SJÖGREN’S SYNDROME (SS)

INTRODUCTION

• Syn : Gougerot–Houwer–Sjogren syndrome / Sicca Syn

• Swedish Ophthalmologist Henrik Sjogren who first described it (1933) ; Mikulicz - 1888

• Defined as a systemic autoimmune disease caused by an immune-mediated inflammation of exocrine glands, and involves salivary, lacrimal and sweat glands, as Sicca Syndrome or with internal organ involvement.

CLINICAL TYPES

• PRIMARY SS - de novo ; assoc with Malignant Lymphomas

• SECONDARY SS - associated rheumatic disorder (RA / SLE / SSc / PBC)

• SICCA SYNDROME – Xerophthalmia + Xerostomia – Internal Organ / Bone Inv

ETIOLOGY

• Female : Male = 9 : 1

• 4/5/6th decade

• Autoimmune ; HLA-B8 / DR3 / Complement allele C4AQO [7] / HLA-DRw52 (Jap)

• Antibodies to the SSA / Ro in relatives

PATHOGENESIS

• Lymphocyte and plasma cell infiltration Auto-antibody production (to ‘Ro’)

• Connective tissue proliferation Lymphocytic Activation

• Glandular cell apoptosis atrophy of glandular structures in affected tissues (salivary glands, sebaceous glands, sweat glands)

• Secondary changes viz Conjunctival / Dacryoadenitis , Parotid Swelling , Angular Cheilits / Stomatitis

CLINICAL FEATURESCUTANOUS MANIFESTATIONS (50%)

Xeroderma, pruritus and scaling

Annular erythema, Papular Erythema including Sweet’s-like lesions (Jap) - graded

Raynaud’s syndrome

Vasculitis : Purpurae - Hyperglobulinemic Purpura and inflammatory vasculitis, including PAN-like lesions

Vitiligo

Sweating abnormalities

Cutaneous Amyloidosis

Alopecia—diffuse and generalized

Pruritis Ani / Pruritis Vulva

Nail fold Capillary Abnormalities (Splinter Hemorrhages / Fingertip Infarcts)

ANNULAR ERYTHEMA

• A

SJOGREN VASCULITIS

• A

XEROPHTHALMIAAka DES

Dry eyes for more than 3 monthsGritty Sensation of sand or gravel in the eyesNeed for tear substitutes more than 3 times a day

Schirmer’s test, performed without anaesthesia (≤5 mm in 5 min) Rose Bengal score or other ocular dye score (Lisamine Green)Fluoroscine flow / Lactoferrin or Lysozyme estimation / Lacrimal Biopsy

43% - Keratoconjunctivitis Sicca with xerostomia23% had associated CTD (RA)

Oral symptoms may precede ocular, or both may occur late in the disease.

SCHIRMER’S TEST

• German Ophthalmologist Otto Schirmer

• determines whether the eye produces enough tears to keep it moist

• This test is used when a person experiences very dry eyes or excessive watering of the eyes

PROCEDURE / INFERENCE• Schirmer's test places a small strip of filter paper inside the lower eyelids

(conjunctival sac). The eyes are closed for 5 minutes. The paper is then removed and the amount of moisture is measured. This technique measures basic tear function.

• A young person normally moistens 15 mm of each paper strip. Because hypolacrimation occurs with aging, 33% of normal elderly persons may wet only 10 mm in 5 minutes. Persons with Sjogren's syndrome moisten less than 5 mm in 5 minutes.

• INTERPRETATION1. Normal which is ≥15 mm wetting of the paper after 5 minutes2. Mild which is 14-9 mm wetting of the paper after 5 minutes3. Moderate which is 8-4 mm wetting of the paper after 5 minutes4. Severe which is <4 mm wetting of the paper after 5 minutes.

• A

ROSE BENGAL DYE

CORNEAL STAINING SCORE (Van Bitzterveld Scoring System)

NONE / MILD

VARIABLE

CENTRAL / DIFFUSE

PUNCTATE

XEROSTOMIA

• Saliva is at first thick and mucoid, but later salivary volume decreases; requirement of liquids to swallow food

• Tongue is red, smooth and dry, and in severe cases there may be difficulty in swallowing dry food.

