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Sjogren Syndrome
Introduction
In the early 1900s, Swedish physician Henrik Sjögren (SHOW-gren) first described a group of women whose chronic arthritis was accompanied by dry eyes and dry mouth. Today, Rheumatologists know more about the syndrome that is named for Sjögren and—most significantly for patients—can offer advice about how to live with it.
Primary Sjogren syndrome is a systemic autoimmune disorder most commonly presenting with sicca symptoms. Sicca refers to dryness most often involving the eyes and mouth due to inflammation and resultant pathology of the lacrimal and salivary glands. Up to one-half of affected individuals also develop extra-glandular involvement implying the occurrence of signs and symptoms in organs distinct from the salivary and lacrimal glands including the joints, skin, lungs, gastrointestinal (GI) tract, nervous system, and kidneys. Sjogren syndrome frequently occurs in conjunction with other autoimmune disorders including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In this setting, authors will refer to it as secondary Sjogren or Sjogren-overlap syndrome. Therapies are directed toward replacing moisture at affected glandular sites and suppressing the autoimmune response locally as well as systemically.[1][2][3]
Etiology
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Etiology
As is the case with the majority of autoimmune disorders, the precise etiology of Sjogren syndrome is unknown. A genetic predisposition involving the major histocompatibility (MHC) locus is likely with individuals sharing haplotypes in the HLA-DQA_DQB_ region having an increased relative risk, although the diseases are described worldwide. These major histocompatibility haplotypes are hypothesized to result in an aberrant immune response in conjunction with certain environmental triggers. Laboratory studies, as well as some indirect epidemiologic evidence, implicates viruses, including Epstein-Barr virus (EBV) as participants in disease pathogenesis.[4][5]
Epidemiology
Sjogren syndrome is far from a rare disorder with an incidence approaching approximately one-half of that of rheumatoid arthritis (RA) or affecting 0.5% to 1.0% of the population.
Between 400,000 and 3.1 million adults have Sjögren's syndrome. This condition can affect people of any age, but symptoms usually appear between the ages of 45 and 55. About half of patients also have rheumatoid arthritis or other connective tissue diseases, such as lupus.
Sjogren has been reported worldwide in adults and more rarely in children, and there appears to be no racial, or geographic bias in incidence. The disorder, however, has a marked predilection for women and similar to SLE, the female:male ratio is approximately 9:1. The disease usually presents in middle age but may occur in children as well as the elderly.[6][7]
As there is no evidence-based standardized screening tool to decide which dry eye patients to refer for Sjogren syndrome workup, there is an underreferral of dry eye patients for Sjogren syndrome workups: hence there is continued underdiagnosis of the disease. [8]
Pathophysiology
The characteristic lesion of Sjogren syndrome is focal lymphocytic sialadenitis (FLS). FLS is a lesion of exocrine glands. Foci of lymphocyte-rich mononuclear cells infiltrate exocrine glandular tissue adjacent to blood vessels and excretory ducts. The foci are comprised predominantly of T lymphocytes. However, B lymphocytes, plasma cells, and other cell types are seen. With more severe disease the foci may become confluent. The infiltrating mononuclear cells, humoral factors such as antibodies and cytokines, or both are hypothesized to cause exocrine gland dysfunction resulting in diminished tear production by the lacrimal glands and diminished saliva production by salivary glands. Also, exocrine glands outside the head and neck may be involved resulting in skin, tracheobronchial and vaginal dryness as well as lung and kidney dysfunction. Rarely, malignant transformation of B lymphocytes can result in non-Hodgkin lymphoma. Immune complexes may deposit in skin, joints and other organs resulting in a systemic vasculitis.[9]
Histopathology
Biopsy of the minor salivary glands is the ideal test to confirm the diagnosis of Sjogren syndrome. The minor salivary glands are accessed by making an incision in the inner lip. However, a biopsy is not mandatory in all cases if the clinical and laboratory features are suggestive of the syndrome. The typical findings on a biopsy will reveal aggregates of more than 50 lymphocytes, some macrophages and plasma cells. CD4 cells are predominant, and about 10% of lymphocytes will be CD5 positive B cells that produce IgG and IgM antibodies.
