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Primary Sjogren's syndrome
Primary Sjogren's syndrome
Autoimmune disease of exocrine glands particularly salivary and lacrimal glands characterized by dry mouth (xerostomia), dry eyes (keratoconjunctivitis sicca); other organs may be affected, including CNS and PNS, skin, and mucosal surfaces of upper airways, vagina, lungs, and kidneys. The primary pathology is lymphocytic infiltration of exocrine glands.
Primary Sjogren's syndrome: Condition occurs in the absence of other known inflammatory disorders.
Secondary Sjogren's syndrome: Condition occurs in the presence of defined connective tissue disease (RA, SLE, scleroderma, PM, or other autoimmune disorder).
San Diego criteria for diagnosis of both primary and secondary Sjogren's syndrome (1986):
Primary Sjogren's Syndrome
Symptoms and objective signs of ocular dryness
Schrimer's test <5 mm wetting/5 min (original criteria: 9 mm/5 min) and
Positive rose bengal or fluorescein staining of cornea or conjunctiva to demonstrate keratoconjunctivitis sicca
Symptoms and objective signs of dry mouth
Decreased parotid flow using Lashley cups
Abnormal minor salivary gland biopsy (focus score of 2 or more on average of 4 evaluable lobules; 1 focus = 50 lymphs/4 mm2)
Evidence of systemic autoimmune disorder
Elevated rheumatoid factor
Elevated ANA >1:160
Presence of SS-A (Ro) or SS-B (La). The latter has a more specific association with Sjogren's syndrome.
SSA and SSB:
Antibodies against SSA/Ro are found in approximately 50% - 80% of patients with the primary Sjogren syndrome and in 15% of patients with secondary Sjögren syndrome). Thus, the absence of anti-SSA/Ro antibodies does not eliminate the diagnosis of primary or secondary Sjögren syndrome.
Antibodies against SSA/Ro are present in 50% of patients with SLE and are sometimes found in healthy individuals. Thus, the presence of antibody against SSA/Ro cannot by itself be used to establish a diagnosis of Sjögren syndrome.
Antibodies against SSB/La are present in 40-50% of patients with primary Sjögren syndrome and in 15% of patients with SLE.- anti-La/SSB has higher specificity. Finding antibodies against SSB/La in patients without antibodies against SSA/Ro is unusual, but this combination has occurred in patients with primary biliary cirrhosis and autoimmune hepatitis.
Titers of anti-SSA/Ro and anti-SSB/La antibodies do not reflect disease activity. Current enzyme-linked immunosorbent assay tests for these antibodies are more sensitive than previous tests. Thus, the specificity is lower.
Antibodies against SSA/Ro are also associated with the annular erythematous lesions of subacute cutaneous lupus. They are also found in the mothers of newborns with neonatal lupus syndromes and congenital heart block, and some of these mothers have or will develop Sjögren syndrome.
Autoantibodies to the human muscarinic acetylcholine receptor of the M3 type (hmAchR M3) have been suggested to elevated in Sjogren syndrome.
Three novel autoantibodies (Secretory Protein-1 (SP-1), Carbonic Anhydrase-6 (CA-6) and Parotid Secretory Protein (PSP) have been identified that may aid in early diagnosis of SS.
Secondary Sjogren's Syndrome
Secondary Sjogren's Syndrome
Symptoms and signs of Sjogren's as defined above plus diagnosis of RA, SLE, scleroderma, polymoyositis, PBC (primary biliary cirrhosis)
Exclusions: sarcoidosis, lymphoma, AIDS, hepatitis, known other causes of sicca, salivary gland enlargement, or autonomic neuropathy
Definite: All criteria for primary Sjogren's syndrome and lack of exclusions in secondary Sjogren's syndrome
Probable: All criteria excepts biopsy
Clinical features:
>90% of patients are women; mean age of diagnosis is 50 years, but even children, adolescents, and young adults can be affected.
Sicca complex defines the disorder:
Keratoconjunctivitis sicca (dry eyes)
Producing the classical complaint of foreign body sensation in the eye.; red eyes (less specific); corneal ulcers (severe cases)
Xerostomia (dry mouth)
Difficulty swallowing food. Adherence of food to buccal surfaces.
Frequent feeling of thirst
Dental caries > tooth loss, Halitosis, oral candidiasis,
Oral candidiasis
Recurrent or chronic episodes of major salivary gland enlargement
Recurrent parotid enlargement may be symmetrical and may be accompanied by fever, tenderness, or erythema.
Xerosis (cutaneous sicca)
Vagnitis sicca
Dryness of mucosa (nasopharynx and URI)
Extraglandular sites of involvement: PM, lungs, GIT, GUT, and even thyroid gland: Xerosis, arthralgia, autoimmune thyrodiditis, hypergammaglobulinemia, lymphopenia, PFT abnormalities, ILD, interstitial nephritis, monoclonal gammopathy, cryoglobulinemia, lymphoma, cutaneous vasculitis.
