Sjögren
Α slowly progressive, autoimmune disease that primarily affects exocrine organs (lacrimal, salivary and
parotid glands). Lymphocytes infiltrate these organs.
Patients with SjS have an increased prevalence of other autoimmune diseases, including celiac
disease, thyroiditis, PBC, IBM and others. According to a study1 young people have higher prevalence of
B-cell associated manifestations including SGE, hypergammaglobulinemia, presence of autoantibodies,
leukopenia, ↓C4 and lymphoma, whereas older people have more frequently dry mouth, ILD and
lymphoma.
•Primary SjS is diagnosed in a patient with KCS who does not have another underlying
rheumatic disease. It is associated with HLA-DRB1*0301, *1501 and with anti-Ro/La.
•Secondary SjS is diagnosed in the presence of another rheumatic disease, most frequently RA.
The immunogenetic findings are usually those of the accompanying disease (ex. HLA-DR4 if RA).
Epidemiology
A female-to-male ratio of >10:1 and is usually diagnosed 40-60yrs, but it also affects children and the
elderly. The annual incidence is 3.9-6.0/100.000, prevalence 0.7-1.5%. The ratio of women to men was
highest in Asian (27:1) and lowest in Black/African American (7:1). The prevalence of secondary SjS
syndrome is 4-30% in RA, 6-20% in SLE and 15-20% in SSc. Men tend to have more serious disease.
Causes
Genetic: HLA-II: DQ, DR (DR2 and DR3 mostly in anti-Ro/La patients), SNPs in IRF5, STAT4, TNFAIP3
(A20). Histological analyses reveal diffuse gene hypomethylation.
Environmental: viruses: Ro52 is induced by IFNs that are produced at high level during viral infection
and enhanced autoantigen expression in tissues may trigger an autoimmune response (Coxsackie, CMV,
retroviruses, HCV, EBV).
Sex hormones: estrogens inhibit the IFN-γ-induced expression of adhesion molecule-1 and exhibit a
protective role regarding autoimmune lesions in salivary and lacrimal glands.
Association with other diseases
-As secondary SjS: RA, SLE, SSc
-Concomitant disease: celiac, Hashimoto, PBC, IBM, NMO-SD
Metrology
ESSPRI (symptoms): mean VAS from 3 domains: limb pain, fatigue, dryness
ESSDAI (activity): 0-123, 12 domains.
0-4: low disease activity
5-13: moderate
≥14: high
Criteria
Inclusion criteria
at least one symptom of ocular or oral dryness (a positive response to at least one)
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 3 times a day?
4) Have you had a daily feeling of dry mouth for ≥3 months?
5) Do you frequently drink liquids to aid in swallowing dry food?
or
in pts with SjS suspicion based on glandular enlargement or the presence of characteristic
extraglandular involvement (defined by a positive item in ≥1 domain of the ESSDAI).
, ≥4 to classify. Sensitivity of 96% and specificity of 95%.
Note that FS and Ro count for 3 points!
Exclusion criteria
1. History of head and neck radiation
2. active HCV (with confirmation by PCR)
3. AIDS
4. sarcoidosis
5. amyloidosis
6. GVHD
7. IgG4-RD
Ocular staining (0-12 total), criterion: ≥5
-fluorescein (for the cornea) targets corneal epithelial defects (score: 0-6)
-lissamine green (for the conjunctiva) stains conjunctival epithelial surfaces lacking mucin
(=damaged or devitalized cells) (score: 0-3 nasal and temporal bulbar conjunctival side → 0-6 total)
Schirmer’s test
Normal: >15mm/5min
Classification criterion: ≤5mm/5min.
Tear breakup time: ≤10 seconds → abnormal
Lymphoma
Patients with SjS have 15-20x risk for the development of non-Hodgkin B-cell lymphoma (5-10%). The
risk is generally higher for primary than for secondary SjS and exceeds that of any other autoimmune
disease.
Risk factors
•Clinical
-persistent parotid enlargement
-palpable purpura
-lymphadenopathy
•Lab
-cryoglobulinemia
-low complement (especially ↓C4)
-RF
-monoclonal proteins (IgM-k is a particular risk factor)
-CD4+ lymphopenia
, •Histology
-presence of GC-like structures in labial gland biopsy
-focus score ≥3
Histology
Several histopathologic types of NHL have been described: extranodal MALT marginal zone B-cell
lymphoma, follicular cell lymphoma, diffuse large B-cell lymphoma and lymphoplasmacytoid lymphoma.