History and Physical
The patient will often complain of a foreign body sensation in their eyes and a dry mouth. On eye exam, the absence of tears may be noted in the inferior conjunctival sac, and the eyes may appear injected. However, referral to an ophthalmologist is mandatory for a slit-lamp exam to be performed. This examination in the presence of vital dye staining is necessary to demonstrate KCS (keratoconjunctivitis sicca) which is the most characteristic ophthalmologic lesion of Sjogren. A Schirmer test will also help confirm ocular dryness. The mouth may appear parched, with a smooth tongue, and thin mucosae. Approximately 50% demonstrate enlarged parotid, and/or submandibular glands at some point. Extraglandular involvement often manifests in polyarthritis, lower extremity purpura, and/or evidence of peripheral neuropathy.
Evaluation
Evaluation of a patient with suspected Sjogren syndrome should include an evaluation of oral and ocular dryness and function. In addition to the history, this may include the performance of a Schirmer test, slit-lamp exam with vital dye staining, salivary flow rate, and/or nuclear scintigraphic evaluation of the salivary glandular function. Assessment of autoantibodies (ANA, RF, SS-A, and SS-B) should also be performed. Of these, SS-A is probably the most sensitive and specific antibody for Sjogren's but alone is not diagnostic since it may be present in other autoimmune disorders and may be absent in up to a third of Sjogren cases. The most specific single test is a minor salivary gland (lip) biopsy which will demonstrate FLS in positive specimens.[10][11][12]
Treatment / Management
Treatment of sicca symptoms involves:
- Dry eyes usually respond to artificial tears applied regularly during the day or to gels applied at night. We usually have patients use a preservative-free drop during the day and a preservative-free gel or ointment at night.
- Punctal occlusion with plugs or cauterization is frequently needed in more severe cases. Cauterization should only be performed after a trial of plugs to ensure the patient is not left with excessive tearing.
- Eye drops that reduce inflammation in the glands around the eyes, such as cyclosporine (Restasis) are used to increase tear production.
- Many patients are helped by serum tears which are derived from their own blood. Most eye centers now have the capability of making these for the patient.
- Drinking water, chewing gum, or using saliva substitutes may relieve dry mouth.
- Some patients benefit from using prescription medications that stimulate saliva flow, such as pilocarpine (Salagen) or cevimuline (Evoxac).
- If patients develop yeast infections, anti-fungal therapies may be used. Humidifiers and nasal saline irrigation may improve nasal dryness. Medications that reduce gastric acid (such as proton-pump inhibitors and H2 blockers) may lessen symptoms of acid reflux. Treatments may help relieve some of the dryness, but usually some dryness persists.
- The first approach to extra-glandular (systemic) major organ-system disease is oral/parenteral corticosteroids.
- Various DMARDs (methotrexate, azathioprine) have been successfully employed as steroid-sparing agents although none is specifically approved for Sjogren.
- Hydroxychloroquine is recommended to treat inflammatory polyarthritis. B cell depletion may have a role in certain severe extra-glandular manifestations (vasculitis). TNF-alpha inhibitors have not proved effective for Sjogren. [13][14][15] (A1)
Differential Diagnosis
- Sarcoidosis
- Rosacea
- Mumps
- Dehydration
- Use of medications- antidepressants, anticholinergics
- Mouth breathing
- Lymphoma
- Advanced age
- Parkinson disease
- Scleroderma
- Rheumatoid arthritis
- AIDS
- Lupus
Pearls and Other Issues
Primary Sjogren patients have an increased relative risk for the development of B-cell non-Hodgkins lymphoma. Many of these lymphomas are extranodal and may involve the salivary glands. Risk factors include persistent salivary gland swelling, enlarging lymph nodes, leukopenia, palpable purpura and low complement C4 at presentation. These patients need to be carefully monitored and referred for oncologic evaluation when appropriate. Current guidelines by the Sjorgen Syndrome Foundation recommend 1) palliation of symptoms, 2) minimizing complications, and 3) proper patient selection when selecting immunosuppressive treatment.
Biological Therapies are used to treat severe cases of Sjogren disease. Rituximab is an option for patients with keratoconjunctivitis sicca, vasculitis, xerostomia and severe parotid gland swelling. All patients on Rituximab must be closely monitored for tumor lysis syndrome (when patients have lymphoma), cytopenia, infusion reactions, hepatitis B reactivation and serious fungal, viral and bacterial infections.
