Chapter 29 Sj gren's Syndrome
Manual of Rheumatology and Outpatient Orthopedic Disorders
Chapter 29 Sj gren's Syndrome
Stuart S. Kassan
Prevalence
Genetics
Pathogenesis
Clinical features
Laboratory studies
Differential diagnosis
Treatment
Sj gren's syndrome (SS) is a chronic inflammatory disease associated with lymphocytic infiltration of exocrine glands. Certain clinical, serologic, and genetic differences are found among patients with SS alone, also called primary SS ( patients with keratoconjunctivitis and xerostomia in the absence of any other definable connective tissue disease). These differences suggest varying etiologies for similar clinical manifestations of disease. The most commonly accepted definition of SS has been the presence of two of the following findings: (a) keratoconjunctivitis sicca (dry eyes), (b) xerostomia (dry mouth), and (c) one of the connective tissue disease syndromes. Secondary SS is defined as keratoconjunctivitis and xerostomia as features of a connective tissue disease. Rheumatoid arthritis (RA) is the most common connective tissue disease seen in association with secondary SS, but others have been well-documented and include systemic lupus erythematosus (SLE), scleroderma, polymyositis, mixed connective tissue disease, and juvenile rheumatoid arthritis. As a result of the obvious shortcomings of the above, purely clinical definition, most recent investigators have included pathologic criteria (see section III ) as supporting evidence of the presence of primary or secondary SS.
The clinical manifestations of the disease were first described in 1888. In 1933, Henrik Sj gren published a monograph describing in great detail the histologic and clinical components of this syndrome, which has often been referred to as Sj gren's syndrome. Confusion later arose between SS and the disease previously reported by Mikulicz in the late 1800s. In 1927, Schaffer and Jacobsen defined two main categories: (a) Mikulicz's disease proper, of unknown etiology and following a benign course, and (b) Mikulicz's syndrome, caused by a variety of disorders such as leukemia, lymphosarcoma, tuberculosis, sarcoidosis, and iodide poisoning . Later, Morgan and Castleman concluded, on the basis of pathologic descriptions, that Mikulicz's disease and SS were identical. Much of the interest in SS during the past decade has focused on the opportunity to study the interrelationships among the autoimmune disorders, lymphoproliferative malignancies, and dysproteinemias, all of which may be features of the syndrome.
I. Prevalence
- Sex. At least 90% of the patients with SS (primary or secondary) in most studies are women.
- Age. Most patients with the disease are over 40 years of age, but the disease may be encountered in persons in the second and third decades of life.
- Other connective tissue diseases in patients with Sj gren's syndrome
- When various populations of patients with SS have been evaluated for the presence of other connective tissue diseases, the results have been as follows :
- RA, 30% to 55%.
- Scleroderma, 5% to 8%.
- SLE, 5% to 10%
- Polymyositis, 2% to 4%.
- Hashimoto's thyroiditis, mixed connective tissue disease, chronic active hepatitis, Raynaud's disease, all with an unknown incidence of SS.
- Alternatively, when evidence of SS is specifically sought in patients with other connective tissue diseases, the results are quite different:
- SLE, more than 50%.
- RA, 20% to more than 50%.
- Scleroderma, 40% to 50%.
- Glandular involvement in Sj gren's syndrome . Eighty percent of SS patients have major salivary gland enlargement . Focal lymphocytic infiltration with linear destruction may be seen in minor salivary glands in labial, nasal, and hard palate mucosa. Involvement of the exocrine glands of the upper and lower respiratory tracts, gastrointestinal tract , vagina, pancreas , and skin has been found in SS.
- Extraglandular involvement
- Gastrointestinal disorders in SS have included the following:
- Esophageal stenosis.
- Atrophic gastritis.
- Pancreatitis.
- Hepatic disorders in patients with SS have included the following:
- Abnormal liver function tests ( especially elevated alkaline phosphatase and g glutamyl transpeptdase) in 45%.
- Primary biliary cirrhosis.
- Chronic active hepatitis.
- Cryptogenic cirrhosis (15% of SS patients in one study).
- Renal disorders have been found in as many as one-third of SS patients and include the following:
- Renal tubular acidosis type 1.
- Nephrogenic diabetes insipidus.
- Chronic interstitial nephritis.
- Immune complex glomerulonephritis.