Regional lymphadenopathy may be a striking feature in some cases.
Increased levels of serum and urinary paraproteins and cryoglobulins.
CNS complications may simulate MS on MRI with multiple regions of increased signal intensity, predominantly within the subcortical and periventricular white matter.
Peripheral Nerve Complications of Sjogren's Syndrome:
Patients with Sjögren syndrome can develop a wide array of peripheral nervous system manifestations, including distal symmetric polyneuropathy, mononeuritis multiplex, sensory and autonomic neuropathy, trigeminal mononeuropathies, and a dorsal root ganglionopathy. It is suggested PNS involvement in Sjogren syndrome is ~16%, while CNS manifestations is ~4%.
Patients with SFN associated with Sjogren syndrome typically present with asymmetric dysesthetic pain and decreased pinprick and temperature in either lenght-dependent on non-length-dependent patterns. Strength and reflexes are preserved. Onset is subacute to indolent, but some patients can progress more rapidly.
Evaluation for Sjögren syndrome should be performed even in the absence of sicca syndrome if the suspicion is high, as the neuropathy may precede sicca syndrome. Serum antibodies may be negative as well; thus, minor salivary gland biopsy is recommended in patients with clinical syndromes strongly suggestive of Sjögren syndrome, including a significant sensory neuropathy and autonomic neuropathy or a dorsal root ganglionopathy.
Sensorimotor neuropathy
Patients with Sjögren syndrome can also develop a length-dependent, large fiber, sensorimotor polyneuropathy. Typically, slowly progressive distal symmetric sensory loss occurs,with weakness limited to toe and foot dorsiflexors when present.
Autonomic dysfunction includes Adie's pupils, anihdoris, compensatory segmental hyperhidrosis, GI dysmotility, and orthostatic changes in BP. Objective testing of autonomic function has yielded varying degrees of decreased cardiovagal function, impaired sympathetic vasomotor activity, or tachycaric responses to head-up tilt. Autonomic features may precede the diagnosis of Sjogren syndrome. The pathology is of autonomic dysfunction in Sjogren syndrome is thought to be related to immune mediated small fiber neuropathy affecting autonomic nerves. Some patient respond to immunotheraphy.
EDX demonstrate an axonal neuropathy.
Nerve biopsy may show small-vessel perivasculitis or vasculitis
Nerve fiber loss may be random or multifocal.
Treatment:
A number of treatments have been used, including plasma exchange, IVIg, rituximab, corticosteroids, cyclophosphamide, and azathioprine. One protocol proposes treating with IVIg (2 g/kg divided over 5 days) followed by monthly infusions.
Ataxic sensory neuropathy (neuronopathy)
Occurs most often in women.
Neuropathy with prominent kinesthetic loss.
Dysesthesias or paresthesia involve face, trunk, and limbs.
Severely affected individuals demonstrate pseudoathetosis of the upper limbs, with an inability to localize the limb in space.
Small fiber functions of pain and temperature are less affected.
Muscle strength preserved but loss of muscle stretch reflexes.
Progression may be indolent or rapidly progressive.
SNAPs are absent in most clinically affected limbs.
Motor nerve conduction studies are normal.
Needle EMG is normal or show minimal denervation potentials.
Nerve biopsy shows loss of myelinated nerve fibers: perivascular inflammation may be present.
No proven treatment but progression may stop and functional improvement may occur.
MRI of the spine can show T2 hyperintensity along the dorsal columns thought to be secondary to sensory ganglia neuron injury, corresponding with pathologic studies demonstrating lymphocyte infiltration of the dorsal root ganglia in affected patients
CIDP is very rarely associated with Sjogren syndrome. It is possible that these isolated cases represent a predisposition to autoimmune disease rather than a direct manifestation of the disease.
Myopathy is uncommon in Sjögren syndrome. Up to 10% of patients with inclusion body myositis have Sjögren syndrome, suggesting a potential link.
Cranial neuropathies have been reported in Sjögren syndrome with the trigeminal nerve being most frequently involved.
Mononeuritis multiplex is very uncommon and tends to occur in the setting of active systemic disease in association with vasculitic involvement of other organs, such as glomerulonephritis or palpable purpura. Low C4 levels, hypergammaglobulinemia, and cryoglobulinemia may be present. Nerve biopsy may be needed in these cases to confirmthe presence of vasculitis.