Enhancing Healthcare Team Outcomes
Sjogren syndrome is a systemic disorder that affects many organs. There is no cure for the disorder. The management revolves around decreasing the morbidity of the symptoms. Besides physicians, both the pharmacist and nurse play a vital role in patient education.
- The patient should be educated on prevention of dental caries, using fluoride-containing toothpaste and using sugar-free chewing gums and lozenges to promote saliva production.
- For dry eyes, the pharmacists should educate the patient on changing the diet and eliminating medications that cause reduced secretions.
- In addition, the pharmacist should educate the patient on proper use of artificial tears and gels.
- Avoiding contact lenses, using warm compresses and seeing an ophthalmologist is the next step.
- Since these patients are also on a number of drugs to prevent arthritis pain, the pharmacist should educate the patient on compliance and what adverse reactions to anticipate.
- The patient should also be referred to a physical therapist to regain joint function and build on muscle strength.
- Finally, the disorder can affect mood and a referral to a mental health counselor may be required.[16][17][18] (Level III)
Outcomes
Mild Sjogren disease has a good prognosis but those with moderate to severe disease have a very poor quality of life. The dry mouth and eyes often cause irritable symptoms which are not well tolerated. In addition, many of these patients develop moderate to severe arthritis and ambulation can be difficult. With advancing age, as the function of the exocrine glands subsides, the symptoms also tend to worsen. In the long run, there is a risk that patients with Sjogren syndrome will develop a lymphoproliferative disorder which can lower the life expectancy.
Women with Sjogren syndrome are also at a high risk for developing complications during pregnancy. Premature deliveries and spontaneous abortions are not uncommon. Finally, patients with Sjogren syndrome who have antiphospholipid antibodies are at risk for developing vascular thrombotic disorders and fetal demise. [19][20][13](level V)
Media
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Sjogrens Parotid Contributed by Steven Carsons, MD
References
Kaneko Y. [Diagnostic (Classification) Criteria and Treatment Guidelines of Collagen-vascular Diseases: Hos to Use and Cautions on Applying Them for General Physicians. Topics: VII. Sjögren Syndrome]. Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine. 2015 Oct:104(10):2149-56 [PubMed PMID: 30160930]
Brito-Zerón P, Retamozo S, Ramos-Casals M. Phenotyping Sjögren's syndrome: towards a personalised management of the disease. Clinical and experimental rheumatology. 2018 May-Jun:36 Suppl 112(3):198-209 [PubMed PMID: 30156544]
Argyropoulou OD, Valentini E, Ferro F, Leone MC, Cafaro G, Bartoloni E, Baldini C. One year in review 2018: Sjögren's syndrome. Clinical and experimental rheumatology. 2018 May-Jun:36 Suppl 112(3):14-26 [PubMed PMID: 30156536]
Baer AN, Akpek EK, Alevizos I, 18-21 April 2018, Washington, DC, USA. 14th International Symposium on Sjögren's Syndrome. Clinical and experimental rheumatology. 2018 May-Jun:36 Suppl 112(3):241-255 [PubMed PMID: 30156551]
Kroese FGM, Haacke EA, Bombardieri M. The role of salivary gland histopathology in primary Sjögren's syndrome: promises and pitfalls. Clinical and experimental rheumatology. 2018 May-Jun:36 Suppl 112(3):222-233 [PubMed PMID: 30156550]