- Pulmonary disorders may be found in 4% to 15% of SS patients and include the following:
- Chronic obstructive pulmonary disease.
- Pulmonary infiltrates (e.g., pseudolymphoma).
- Fibrosing alveolitis.
- Myositis, often of an indolent nature, may be encountered in SS. Up to 50% of patients have been found to exhibit, on random muscle biopsy specimens, abnormalities consisting of interstitial and perivascular fibrosis, inflammatory infiltrates, or both.
- Vasculitis is present in fewer than 10% of SS patients. It may be seen in association with the following:
- Myositis.
- Mononeuritis multiplex .
- Axonal neuropathy.
- Central nervous system involvement (in which immune vasculopathy and anti-SS antibodies may play a pathogenetic role).
- Immune complex glomerulonephritis.
- Purpura.
- Malignancy in Sj gren's syndrome
- Non-Hodgkin's lymphoma has been found to occur more often in patients with SS (primary or secondary); the relative risk is 44 times the expected incidence. Patients with a history of parotid enlargement, splenomegaly, and lymphadenopathy are at greatest risk for development of lymphoma.
- Waldenstr m's macroglobulinemia appears to be more frequent in SS, but the risk is unknown.
- Pseudolymphoma in SS is characterized by extraglandular extension of lymphoproliferation that is clinically and histologically benign. The incidence is not known.
- Other malignancies reported to coexist with SS include Kaposi's sarcoma, immunoblastic lymphadenopathy, and immunoblastic sarcoma.
II. Genetics. Histocompatibility testing of patients with SS has demonstrated a genetic dichotomy between patients with primary SS (SS alone) and those with secondary SS (SS associated with another connective tissue disease, generally RA).
- Primary sicca syndrome has a significantly increased association with HLA-B8, HLA-DR3, and certain B-lymphocyte allo-antigens.
- The above HLA associations are usually not found in patients with secondary sicca syndrome. In the case of patients with SS and RA, there is an increased incidence of the HLA-DR4 antigen (that antigen found most often in seropositive RA alone).
- Family studies show that relatives of SS patients may have an increased incidence of serum auto-antibodies, positive results on Schirmer's test, elevated gamma globulin levels, and RA. The studies of HLA antigens in primary SS from different ethnic groups show different associations: HLA-DR5 is found in Greeks, HLA-DR11 in Israelis, and HLA-DRw3 in Japanese patients.
III. Pathogenesis. Findings in SS pertaining to pathogenesis may be classified as follows:
- Abnormalities of humoral immunity
- Anti-salivary duct antibody is present more frequently in secondary SS (70% positive) than in primary SS (10% positive). No differences in other organ-specific antibodies (e.g., anti- thyroid and anti- gastric parietal cell antibodies) have been found between primary and secondary SS.
- Non “organ-specific auto-antibodies
- Immunoglobulin M (IgM) rheumatoid factor (RF) is the most common type of RF in all cases of SS.
- Immunoglobulin G and immunoglobulin A rheumatoid factors seem to be elevated in primary SS more often than in secondary SS.
- Antinuclear antibody (ANA) positivity was found in 64% to 68% of all SS cases, in which the frequencies of positivity vary between primary and secondary SS. ANA patterns tend to be speckled because of the anti-SS-B antibodies found in SS.
- Antibodies to soluble acidic nuclear antigens extracted from lymphoid cell lines.
- SS-A (or Ro) antibodies are present in the following percentages:
- Primary SS, 70%.
- SS with RA, 1%.
- SS with SLE, 33%.
- SS-B (or Ha, La) antibodies are present in the following percentages:
- Primary SS, 50% to 70%.
- SS with RA, 3% to 5%.
- SS with SLE, 73%.
- Abnormalities of cellular immunity and immune regulation in Sj gren's syndrome. There seem to be normal absolute numbers and proportions of peripheral B and T cells. No increase of circulating B cells has been found despite a higher incidence of auto-antibodies, hypergammaglobulinemia, and circulating immune complexes. Evidence suggests the presence of a serum blocking factor that may decrease the percentage of T cells . Natural cell-mediated cytotoxicity is depressed in both primary and secondary SS. The autologous mixed lymphocyte reaction is more depressed in secondary than in primary SS. Studies of T-lymphocyte subsets in SS have yielded conflicting results. A decreased number of helper T cells (CD4+) and suppressor T cells (CD8+) have been reported. Overall, it seems that B-cell activation is the most consistent immunoregulatory aberration in SS patients. It may begin as a polyclonal activation evolving to oligoclonal and monoclonal activation and may end in a transformation to a malignant monoclonal proliferation .
