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Sjögren’s syndrome (SjS)

Systemic autoimmune disease that primarily affects the exocrine glands (mainly the salivary and lacrimal glands) and results in the severe dryness of mucosal surfaces, principally in the mouth and eyes.

Introduction

Systemic autoimmune disease that primarily affects the exocrine glands (mainly the salivary and lacrimal glands) and results in the severe dryness of mucosal surfaces, principally in the mouth and eyes.

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History

41572_2016_article_bfnrdp201647_fig1_html
Milestones in the history of SjS compressed in 100 years (1882–1982 | Brito-Zerón, P., Baldini, C., Bootsma, H., Bowman, S. J., Jonsson, R., Mariette, X., … Ramos-Casals, M. (2016). Sjögren syndrome. Nature Reviews Disease Primers, 2(1), 16047. https://doi.org/10.1038/nrdp.2016.47

The first recorded ocular findings in SS were made by Dr W.B. Hadden in 1888 who noted the association of dry eyes with dry mouth and filamentary keratitis. Hadden introduced the term xerostomia. Johann Mikulicz described the disorder in 1892. Mikulicz’s patient was a 42-year-old farmer with bilateral parotid and lacrimal gland enlargement associated with a small round cell infiltrate. At autopsy, the swollen lacrimal, submandibular, and parotid glands were studied histologically by Mikulicz who described mononuclear infiltration of the lacrimal and salivary glands. This was the first description of what we now refer to as SS. Subsequently, the term Mikulicz syndrome was used to refer to swelling of the lacrimal and parotid glands due to a variety of causes (i.e., tuberculosis, other infections, sarcoidosis, and lymphoma) and evidently this is a misnomer. In fact, Mikulicz syndrome, Mikulicz disease, and SS are synonyms. In 1925, Gougerot, a French ophthalmologist, described the association of lacrimal gland hypofunction and filamentary keratitis. In 1933, a Swedish ophthalmologist, Henrik Sjögren, wrote the most comprehensive article on the subject and referred to the dry eye condition as keratoconjunctivitis sicca (KCS). He described clinical and histologic findings in 19 women, 13 of whom had probable rheumatoid arthritis (RA), with dry mouth and dry eyes. In 1936, Duke Elder honored Sjögren by naming the disease SS. In 1953, Morgan and Castleman presented a case study of a patient with SS and rekindled interest in the condition originally known as “Mikulicz’s disease.” Subsequently, these patients have been termed SS, whereas the term Mikulicz is still occasionally used to refer to the lymphoepithelial islands seen on glandular biopsy. The clinical features of the disease just summarized and as we currently recognize it in its florid form were outlined in 1956 by Bloch.


Classification

  • Primary SS (pSS) “Sicca syndrome” (characteristic decrease in tears and saliva)
  • Secondary SS: Appears in the setting of another autoimmune diseases:
    • Systemic lupus erythematosus (15–36%)
    • Rheumatoid arthritis (20–32%)
    • Limited/progressive systemic sclerosis (11–24%)
Polyautoimmunity in Sjögren’s syndrome: SS has been described in association with a large variety of both organ-specific and systemic ADs including autoimmune thyroid disease (AITD), RA, SLE, SSc, autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), etc. | AIH: autoimmune hepatitis; AITD: autoimmune thyroid disease; MS: multiple sclerosis; PBC: primary biliary cirrhosis; RA: rheumatoid arthritis; SLE: systemic lupus erythematosus; SSc: systemic sclerosis; SS: Sjögren’s syndrome | Sarmiento-Monroy JC, Mantilla RD, Rojas-Villarraga A, et al. Sjögren’s syndrome. In: Anaya JM, Shoenfeld Y, Rojas-Villarraga A, et al., editors. Autoimmunity: From Bench to Bedside [Internet]. Bogota (Colombia): El Rosario University Press; 2013 Jul 18. Chapter 28. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459485/