• Parotid duct narrowing and web formation may develop. Recurrent episodes of swelling of one or both parotid glands or, less often, the submaxillary and sublingual glands, may be due to autoimmune inflammation or infection, which is common

• Dental caries - severe and progressive• The lips are red, dry and scaly. There are frequently cracks at

the corners of the mouth. • Chronic oral candidiasis is frequent

• AA

TESTING

Unstimulated whole salivary flow (>1.5 ml in 15 min)

Parotid sialography showing the presence of diffuse sialectasias (punctate, cavitary, or destructive pattern), without evidence of obstruction in the major ducts

Salivary scintigraphy showing delayed uptake, reduced concentration and/or delayed excretion of tracer

Focal lymphocytic sialoadenitis (focus score ≥1) on HPE (the number of mononuclear cell infiltrates containing at least 50 inflammatory cells in a 4 mm2 glandular section)

UNSTIMULATED WHOLE SALIVARY FLOW

• a

OTHER MANIFESTATIONS

Arthralgia and arthritis

Myalgia and myositis

ENT : Sinusitis / Hearing Loss / TPRD / Atrophic Rhinitis

GI : GERD / Achlorhydria

Resp : Interstitial pneumonitis, pulmonary fibrosis and pulmonary hypertension

Nephro : Interstitial nephritis, Renal Tubular Acidosis

Neuro : migraine, neuropathies, cerebral vasculitis

MISCELLANEOUS

• In patients without associated connective tissue disease, mild articular symptoms occur in 83%, with mild synovitis

• Cervical or generalized LAN

• Hepatosplenomegaly

• AA

American-EU Consensus Classification Criteria : SS (1989 1996)

1. Ocular symptoms: at least one of:1 Dry eyes for more than 3 months2 Gritty Sensation of sand or gravel in the eyes3 Need for tear substitutes more than 3 times a day

2. Oral symptoms: at least one of:1 Dry mouth for more than 3 months2 Recurrently or persistently swollen salivary glands as an adult 3 Need liquids to swallow dry food

3. Ocular signs—at least one of the following two tests positive:1 Schirmer’s test, performed without anaesthesia (≤5 mm in 5 min) 2 Rose Bengal score or other ocular dye score

4. Histopathology: in minor salivary glands, focal lymphocytic sialoadenitis (focus score ≥1).

5. Salivary gland involvement: a positive result for at least one of the following diagnostic tests:

1 Unstimulated whole salivary flow (≤1.5 ml in 15 min) 2 Parotid sialography showing the presence of diffuse sialectasias (punctate, cavitary, or destructive pattern), without evidence of obstruction in the major ducts 3 Salivary scintigraphy showing delayed uptake, reduced concentration and/or delayed excretion of tracer

6. Autoantibodies – SSA (Ro) / SSB (La)

Criteria

For primary SS • In patients without any potentially associated disease, primary

SS may be defined as follows: • a. The presence of any four of the six items is indicative of

primary SS, as long as either item 4 (Histopathology) or 6 (Serology) is positive.

• b. The presence of any three of the four objective criteria items (that is, items 3, 4, 5, 6)

For secondary SS • In patients with a potentially associated disease, the presence

of item 1 or item 2 plus any two from among items 3, 4, and 5 may be considered as indicative of secondary SS

Proposed classification criteria for SS : ACR (2012)

• 1. Positive serum anti-SSA/Ro and/or anti-SSB/La or (positive rheumatoid factor and ANA titer 1:320)

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

• 3. Keratoconjunctivitis sicca with ocular staining score 3 (assuming that individual is not currently using daily eye drops for glaucoma and has not had corneal surgery or cosmetic eyelid surgery in the last 5 years)

Prior diagnosis of any of the following conditions would exclude participation in SS studies or therapeutic trials because of overlapping clinical features or interference with criteria tests: Head / Neck Radiation HCV Inf