Extranodal marginal zone MALT lymphomas: the most usual type. They arise in extranodal
sites such as the salivary glands but also occasionally in the stomach, orbital adnexa, nasopharynx, lungs,
kidneys, liver and skin. They are present at ≥1 extranodal site in 20% and may disseminate to other sites,
including other salivary glands, the lacrimal glands, lung, stomach and cervical nodes. Usually low grade
and characterized by a small tumor burden. However, the finding (in biopsy) of a monoclonal B-cell
population doesn’t necessarily indicate the presence of malignant lymphoma.
The non-Hodgkin lymphoma subtype of marginal zone lymphoma represents a group of
lymphomas that have been historically classified together because they appear to arise from post-
germinal center marginal zone B cells and share a similar immunophenotype. The marginal zone is a
specific area on the outer edge (or ‘margin’) of a lymphoid follicle; it's the region where B-cells interact
with antigens filtered from the blood or lymph.
Subtypes of marginal zone lymphoma:
-Extranodal marginal zone lymphoma (MALT)
-Nodal marginal zone lymphoma
-Splenic marginal zone lymphoma
-Primary cutaneous marginal zone lymphoma
MALT lymphoma prognostic index (MALT-IPI), each factor scoring 1 point:
-Age >70yrs
-Ann-Arbor stage III/IV
-↑LDH
Pathophysiology
The pathogenesis of lymphoma in SjS is complex and reflects chronic antigenic stimulation leading to B
cell proliferation, hyperreactivity and eventually selection of a single B cell to undergo monoclonal
proliferation. MALT lymphomas probably occur in ectopic GC-like structures. BAFF may play a significant
role in this process. Upregulation of the anti-apoptotic protein Bcl-2 by BAFF has been shown to
promote survival of non-Hodgkin lymphoma cells. BAFF levels correlate with tumour severity. Genetic
abnormalities, like polymorphisms in TNFAIP3 (encodes A20, a deubiquitinase for TRAF6 and NEMO,
inhibiting NF-kB signaling), are found in >75% of SjS patients with MALT lymphoma.
Staging
modified Ann-Arbor system
Α slowly progressive, autoimmune disease that primarily affects exocrine organs (lacrimal, salivary and
parotid glands). Lymphocytes infiltrate these organs.
Patients with SjS have an increased prevalence of other autoimmune diseases, including celiac
disease, thyroiditis, PBC, IBM and others. According to a study1 young people have higher prevalence of
B-cell associated manifestations including SGE, hypergammaglobulinemia, presence of autoantibodies,
leukopenia, ↓C4 and lymphoma, whereas older people have more frequently dry mouth, ILD and
lymphoma.
•Primary SjS is diagnosed in a patient with KCS who does not have another underlying
rheumatic disease. It is associated with HLA-DRB1*0301, *1501 and with anti-Ro/La.
•Secondary SjS is diagnosed in the presence of another rheumatic disease, most frequently RA.
The immunogenetic findings are usually those of the accompanying disease (ex. HLA-DR4 if RA).
Epidemiology
A female-to-male ratio of >10:1 and is usually diagnosed 40-60yrs, but it also affects children and the
elderly. The annual incidence is 3.9-6.0/100.000, prevalence 0.7-1.5%. The ratio of women to men was
highest in Asian (27:1) and lowest in Black/African American (7:1). The prevalence of secondary SjS
syndrome is 4-30% in RA, 6-20% in SLE and 15-20% in SSc. Men tend to have more serious disease.
Causes
Genetic: HLA-II: DQ, DR (DR2 and DR3 mostly in anti-Ro/La patients), SNPs in IRF5, STAT4, TNFAIP3
(A20). Histological analyses reveal diffuse gene hypomethylation.
Environmental: viruses: Ro52 is induced by IFNs that are produced at high level during viral infection
and enhanced autoantigen expression in tissues may trigger an autoimmune response (Coxsackie, CMV,
retroviruses, HCV, EBV).
Sex hormones: estrogens inhibit the IFN-γ-induced expression of adhesion molecule-1 and exhibit a
protective role regarding autoimmune lesions in salivary and lacrimal glands.
Association with other diseases
-As secondary SjS: RA, SLE, SSc
-Concomitant disease: celiac, Hashimoto, PBC, IBM, NMO-SD
Metrology
ESSPRI (symptoms): mean VAS from 3 domains: limb pain, fatigue, dryness
ESSDAI (activity): 0-123, 12 domains.