Treatment: No randomized placebo-controlled trials of immunotherapies in Sjögren syndrome have been conducted. Small fiber neuropathies aremanaged primarily symptomatically, although some patients have reported improvement with IV immunoglobulin (IVIg). Symptomatic management is also usually used in axonal sensorimotor neuropathy, although a response to immunotherapy has been reported. Dorsal root ganglionopathy tends to be refractory to immunotherapy. Mononeuritis multiplex with documented vasculitis is treated with high-dose corticosteroids, rituximab, or cyclophosphamide.
https://pmc.ncbi.nlm.nih.gov/articles/PMC8205474/
https://pmc.ncbi.nlm.nih.gov/articles/PMC10087501/
https://www.mdpi.com/2077-0383/9/7/2299
Modern Rheumatology, Volume 19, Issue 4, 1 August 2009, Pages 437–440, https://doi.org/10.3109/s10165-009-0180-2
The classification of Sjögren syndrome applies to any individual who meets the inclusion criteria, does not have any of the conditions listed as exclusion criteria, and has a score of 4 or more when the weights from the five criteria items below are summed.
These inclusion criteria are applicable to any patient with at least one symptom of ocular or oral dryness, defined as a positive response to at least one of the following questions:
Have you had daily, persistent, troublesome dry eyes for more than 3 months?
Do you have a recurrent sensation of sand or gravel in the eyes?
Do you use tear substitutes more than 3 times a day?
Have you had a daily feeling of dry mouth for more than 3 months?
Do you frequently drink liquids to aid in swallowing dry food? or to any patient in whom there is suspicion of Sjögren syndrome from the European League Against Rheumatism Sjögren Syndrome Disease Activity Index questionnaire (at least one domain with a positive item).
Exclusion criteria include prior diagnosis of any of the following conditions, which would exclude diagnosis of Sjögren syndrome and participation in Sjögren syndrome studies or therapeutic trials because of overlapping clinical features or interference with criteria tests: history of head and neck radiation treatment, active hepatitis C infection (with confirmation by polymerase chain reaction [PCR]), acquired immunodeficiency syndrome (AIDS), sarcoidosis, amyloidosis, graft versus host disease, or IgG4-related disease.
2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren's syndrome
2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren's syndrome
The final classification criteria are based on the weighted sum of five items: anti-SSA/Ro antibody positivity and focal lymphocytic sialadenitis with a focus score of ≥1 foci/4 mm2, each scoring 3; an abnormal Ocular Staining Score of ≥5 (or van Bijsterveld score of ≥4), a Schirmer's test result of ≤5 mm/5 min and an unstimulated salivary flow rate of ≤0.1 mL/min, each scoring 1. Individuals with signs and/or symptoms suggestive of SS who have a total score of ≥4 for the above items meet the criteria for primary SS. Sensitivity and specificity against clinician-expert—derived case/non-case status in the final validation cohort were high, that is, 96% (95% CI92% to 98%) and 95% (95% CI 92% to 97%), respectively.
The minor salivary gland (MSG) tissue can be diagnostically examined by using the focus score (FS) which describes the number of cell infiltrates of at least 50 mononuclear cells within 4 mm2 (i.e., a focal infiltrate).
The focus score (J Rheumatol. 2002;29(5):938-44) is: less than 1 per 4 mm squared.
N.B.: Focus scores greater than one histologically support a diagnosis of Sjogren syndrome (Oral Maxillofac Surg Clin North Am. 2014;26(1):13-22). Therefore, the histologic findings DO NOT support a diagnosis of Sjogren syndrome in this patient; however, Sjogren syndrome cannot be ruled out based on histologic findings alone, due to sampling error. The findings have been correlated with the results of serology studies, available in the patient's electronic medical record (EPIC) at the time of sign out. A review of the patient's medication list as available in EPIC may be of merit.
A focus has been defined as 50 or more lymphocytes or plasma cells or both lobules are included in this biopsy; a biopsy of five or more lobules is recommended.
In practice however any 3 out of 4 criteria is used for the diagnosis of Sjogren syndrome:
Objective evidence of dry eyes.
Objective evidence of dry mouth.
Anti-SSA positivity.
Focal lymphocytic sialadenitis with a focus score of at least or more than 1/4 mm2
Case 1:
Case 1:
BX is a 62 y.o. female who came to rheumatology clinic for follow up evaluation of Sjogrens. Patient was previously diagnosed with Sjogrens (sicca symptoms and neuropathy) because of lip biopsy that was consistent with Sjogrens and +SSA. Patient was previously on Plaquenil but stopped due to visual concerns. This was more a personal preference rather than a direct contraindication from ophthalmology. However patient felt while she was on Plaquenil 200 mg daily it was not helping either her neuropathy or Sicca symptoms. Currently she is not on any immunosuppressive therapy for Sjogren's. She manages Sicca symptoms conservatively. Follows with neurology for small fiber neuropathy and is currently on gabapentin. Neurology is considering repeat EMG/NCS to ascertain polyneuropathy. Will repeat serology workup. In the future if neuropathy symptoms worsen or become uncontrolled, Sicca symptoms get worse, inflammatory joint pain arises can consider reintroduction of Plaquenil or discuss other potential immunosuppressive agents. For now we will maintain off any immunosuppressive therapy.
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