criswell L, Baer A, Challacombe S, Lanfranchi H, Schiødt M, Umehara H, Vivino F, Zhao Y, Dong Y, Greenspan D, Heidenreich AM, Helin P, Kirkham B, Kitagawa K, Larkin G, Li M, Lietman T, Lindegaard J, McNamara N, Sack K, Shirlaw P, Sugai S, Vollenweider C, Whitcher J, Wu A, Zhang S, Zhang W, Greenspan J, Daniels T; Sjögren's International Collaborative Clinical Alliance (SICCA) Research Groups. American College of Rheumatology classification criteria for Sjogren’s syndrome: a data-driven, expert consensus approach in the Sjogren’s International Collaborative clinical alliance cohort. Arthritis Care Res (Hoboken). 2012 Apr;64(4):475-87.

14. Suresh L, Malyavantham K, Shen L, Ambrus JL., Jr. Investigation of novel autoantibodies in Sjogren’s syndrome utilizing Sera from the Sjogren’s international collaborative clinical alliance cohort. BMC Ophthalmol. 2015 Apr 10;15:38.

15. Kassan SS, Moutsopolous HM. Clinical manifestations and early diagnosis of Sjögren syndrome. Arch Intern Med. 2004 Jun 28;164(12):1275-84.

16. Cornec D, Jousse-Joulin S, Marhadour T, et al. Salivary gland ultrasonography improves the diagnostic performance of the 2012 American College of Rheumatology classification criteria for Sjögren’s syndrome. Rheumatology (Oxford). 2014 Sep;53(9):1604-7.

17. Ohyama K, Moriyama M, Hayashida JN, Tanaka A, Maehara T, Ieda S, Furukawa S, Ohta M, Imabayashi Y, Nakamura S. Saliva as a potential tool for diagnosis of dry mouth including Sjögren’s syndrome. Oral Dis. 2015 Mar;21(2):224-31.

18. Katsiougiannis S, Wong DT. The proteomics of saliva in Sjögren’s syndrome. Rheum Dis Clin North Am. 2016 Aug;42(3):449-56

19. Vivino FB, Carsons SE, Foulks G, Daniels TE, Parke A, Brennan MT, Forstot SL, Scofield RH, Hammitt KM. New treatment guidelines for Sjögren’s disease. Rheum Dis Clin North Am. 2016 Aug;42(3):531-51.

20. Walt JG, Rowe MM, Stern KL. Evaluating the functional impact of dry eye: the Ocular Surface Disease Index [abstract]. Drug Inf J. 1997;31:1436.

21. Christensen LB, Petersen PE, Thorn JJ, Schiødt M. Dental caries and dental health behaviors of patients with primary Sjögren syndrome. Acta Odontol Scand. 2001 Jun;59(3):116-20.