AIDS Sarcoidosis AmyloidosisGVHD

Disease Associations• Connective tissue disease (rheumatoid arthritis (26%), systemic sclerosis (22%)• Sweet’s syndrome• Lymphoproliferative disorders—B and T cell, and MALT associated• Primary biliary cirrhosis• Lipodystrophy• Granulomatous panniculitis• Behcet’s disease• Coeliac disease • Hypothyroidism and thyroiditis • Myasthenia gravis • Haemochromatosis • Dermatitis herpetiformis• Darier’s disease• Sarcoidosis • Waldenstrom’s hyperglobulinaemic purpura

DDx (SS)

• HIV infection diffuse infiltrative lymphocytosis syndrome (DILS), which is characterized by parotid enlargement; involvement of the renal, lung, and gastrointestinal systems

• Chronic GVHD may mimic symptoms

• SLE might be considered, especially at onset of the disease. Autoimmune thyroid dysfunction may be present.

DDx (SS)

• Amyloidosis• Sarcoidosis• Bulimia• Pancreatitis, Chronic• Polymyositis• Rheumatoid Arthritis• Salivary Gland Tumors, Major, Benign• Salivary Gland Tumors, Minor, Benign• Scleroderma• Tuberculosis

DDx (SICCA SYN)• Medications (eg, antidepressants, anticholinergics, beta-blockers, diuretics,

antihistamines, some antiarrhythmic and antiepileptic drugs) • Anxiety and depression• Complications from contact lenses• Dehydration / Age• Hypervitaminosis A• Mucous membrane pemphigoid• Environmental irritants• Mouth breathing• Chronic blepharitis• Chronic conjunctivitis• Rosacea• Therapeutic radiation or surgery to the head and neck• Parkinson disease• Amyloidosis• Sarcoidosis• Lymphoma

DDx (PAROTIDOMEGALY)

INVESTIGATIONS

• Se Globulin • RA (52% Primary ; 98% Secondary)• ANA (>50%) speckled, and nucleolar factor is only

occasionally found). • Anti-dsDNA / Anti-RNP rarely found in the sicca syndrome

alone. • Anti-Ro (also called SS-A) and anti-La (SS-B) are frequently

found (53%), associated with vasculitis, purpura, LAN• Antibodies to Lupus Anticoagulant / APLA• Antibodies to carbonic anhydrase 11 can be seen in patients

with Sjogren syndrome who have primary billiary cirrhosis.

• Anti-La assoc with Annular Erythema

• Antibody to salivary duct epithelium can be demonstrated in approximately 50%

• Thyroglobulin antibodies are present in 25% of cases

• Leukopenia and eosinophilia may be seen. ESR generally raised.

• Presence of anti–alpha-Fodrin antibody (reliable diagnostic marker of juvenile Sjogren syndrome)

• Creatinine clearance may be diminished in up to 50% of patients

• High alkaline phosphatase level – s/o Primary Biliary Cirrhosis

• Elevated transaminase levels –s/o Chr Hepatitis

• Hypokalemia

HPE

• a

TREATMENT

• Symptomatic treatment for the dryness of the eyes is best accomplished by lubricating agents, such as 0.5% Methylcellulose eye drops instilled into the eyes four or five times daily.

• Bromhexine 16 mg three times daily has been found to increase the lacrimal secretion, but has no effect on salivary flow

• Artificial saliva / Steam inhalation / Humidifier – Respiratory Tract

• Systemic corticosteroids reducing parotid swelling, but rarely increase parotid or lacrimal secretion.

• Ciclosporin improved subjective xerostomia and may reduce histopathological progression.

• Nifedipine may help Raynaud’s phenomenon.• Associated Polymyositis improved with monthly intravenous

pulse CPA therapy.• Annular erythema in Japanese patients may be controlled by

prednisolone 10–20 mg/day or by dapsone. • Graduated compression hosiery for hyperglobulinaemic purpura

SICCA SYN

BIOLOGICS

• Reports on the use of Rituximab in patients with primary Sjogren syndrome - improved saliva flow rate, lacrimal gland function, vasculitis, and peripheral neuropathy

• Eparazumab ?????

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