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Sjogren Syndrome




Epidemiology: 9:1 female; age : 50 yr 
0.3-1 person / 1000 person prevalance

Pathogenesis: Harrisons'
Sjögren’s syndrome is characterized by both lymphocytic infiltrations of the exocrine glands and B lymphocyte hyperreactivity. An oligomonoclonal B cell process, which is characterized by cryoprecipitate monoclonal immunoglobulins (IgMκ or IgAκ) with rheumatoid factor activity, is evident in up to 10% of patients.

Ro/SS-A autoantigen consists of two polypeptides (52 and 60 kDa, respectively) in conjunction with cytoplasmic RNAs, whereas the 48-kDa La/SS-B protein is bound to RNA III polymerase transcripts. 


The major infiltrating cells in the affected exocrine glands are activated T lymphocytes in mild lesions, whereas B cells prevail in severe lesions. Macrophages and dendritic cells are also found. 
The number of macrophages positive for interleukin (IL) 18 has been shown to be associated with parotid gland enlargement and low serum levels of the C4 component of complement, both of which are adverse predictors for lymphoma development.

Ductal and acinar epithelial cells appear to play a significant role in the initiation and perpetuation of autoimmune injury. These cells (1) express costimulatory molecules, and inappropriately the intracellular autoantigens Ro/SS-A and La/SS-B on their membranes, acquiring the capacity to provide signals essential for lymphocytic activation; (2) produce proinflammatory cytokines and lymphocyte attracting chemokines necessary for sustaining the autoimmune lesion and allowing the formation of ectopic germinal centers, a finding predicting lymphoma development; and (3) express functional receptors of innate immunity, particularly Toll-like receptors (TLRs) 3, 7, and 9, molecules which may account for the initiation of the autoimmune reactivity.



Clinical Features: 


Best way to understand clinical features;
  1. Non-specific symptoms of Fatigue, Arthralgia, Raynaud's
  2. Lymphocytic infiltration of the exocrine gland (dry mouth, dry eyes)
  3. Lymphocytic infiltration of epithelial cells beyond exocrine glands (Peri epithelial lesions of Liver, Kidney, Lung)
  4. B lymphocyte hyperreactivity (Immune complex-mediated illness of Kidney, Lung, Nerve). 
  5. B cell lymphoma - mostly B cell NHL , MALT is the most common type

Hallmark: Exocrinopathy (dry eyes, dry mouth), Fatigue, Joint pain (Triad present in 80 %) patients
Primary SS: Isolation or in association with organ-specific autoimmune presentation (thyroiditis, PBC, Cholangitis)
Secondary SS / Associated SS: In association with RA, SLE, Scleroderma, DM

Systemic complications present in 30-40% of patients (double the risk of B cell lymphoma) may often provide the first clue to the diagnosis 
B cell lymphoma present in 5-10 % life time risk in patients with Primary SS. Risk of B cell lymphoma is 15-20 times higher than in general population. This is due to chronic  



Clinical Features: Harrisons'
  • Glandular Features: Xerostomia, Keratoconjunctivitis sicca, Parotid gland involvement, vaginal dryness, dental caries may be other clues 
  • Extra glandular features -- seen in 1/3rd patients but rare in patients with associated RA : 5 features 
    • Arthritis 
    • Raynaud's
    • Renal Tubular Acidosis 
    • Vasculitis 
    • Lymphoma

Clinical ManifestationPercentRemarks
Non-Specific
Fatigability/Myalgias25Fibromyalgia
Arthralgias/Arthritis60Usually non-erosive, leading to Jaccoud’s arthropathy
Raynaud’s phenomenon37In one-third of patients, precedes sicca manifestations
Peri-Epithelial
Lung involvement14Small airway disease/lymphocyte interstitial pneumonitis
Kidney involvement9Interstitial kidney disease is usually asymptomatic
Liver involvement6Primary biliary cirrhosis stage I
Immune-Complex mediated
Small vessel vasculitis Purpura, urticarial lesions
Peripheral neuropathy2Polyneuropathy, either sensory or sensorimotor
Glomerulonephritis Membranoproliferative
Lymphoma
Lymphoma6Glandular MALTa lymphoma is the most common


Pediatric Primary Sjogren Syndrome
  • Parotitis is often a presentation, not in a part of classification criteria 
  • Sicca syndrome is not a prominent feature, suggesting a possibility that organ damage has not fully occurred yet
  • SSA antibodies may not be present in younger patients. 
  • SSA positive, USG, Parotitis may help classify the majority of the diagnosis 
  • SSA negative patients had RF and Hypergammaglobuminemia

Diagnosis: 
Often clinical based on the classic triad of clinical presentation
Requires immunological proof: Anti-SSA ab, or focal lymphocytic sialoadenitis on biopsy of labial salivary gland 

Systemic 


DDx: More common condition with same presentations: Fibromyalgia and other chronic pain syndromes 
SSA-negative patients can also meet the classification criteria. Note, half of the SSA negative adults patients have anti-centromere antibody



