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.
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.
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%)
Typically presents in middle-aged women as dryness of various body surfaces
Characterized by peri-epithelial lymphocytic infiltration of the affected tissue or the deposition of the immune complex
Salivary & lacrimal glands:
Progressive lymphocytic infiltration
Acinar cell destruction
Proliferation of duct epithelium
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
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
Pulmonary involvement (9–12%): Normally after many years of disease activity
Interstitial lung disease
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
Sensory neuropathy (10–25%)
Neuromyelitis optica spectrum disorders (NMOSD)
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)
Ocular staining score (≥ 3)
Biopsy of salivary gland (GOLD STANDARD): Lymphocytic sialadenitis
Positive ANA titre:
Anti-SSA/Ro & Anti-SSB/La
Sjögren’s International Collaborative Clinical Alliance (SICCA) criteria.
Based entirely on objective measures
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)
Anti-centromere antibodies (ACA)
Rare: Anti-Ki/SL, anti-Ku, and anti-p80 coilin antibodies
Focal lymphocytic infiltration in otherwise normal-appearing glandular acini (histological hallmark)
While some of these are defined as SS exclusion criteria, others are considered mimics of SS symptoms such as trauma and scarring.
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
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.