Kiadaliri AA, Mohammad AJ, Englund M. Hospitalizations due to systemic connective tissue diseases: Secular trends and regional disparities in Sweden, 1998-2016. International journal of rheumatic diseases. 2018 Nov:21(11):1900-1906. doi: 10.1111/1756-185X.13341. Epub 2018 Aug 30 [PubMed PMID: 30168267]
Alani H, Henty JR, Thompson NL, Jury E, Ciurtin C. Systematic review and meta-analysis of the epidemiology of polyautoimmunity in Sjögren's syndrome (secondary Sjögren's syndrome) focusing on autoimmune rheumatic diseases. Scandinavian journal of rheumatology. 2018 Mar:47(2):141-154. doi: 10.1080/03009742.2017.1324909. Epub 2017 Sep 20 [PubMed PMID: 28927315]
Level 1 (high-level) evidenceBunya VY, Fernandez KB, Ying GS, Massaro-Giordano M, Macchi I, Sulewski ME, Hammersmith KM, Nagra PK, Rapuano CJ, Orlin SE. Survey of Ophthalmologists Regarding Practice Patterns for Dry Eye and Sjogren Syndrome. Eye & contact lens. 2018 Nov:44 Suppl 2(Suppl 2):S196-S201. doi: 10.1097/ICL.0000000000000448. Epub [PubMed PMID: 29369232]
Level 3 (low-level) evidenceTzioufas AG, Goules AV. Limited efficacy of targeted treatments in Sjögren's syndrome: why? Clinical and experimental rheumatology. 2018 May-Jun:36 Suppl 112(3):27-28 [PubMed PMID: 29998826]
De Vita S, Gandolfo S, Zandonella Callegher S, Zabotti A, Quartuccio L. The evaluation of disease activity in Sjögren's syndrome based on the degree of MALT involvement: glandular swelling and cryoglobulinaemia compared to ESSDAI in a cohort study. Clinical and experimental rheumatology. 2018 May-Jun:36 Suppl 112(3):150-156 [PubMed PMID: 30156548]
Martel A, Coiffier G, Bleuzen A, Goasguen J, de Bandt M, Deligny C, Magnant J, Ferreira N, Diot E, Perdriger A, Maillot F. What is the best salivary gland ultrasonography scoring methods for the diagnosis of primary or secondary Sjögren's syndromes? Joint bone spine. 2019 Mar:86(2):211-217. doi: 10.1016/j.jbspin.2018.06.014. Epub 2018 Jul 24 [PubMed PMID: 30053612]
Baer AN, Walitt B. Update on Sjögren Syndrome and Other Causes of Sicca in Older Adults. Rheumatic diseases clinics of North America. 2018 Aug:44(3):419-436. doi: 10.1016/j.rdc.2018.03.002. Epub [PubMed PMID: 30001784]
Sumida T, Azuma N, Moriyama M, Takahashi H, Asashima H, Honda F, Abe S, Ono Y, Hirota T, Hirata S, Tanaka Y, Shimizu T, Nakamura H, Kawakami A, Sano H, Ogawa Y, Tsubota K, Ryo K, Saito I, Tanaka A, Nakamura S, Takamura E, Tanaka M, Suzuki K, Takeuchi T, Yamakawa N, Mimori T, Ohta A, Nishiyama S, Yoshihara T, Suzuki Y, Kawano M, Tomiita M, Tsuboi H. Clinical practice guideline for Sjögren's syndrome 2017. Modern rheumatology. 2018 May:28(3):383-408. doi: 10.1080/14397595.2018.1438093. Epub 2018 Mar 13 [PubMed PMID: 29409370]
Level 1 (high-level) evidenceSeror R, Mariette X. Guidelines for treatment of primary Sjögren's syndrome: a first useful stone but still much to do. Rheumatology (Oxford, England). 2017 Oct 1:56(10):1641-1642. doi: 10.1093/rheumatology/kex320. Epub [PubMed PMID: 28957571]
Price EJ, Rauz S, Tappuni AR, Sutcliffe N, Hackett KL, Barone F, Granata G, Ng WF, Fisher BA, Bombardieri M, Astorri E, Empson B, Larkin G, Crampton B, Bowman SJ, British Society for Rheumatology Standards, Guideline and Audit Working Group. The British Society for Rheumatology guideline for the management of adults with primary Sjögren's Syndrome. Rheumatology (Oxford, England). 2017 Oct 1:56(10):e24-e48. doi: 10.1093/rheumatology/kex166. Epub [PubMed PMID: 28957550]