Diagnosis: Harrisons'
TABLE 354-5
Revised International Classification Criteria for Sjögren’s Syndrome,b,c

  1. Ocular symptoms: a positive response to at least one of three validated questions.

    1. Have you had daily, persistent, troublesome dry eyes for >3 months?

    2. Do you have a recurrent sensation of sand or gravel in the eyes?

    3. Do you use tear substitutes more than three times a day?

  2. Oral symptoms: a positive response to at least one of three validated questions.

    1. Have you had a daily feeling of dry mouth for >3 months?

    2. Have you had recurrent or persistently swollen salivary glands as an adult?

    3. Do you frequently drink liquids to aid in swallowing dry foods?

  3. Ocular signs: objective evidence of ocular involvement defined as a positive result to at least one of the following two tests:

    1. Shirmer’s I test, performed without anesthesia (≤5 mm in 5 min)

    2. Rose Bengal score or other ocular dye score (≥4 according to van Bijsterveld’s scoring system)

  4. Histopathology: In minor salivary glands focal lymphocytic sialoadenitis, with a focus score ≥1.

  5. Salivary gland involvement: objective evidence of salivary gland involvement defined by a positive result to at least one of the following diagnostic tests:

    1. Unstimulated whole salivary flow (≤1.5 mL in 15 min)

    2. Parotid sialography

    3. Salivary scintigraphy

  6. Antibodies in the serum to Ro/SS-A or La/SS-B antigens, or both.

aExclusion criteria: past head and neck radiation treatment, hepatitis C infection, AIDS, preexisting lymphoma, sarcoidosis, graft-versus-host disease, use of anticholinergic drugs. bPrimary Sjögren’s syndrome: any four of the six items, as long as item IV (histopathology) or VI (serology) is positive; or any three of the four objective-criteria items (III, IV, V, VI). cIn patients with a potentially associated disease (e.g., another well-defined connective tissue disease), the presence of item I or item II plus any two from among items III, IV, and V may be considered indicative of secondary Sjögren’s syndrome.

RULE OUT 7 things: GRAL-CSM
GVHD
Radiation
AIDS
Lymphoma 
Hepatitis C - C 
Sarcoidosis 
Meds 


Imaging: Serial imaging with USG to look for exocrine glands (parotid and sub-mandibular) could be done but is not a part of the classification criteria. 
Hypoechoic and anechoic areas. In some areas, hypervascularization may be seen as well. 

Measuring Disease Activity. 
2 Disease activity measuring index has been validated. 

ERLAR SS patient-reported index: mean of 3 visual indexes including, mouth and eye dryness, fatigue and pain

EULAR SS DAI: is used to assess systemic complications of the disease in 12 domains. Used only in the clinical trial. 
  • First used in Bliss Study
Every 1-2 yr monitoring or every 6 months in high-risk patients: CBC, SPEP, RF, C3, C4, RF, Cryoglobulin for lymphoma monitoring. However, no data to support this practice. PET may be of help. A tissue biopsy is needed. 

Treatment:
  • HCQ in SS study previously was negative. 
  • Sjögren's syndrome Lancet 2005
  • Dryness: 
    • Muscarinic agonists. Pilocarpine HCL (5 mg better than placebo but no benefit of 2.5 mg compared to placebo) 61 vs 31% for dry mouth, 42% vs 26 % for dry eyes in clinical training, and subalamine ? HCL  ; SE: Sweating, increase dose gradually
    • Topical cyclosporine eye drops: 0.05 - 0.1 % drops 
  • Regular dental exam and oral hygiene
  • Tylenol for pain
  • NSAIDs for joint pain
  • Gabapentin, Pregabalin Duloxetine for Neuropathic pain
  • No drug effective for Fatigue 
  • No immunomodulatory drugs have shown benefit 
  • Severe organ involvement: Use similar to that in SLE although only HCQ is the only drug used in RCT. RCT failed to show any benefit in the primary outcome of 30% or more of 2 of 3 patient-reported outcomes. However, HCQ showed benefits in an open-label study. However, patients in RCT had lower disease severity at entry.  
  • Few biologics have been studied with no benefit seen in RCT.  
    • Infliximab and Etanercept failed to show any benefit in the composite primary outcome of the visual analog scale of 3 main symptoms
    • 4 RCT has studied Rituximab. 
      • Trial 1: 17 patient. 2 doses of Rituximab. Benefit seen. 
      • Trial 2: 30 patients. The primary endpoint of stimulated salivary flow and patient-reported improvement showed improvement. 
      • Trial 3: 120 patients. No benefit was noted for the composite endpoint of 2/4 endpoint (global disease, pain, fatigue, dryness) at 24 weeks. 
      • TRACTIS: 110 patients. NO benefit was noted in fatigue or dryness but less deterioration in dryness and salivary flow 
    • Bliss Study (small study): Belimumab
        • 2 Lymphoma
        • 1 Pneumococcal Meningitis 
        • Even though a small study, the first study with positive data 
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