Aetiology

Typically presents in middle-aged women as dryness of various body surfaces

Fourth-stage-model for the pathophysiology of Sjögren’s syndrome: Aetiology of SS is multifactorial, in which a mosaic of predisposing and stochastic factors play in concert for the induction of loss tolerance and subsequent organ damage. The pre-clinical stage is characterized by the presence of autoantibodies in serum before the clinical onset, as well as pro-inflammatory markers and lymphocytic infiltrates in salivary glands. The clinical-stage has a broad spectrum of subphenotypes which can influence the outcome of patients with Sjögren’s syndrome. Note that familial autoimmunity corresponds to the presence of different autoimmune diseases in a nuclear family. | AD: autoimmune disease; AITD: autoimmune thyroid disease; CMV: cytomegalovirus; EBV: Epstein-Barr virus; HCV: hepatitis C virus; MHC: major histocompatibility complex; RA: rheumatoid arthritis; RF: rheumatoid factor; SLE: systemic lupus erythematosus; SS: Sjögren’s syndrome; SSc: systemic sclerosis; TCR: T Cell receptor. | Sarmiento-Monroy JC, Mantilla RD, Rojas-Villarraga A, et al. Sjögren’s syndrome. In: Anaya JM, Shoenfeld Y, Rojas-Villarraga A, et al., editors. Autoimmunity: From Bench to Bedside [Internet]. Bogota (Colombia): El Rosario University Press; 2013 Jul 18. Chapter 28. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459485/

Pathophysiology

Characterized by peri-epithelial lymphocytic infiltration of the affected tissue or the deposition of the immune complex

Sequence of physiopathological mechanisms in Sjögren’s syndrome development: In genetically predisposed individuals, a trigger factor (most probably an epitheliotropic virus), activates the exocrine glands’ epithelium. This leads to the recruitment, activation and expansion of lymphocytes. Immunologically-activated or apoptotic glandular epithelial cells that expose autoantigens might drive autoimmune-mediated tissue injury. Alterations in several immune mediators, such as up-regulation of type I interferon-regulated genes, abnormal expression of B-cell-activating factor and activation of the interleukin-23–type 17 T-helper cell pathway, might play a role. Extension of the pathological process that affects the exocrine glands into periepithelial and extraepithelial tissue can cause a considerable percentage of patients to exhibit systemic findings. Histologically normal MSG biopsy is shown in frame A; in comparison, a MSG biopsy from a SS patient is depicted in frame B, which shows lymphocytic infiltrates in the central region of the lobule. Frame C is a normal salivary gland biopsy. Frames D, E, F and G are from a patient with SS. Frames F and G show high endothelial venules containing red blood cells and lymphocytes migrating into the gland. | Ab: antibodies; AOD: age at onset of disease; APCs: antigen-presenting cells; AQP5: aquaporin 5; BAFF: B cell-activating factor; CXCR5: C-X-C chemokine receptor type 5; DCs: dendritic cells; EBV: Epstein-Barr virus; GEC: glandular epithelial cells; IRF: interferon regulatory factor; MMPs: matrix metalloproteinases; NO: nitric oxide; STAT4: signal transducer and activator of transcription 4; TIMPs: tissue inhibitors of metalloproteinases; TLRs: Toll-like receptors. | Photomicrographs of the MSG biopsies: Goicovich et al. (207). | Sarmiento-Monroy JC, Mantilla RD, Rojas-Villarraga A, et al. Sjögren’s syndrome. In: Anaya JM, Shoenfeld Y, Rojas-Villarraga A, et al., editors. Autoimmunity: From Bench to Bedside [Internet]. Bogota (Colombia): El Rosario University Press; 2013 Jul 18. Chapter 28. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459485/

Characteristic feature:

  • Salivary & lacrimal glands:
    • Progressive lymphocytic infiltration
    • Acinar cell destruction
    • Proliferation of duct epithelium

Clinical features

Wide variety of presentations, ranging from the local involvement of exocrine glands with keratoconjunctivitis sicca and xerostomia (the leading signs of the disease) to the systemic, extraglandular involvement of multiple organs

Sicca symptoms:

Hallmark manifestation and M/C manifestation of Sjögren’s syndrome, with up to 98% of cases of the disease which may also present with various organ manifestations.
  • Keratoconjunctivitis sicca (KCS) (dry conjunctiva & cornea) (5-35% cases): Foreign-body sensation, burning/soreness of eyes and increased sensitivity to light
  • Xerostomia (dry mouth) (20% cases) : Difficulties talking for extended periods and while chewing/insalivating dry food
  • Nocturnal cough
  • Dry cough
  • Episodic/chronic bilateral parotid gland swelling (34% cases)
primary-sjogrens-syndrome-pathogenesis-clinical-findings
The Calgary Guide | http://calgaryguide.ucalgary.ca/

Extraglandular manifestations:

  • Non-erosive polyarthritis (50% cases, M/C extraglandular manifestation)
  • Pulmonary involvement (9–12%): Normally after many years of disease activity
    • Interstitial lung disease
    • Follicular bronchiolitis
  • Cutaneous lesions (10%):
    • Small & medium vessels vasculitis of lower limbs
    • Other lesions: Annular erythema, urticarial vasculitis, or hypergammaglobulinemic purpura
  • Renal involvement (5%):
    • Distal renal tubular acidosis (RTA type 1) with hypokalemic muscular hypotonia
    • Glomerulonephritis (rare)
  • CNS manifestations:
    • Sensory neuropathy (10–25%)
    • Neuromyelitis optica spectrum disorders (NMOSD)
Clinical spectrum of Sjögren’s syndrome: SS has a wide clinical spectrum which extends from benign local exocrinopathy to systemic disorder that affects parenchymal organs. It may also be associated with lesions due to immune complex hyperproduction and vasculitic involvement (e.g., purpura, peripheral neuropathy, glomerulonephritis). In some patients, SS could evolve to malignat lymphoma | AD: autoimmune disease; AIH: autoimmune hepatitis; AITD: autoimmune thyroid disease; CHB: congenital heart block; CNS: central nervous system; CV: cardiovascular; GI: gastrointestinal; GMN: glomerulonephritis; G-T: genital tract; L-T: laryngo-tracheal; MALT: mucosal-associated lymphoid tissue; Ph-O: pharyngo-oesopheal; PBC: primary biliary cirrhosis; PNS: peripheral nervous system; RA: rheumatoid arthritis; SLE: systemic lupus erythematosus; SS: Sjögren’s syndrome; SSc: systemic sclerosis. | Sarmiento-Monroy JC, Mantilla RD, Rojas-Villarraga A, et al. Sjögren’s syndrome. In: Anaya JM, Shoenfeld Y, Rojas-Villarraga A, et al., editors. Autoimmunity: From Bench to Bedside [Internet]. Bogota (Colombia): El Rosario University Press; 2013 Jul 18. Chapter 28. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459485/


Diagnosis

There is no sign, symptom, or test that is unique to this syndrome. The diagnosis of SS is based on the combination of sicca symptoms and the presence of the autoimmune phenomena characterized by the activation of T and/or B cells.

American-European Consensus Group (AECG) criteria:

Revised in 2002 in in a joint effort by the major societies, ACR (American College of Rheumatology) and EULAR (European League Against Rheumatism)
  1. Ocular staining score (≥ 3)
  2. Biopsy of salivary gland (GOLD STANDARD): Lymphocytic sialadenitis
  3. Positive ANA titre:
    • Anti-SSA/Ro & Anti-SSB/La
Scheme illustrating the classification criteria (according to The American-European Consensus Group) for secondary Sjögren’s syndrome: Ocular objective tests: Schirmer’s I test (A) and ocular color score, eg, lissamine green (B). Oral objective tests: unstimulated salivary flow (C), salivary gland scintigraphy, and sialography-imaging test of the parotid glands. (D) showing foci of lymphocytes (arrows). | Histological image of the minor salivary glands (H&E; image courtesy: Professor Daniela Assis do Vale, Oral and Maxillofacial Pathology Department, School of Dentistry, University of Sao Paulo, Sao Paulo, Brazil | Pasoto, S. G., Adriano de Oliveira Martins, V., & Bonfa, E. (2019). Sjögren’s syndrome and systemic lupus erythematosus: links and risks. Open access rheumatology : research and reviews, 11, 33–45. https://doi.org/10.2147/OARRR.S167783

Sjögren’s International Collaborative Clinical Alliance (SICCA) criteria.

Based entirely on objective measures
Sicca assessment in Sjögren’s syndrome | MSG: minor salivary gland; SICCA-OSS: Sjögren’s international Collaborative Clinica Alliance Ocular Staining Score. | Sarmiento-Monroy JC, Mantilla RD, Rojas-Villarraga A, et al. Sjögren’s syndrome. In: Anaya JM, Shoenfeld Y, Rojas-Villarraga A, et al., editors. Autoimmunity: From Bench to Bedside [Internet]. Bogota (Colombia): El Rosario University Press; 2013 Jul 18. Chapter 28. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459485/

Schirmer’s test:

schirmertest

Autoantibody markers:

SS is characterized by a strong polyclonal B cell activation leading to chronic hypergammaglobulinemia, higher levels of ß2 microglobulinemia, and concomitant presence of a variety of circulating organ specific and non-specific autoantibodies
  • Rheumatoid factor (antibody reactive with self IgG) (75%)
    • Regardless of coexisting rheumatoid arthritis
  • Anti-nuclear antibodies (ANAs):
    • Anti-Ro/SSA (50–70% cases)
    • Anti-La/SSB antibodies (30–60% cases, more specific)
  • Other autoantibodies:
    • Anti-centromere antibodies (ACA)
    • Rare: Anti-Ki/SL, anti-Ku, and anti-p80 coilin antibodies
Antinuclear antibodies test (indirect immunofluorescence on HEp-2 cells) showing the nuclear fine speckled pattern (A). Illustrative image of anti-Ro (SSA) and anti-La (SSB) antibodies detected by counterimmunoelectrophoresis (B). 1, 2, 6, 7: negative serum samples; 3, 4: serum samples positive for anti-Ro (SSA) and anti-La (SSB); 5: serum sample positive for other reactivity (anti-U1RNP). | Pasoto, S. G., Adriano de Oliveira Martins, V., & Bonfa, E. (2019). Sjögren’s syndrome and systemic lupus erythematosus: links and risks. Open access rheumatology : research and reviews, 11, 33–45. https://doi.org/10.2147/OARRR.S167783