López-Pintor RM, Fernández Castro M, Hernández G. Oral involvement in patients with primary Sjögren's syndrome. Multidisciplinary care by dentists and rheumatologists. Reumatologia clinica. 2015 Nov-Dec:11(6):387-94. doi: 10.1016/j.reuma.2015.03.010. Epub 2015 May 26 [PubMed PMID: 26022574]
Brito-Zerón P, Theander E, Baldini C, Seror R, Retamozo S, Quartuccio L, Bootsma H, Bowman SJ, Dörner T, Gottenberg JE, Mariette X, Bombardieri S, de Vita S, Mandl T, Ng WF, Kruize AA, Tzioufas A, Vitali C, Buyon J, Izmirly P, Fox R, Ramos-Casals M, Eular Sjögren Syndrome Task Force. Early diagnosis of primary Sjögren's syndrome: EULAR-SS task force clinical recommendations. Expert review of clinical immunology. 2016:12(2):137-56. doi: 10.1586/1744666X.2016.1109449. Epub 2015 Dec 22 [PubMed PMID: 26691952]
Milin M, Cornec D, Chastaing M, Griner V, Berrouiguet S, Nowak E, Marhadour T, Saraux A, Devauchelle-Pensec V. Sicca symptoms are associated with similar fatigue, anxiety, depression, and quality-of-life impairments in patients with and without primary Sjögren's syndrome. Joint bone spine. 2016 Dec:83(6):681-685. doi: 10.1016/j.jbspin.2015.10.005. Epub 2016 Jan 13 [PubMed PMID: 26774177]
Level 2 (mid-level) evidenceFlores-Chávez A, Kostov B, Solans R, Fraile G, Maure B, Feijoo-Massó C, Rascón FJ, Pérez-Alvarez R, Zamora-Pasadas M, García-Pérez A, Lopez-Dupla M, Duarte-Millán MÁ, Ripoll M, Fonseca-Aizpuru E, Guisado-Vasco P, Pinilla B, de-la-Red G, Chamorro AJ, Morcillo C, Fanlo P, Soto-Cárdenas MJ, Retamozo S, Ramos-Casals M, Brito-Zerón P, GEAS-SS SEMI Registry. Severe, life-threatening phenotype of primary Sjögren's syndrome: clinical characterisation and outcomes in 1580 patients (GEAS-SS Registry). Clinical and experimental rheumatology. 2018 May-Jun:36 Suppl 112(3):121-129 [PubMed PMID: 30156546]
Al Hamad A, Lodi G, Porter S, Fedele S, Mercadante V. Interventions for dry mouth and hyposalivation in Sjögren's syndrome: A systematic review and meta-analysis. Oral diseases. 2019 May:25(4):1027-1047. doi: 10.1111/odi.12952. Epub 2018 Sep 27 [PubMed PMID: 30086205]
Level 1 (high-level) evidenceBjörk A, Mofors J, Wahren-Herlenius M. Environmental factors in the pathogenesis of primary Sjögren's syndrome. Journal of internal medicine. 2020 May:287(5):475-492. doi: 10.1111/joim.13032. Epub 2020 Feb 27 [PubMed PMID: 32107824]
Lessard CJ, Li H, Adrianto I, Ice JA, Rasmussen A, Grundahl KM, Kelly JA, Dozmorov MG, Miceli-Richard C, Bowman S, Lester S, Eriksson P, Eloranta ML, Brun JG, Gøransson LG, Harboe E, Guthridge JM, Kaufman KM, Kvarnström M, Jazebi H, Cunninghame Graham DS, Grandits ME, Nazmul-Hossain AN, Patel K, Adler AJ, Maier-Moore JS, Farris AD, Brennan MT, Lessard JA, Chodosh J, Gopalakrishnan R, Hefner KS, Houston GD, Huang AJ, Hughes PJ, Lewis DM, Radfar L, Rohrer MD, Stone DU, Wren JD, Vyse TJ, Gaffney PM, James JA, Omdal R, Wahren-Herlenius M, Illei GG, Witte T, Jonsson R, Rischmueller M, Rönnblom L, Nordmark G, Ng WF, UK Primary Sjögren's Syndrome Registry, Mariette X, Anaya JM, Rhodus NL, Segal BM, Scofield RH, Montgomery CG, Harley JB, Sivils KL. Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren's syndrome. Nature genetics. 2013 Nov:45(11):1284-92. doi: 10.1038/ng.2792. Epub 2013 Oct 6 [PubMed PMID: 24097067]
Baldini C, Fulvio G, La Rocca G, Ferro F. Update on the pathophysiology and treatment of primary Sjögren syndrome. Nature reviews. Rheumatology. 2024 Aug:20(8):473-491. doi: 10.1038/s41584-024-01135-3. Epub 2024 Jul 9 [PubMed PMID: 38982205]