- Viral studies. Tubuloreticular structures have been identified in labial salivary gland tissue and renal endothelium from SS patients. No successful viral isolation from salivary gland tissues has been accomplished. In one study, elevated titers of antibody to cytomegalovirus were found in SS.
- Immune complexes. Elevated levels of immune complexes and abnormal clearance of these complexes by the reticuloendothelial system have been demonstrated in active SS. Their role in the pathogenesis of disease is unclear, but they may be important in vasculitic states and glomerulonephritis.
- Graft-versus-host disease. GVH-initiated SS resembling spontaneous SS suggests a possible pathophysiologic mechanism for the development of SS and other connective tissue diseases in humans and extends previous observations limited to animal models.
- Human immunodeficiency virus (HIV) infection. Patients with HIV infection may manifest a clinical picture indistinguishable from that of SS. These patients usually do not demonstrate antibodies to Ro (SS-A) or La (SS-B) cellular antigens and the intralesional T cells are CD8(+), as opposed to CD4(+) in autoimmune SS.
IV. Clinical features
- Ocular symptoms may not be present in one-third to one-half of patients at any one time during the course of their disease despite definite pathologic changes. However, approximately 95% of SS patients will have ocular symptoms at some time.
- Xerostomia is an infrequent presenting sign of SS, but about 90% of patients will have sialographic abnormalities of the parotids. Salivary gland enlargement, primarily of the parotid gland, is present in one-third of SS patients and is usually bilateral. Lacrimal gland enlargement is unusual (4%).
V. Laboratory studies
- Specific tests
- Tests of functional abnormalities
- Schirmer's test. Five millimeters of unstimulated wetting of filter paper in 5 minutes (17% false-positive and 15% false-negative results).
- Parotoid salivary flow rate.
- Results of radionuclide scan of the parotid glands (pertechnetate Tc 99m) may be falsely abnormal as a result of other abnormalities of the parotid gland (see section VI ).
- Parotid gland sialography is performed by introducing radiopaque dye into the parotid duct system. The abnormalities seen in SS include acinar and duct atrophy with puddling of dye, main duct enlargement, and retention of contrast material. All the above may be seen in chronic parotitis with causes other than SS.
- Tests of anatomic abnormalities
- Rose bengal staining of the cornea may be helpful in confirming the diagnosis but is not specific (4% false-positive and 5% false-negative results).
- Parotid gland sialography (see section V.A.1.d ).
- Biopsy
- Minor salivary glands. Abnormalities are nicely demonstrated by lip biopsy.
- Lacrimal glands and parotid glands. Abnormalities are similar to those found in the minor salivary glands of the lip. Because of the relative lack of morbidity associated with lip biopsies, this procedure is preferred over lacrimal or parotid gland biopsies as a diagnostic tool.
- Nonspecific laboratory abnormalities. These changes are also often seen in other states of inflammation and in many autoimmune diseases.
- Elevated erythrocyte sedimentation rate, 80%.
- Anemia, 40%.
- Leukopenia, fewer than 30%.
- Hypergammaglobulinemia, 80%.
- Positive RF, >90%.
- Positive ANA, 70%.
- Circulating cryoglobulins may be 30%.
VI. Differential diagnosis. The salivary gland involvement in SS may be confused with numerous other conditions.
- Infection of salivary glands
- Viral. Coxsackievirus infection, mumps, cytomegalic inclusion disease, HIV infection.
- Bacterial. Acute sialoadenitis is often seen in dehydrated, debilitated patients. Chronic bacterial sialoadenitis is frequently associated with obstruction of the salivary ducts by inspissated saliva.
- Fungal. Actinomycosis or histoplasmosis.
- Tuberculosis. Rare.
- Granulomatous disease. Sarcoidosis.
- Other infiltrative disorders
- Primary neoplasms of the parotid gland.
- Leukemia.
- Amyloidosis.
- Lymphoma of intraparotid lymph nodes.
- Burkitt's lymphoma.
- Pseudolymphoma.