MSG biopsy:

  • Focal lymphocytic infiltration in otherwise normal-appearing glandular acini (histological hallmark)
Histopathologic image of focal lymphoid infiltration in the minor salivary gland associated with Sjögren syndrome. Lip biopsy. H & E stain. | KGH assumed (based on copyright claims). – CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=513949

Differential diagnosis:

While some of these are defined as SS exclusion criteria, others are considered mimics of SS symptoms such as trauma and scarring.
Approach of patient with sicca syndrome and differential diagnosis | ACR: American College of Rheumatology; AECG: American-European Consensus Group; AIDS: acquired immunodeficiency syndrome; CRP: C reactive protein; ESR: erythrocyte sedimentation rate; GVHD: graft-versus host disease; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; HRCT: high resolution computed tomography; MS: multiple sclerosis; MSG: Minor salivary gland; SSRI: selective serotonin reuptake inhibitor; TNFi: tumour necrosis factor inhibitors. | Sarmiento-Monroy JC, Mantilla RD, Rojas-Villarraga A, et al. Sjögren’s syndrome. In: Anaya JM, Shoenfeld Y, Rojas-Villarraga A, et al., editors. Autoimmunity: From Bench to Bedside [Internet]. Bogota (Colombia): El Rosario University Press; 2013 Jul 18. Chapter 28. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459485/

Management

Education, prevention, substitution, stimulation (sicca syndrome), and immunointervention (organ involvement) are the steps to follow when treating patients with SS.

Management of sicca syndrome:

While symptomatic treatment with saliva substitutes and eye drops are effective in the relief of sicca syndrome complaints, immunomodulatory and immunosuppressive agents are used in patients with severe EGM and should be tailored to the specific organ involved
Therapeutic algorithm for the treatment of sicca features in Sjögren’s syndrome: First step in the management of sicca symptoms always consists of topical therapies; systemic therapies represent the next step if topical interventions are not effective. Patients with acceptable salivary flow outputs might have poor tolerance of saliva substitutes owing to the ‘sticky’ feeling they can cause; in these patients, mechanical and/or gustatory stimulation (sugar-free candies and chewing gum) might be a useful first-line therapy before intervention with muscarinic receptor agonists (pilocarpine or cevimeline) is considered. Limited evidence is available for the treatment of sicca features other than those affecting the eyes and mouth in primary SS. Lacrimal punctal occlusion using plugs or thermal cautery can be useful in refractory and/or severe cases. | ENT: ear, nose and throat; SS: Sjögren’s syndrome. | Ramos-Casals M, Brito-Zerón P, Sisó-Almirall A, Bosch X, Tzioufas AG. Topical and systemic medications for the treatment of primary Sjögren’s syndrome. Nat Rev Rheumatol. 2012;8:399–411.

Management of extra-glandular manifestations :

Systemic therapy should be tailored to the organ affected and the severity. All the drugs currently used in the treatment of ADs have also been administered to patients with SS in order to improve sicca symptoms and modify the immune inflammatory pathways involved in disease progression.
Therapeutic algorithm for treatment of extra-glandular manifestations in Sjögren’s syndrome: Corticosteroids should be used at the minimum dose and length of time necessary. No data are available on immunosuppressive maintenance therapy; thus, regimens similar to those used in other autoimmune diseases (systemic lupus erythematosus, vasculitis) are recommended. | CNS: central nervous system; IVIg: intravenous immunoglobulin; SS: Sjögren’s syndrome. | Ramos-Casals M, Brito-Zerón P, Sisó-Almirall A, Bosch X, Tzioufas AG. Topical and systemic medications for the treatment of primary Sjögren’s syndrome. Nat Rev Rheumatol. 2012;8:399–411.

Summary

41572_2016_article_bfnrdp201648_figa_html
Brito-Zerón, P., Baldini, C., Bootsma, H., Bowman, S. J., Jonsson, R., Mariette, X., … Ramos-Casals, M. (2016). Sjögren syndrome. Nature Reviews Disease Primers, 2(1), 16047. https://doi.org/10.1038/nrdp.2016.47

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