0-4: low disease activity
5-13: moderate
≥14: high
Criteria
Inclusion criteria
at least one symptom of ocular or oral dryness (a positive response to at least one)
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 3 times a day?
4) Have you had a daily feeling of dry mouth for ≥3 months?
5) Do you frequently drink liquids to aid in swallowing dry food?
or
in pts with SjS suspicion based on glandular enlargement or the presence of characteristic
extraglandular involvement (defined by a positive item in ≥1 domain of the ESSDAI).
, ≥4 to classify. Sensitivity of 96% and specificity of 95%.
Note that FS and Ro count for 3 points!
Exclusion criteria
1. History of head and neck radiation
2. active HCV (with confirmation by PCR)
3. AIDS
4. sarcoidosis
5. amyloidosis
6. GVHD
7. IgG4-RD
Ocular staining (0-12 total), criterion: ≥5
-fluorescein (for the cornea) targets corneal epithelial defects (score: 0-6)
-lissamine green (for the conjunctiva) stains conjunctival epithelial surfaces lacking mucin
(=damaged or devitalized cells) (score: 0-3 nasal and temporal bulbar conjunctival side → 0-6 total)
Schirmer’s test
Normal: >15mm/5min
Classification criterion: ≤5mm/5min.
Tear breakup time: ≤10 seconds → abnormal
Lymphoma
Patients with SjS have 15-20x risk for the development of non-Hodgkin B-cell lymphoma (5-10%). The
risk is generally higher for primary than for secondary SjS and exceeds that of any other autoimmune
disease.
Risk factors
•Clinical
-persistent parotid enlargement
-palpable purpura
-lymphadenopathy
•Lab
-cryoglobulinemia
-low complement (especially ↓C4)
-RF
-monoclonal proteins (IgM-k is a particular risk factor)
-CD4+ lymphopenia
, •Histology
-presence of GC-like structures in labial gland biopsy
-focus score ≥3
Histology
Several histopathologic types of NHL have been described: extranodal MALT marginal zone B-cell
lymphoma, follicular cell lymphoma, diffuse large B-cell lymphoma and lymphoplasmacytoid lymphoma.
Extranodal marginal zone MALT lymphomas: the most usual type. They arise in extranodal
sites such as the salivary glands but also occasionally in the stomach, orbital adnexa, nasopharynx, lungs,
kidneys, liver and skin. They are present at ≥1 extranodal site in 20% and may disseminate to other sites,
including other salivary glands, the lacrimal glands, lung, stomach and cervical nodes. Usually low grade
and characterized by a small tumor burden. However, the finding (in biopsy) of a monoclonal B-cell
population doesn’t necessarily indicate the presence of malignant lymphoma.
The non-Hodgkin lymphoma subtype of marginal zone lymphoma represents a group of
lymphomas that have been historically classified together because they appear to arise from post-
germinal center marginal zone B cells and share a similar immunophenotype. The marginal zone is a
specific area on the outer edge (or ‘margin’) of a lymphoid follicle; it's the region where B-cells interact
with antigens filtered from the blood or lymph.
Subtypes of marginal zone lymphoma:
-Extranodal marginal zone lymphoma (MALT)
-Nodal marginal zone lymphoma
-Splenic marginal zone lymphoma
-Primary cutaneous marginal zone lymphoma
MALT lymphoma prognostic index (MALT-IPI), each factor scoring 1 point:
-Age >70yrs
-Ann-Arbor stage III/IV
-↑LDH
Pathophysiology
The pathogenesis of lymphoma in SjS is complex and reflects chronic antigenic stimulation leading to B
cell proliferation, hyperreactivity and eventually selection of a single B cell to undergo monoclonal
proliferation. MALT lymphomas probably occur in ectopic GC-like structures. BAFF may play a significant
role in this process. Upregulation of the anti-apoptotic protein Bcl-2 by BAFF has been shown to
promote survival of non-Hodgkin lymphoma cells. BAFF levels correlate with tumour severity. Genetic
abnormalities, like polymorphisms in TNFAIP3 (encodes A20, a deubiquitinase for TRAF6 and NEMO,
inhibiting NF-kB signaling), are found in >75% of SjS patients with MALT lymphoma.
Staging
modified Ann-Arbor system