- Systemic diseases
- Cirrhosis.
- Diabetes mellitus.
- Hyperlipoproteinemias (types 3, 4, 5).
- Obesity.
- Pregnancy and lactation.
- HIV disease.
- Gouty parotitis (rare).
- Cushing's disease.
- Cystic fibrosis.
- Nutritional deficiency
- Starvation.
- Vitamin B 6 deficiency.
- Vitamin C deficiency.
- Vitamin A deficiency.
- Drugs associated with the development of dry mouth
- Sedatives.
- Hypnotics.
- Narcotics.
- Phenothiazines.
- Atropine.
- Propantheline.
- Antiparkinsonian drugs.
- Antihistamines.
- Ephedrine.
- Epinephrine.
- Amphetamines.
VII. Treatment. No controlled trials have been undertaken in the therapy of the systemic manifestations of SS. In general, the approach to treatment has been empiric. Vasculitis, renal disease (immune complex-mediated or otherwise ), myositis, alveolitis, cryoglobulinemia, and other manifestations have mostly been treated in the past with corticosteroids, immunosuppressive agents , or both, depending on the severity of disease. Because the cytotoxic drugs are immunosuppressive and renal transplant patients and others treated with the agents have an increased incidence of lymphoma (as do untreated SS patients), it is advisable to avoid their use in SS.
- Ocular abnormalities. Artificial tears are the mainstay of treatment. Solutions consisting of methylcellulose and polyvinyl alcohol are useful. The dosage varies from two drops four times daily to every 15 minutes depending on the clinical state. Inserts placed into the conjunctival sac that release small amounts of methylcellulose during many hours are presently available and may be beneficial in some patients. Lacrimal duct occlusion , temporary or permanent, may enhance local moisture. Bromhexine, a secretagog, is presently being studied in clinical trials for use in the United States.
- Xerostomia. Salagen (pilocarpine hydrochloride) tablets are indicated for the treatment of symptoms of xerostomia from salivary gland hypofunction. As a cholinergic parasympathetic agent, pilocarpine can increase secretion of the salivary glands. The usual initial dose is 5 mg tid. It is contraindicated in patients with asthma, iritis, and narrow angle glaucoma. Side effects include abdominal cramps and sweating. Lubrication of the mouth and mild secretagogs, such as lemon-flavored juice or lubricating agents proper (water, methylcellulose), are useful. More potent secretagogs may exacerbate the signs and symptoms of parotitis. Prevention of states of dehydration in SS is very important, as dehydration may enhance the formation of parotid ductal calculi. Avoidance of drugs that may aggravate oral dryness (e.g., narcotics, antihistamines, anticholinergics) is also important.
- Parotid enlargement. In the past, numerous modes of therapy have been employed to treat parotid enlargement.
- Parotid irradiation has been associated with an increased incidence of lymphoma in SS patients. Because of its oncogenic potential, this form of therapy should not be used in SS.
- Surgical removal is often technically difficult, and resultant nonhealing fistulae and facial nerve damage preclude this mode of therapy.
- Drug therapy for symptomatic inflammatory parotid enlargement
- Nonsteroidal antiinflammatory drugs. Useful regimens include 25 to 50 mg of indomethacin four times daily or 400 mg of ibuprofen four times daily.
- Corticosteroid therapy should be limited to those with severe, recalcitrant disease because of the risk for corticosteroid toxicity. The regimen is 20 to 40 mg/d with dosage tapering as soon as a clinical response is obtained.
- Oral pilocarpine therapy has been recently approved by the Food and Drug Administration for use in SS. It may be helpful in patients with sicca symptomatology in dosages of 5 mg three or four times daily (see section VII.B. above).
- Hydroxychloroquine has also been studied in SS, and its effects have been very modest in treating sicca symptoms or fatigue symptoms.
- Cytotoxic therapy (specifically azathioprine, cyclophosphamide, chlorambucil, methotrexate) does not seem to offer any significant benefit unless one is treating a true malignancy (lymphoma) or an invasive form of pseudolymphoma in SS.
Books@Ovid
Copyright 2000 by Lippincott Williams & Wilkins
Stephen A. Paget, M.D., Allan Gibofsky, M.D., J.D. and John F. Beary, III, M.D.
Manual of Rheumatology and Outpatient Orthopedic Disorders
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