Sjögren's Syndrome

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Sjogren's Syndrome: A guide for the Patient
Sjogren's Syndrome Questions and Answers
Researchers identify possible Sjögren's trigger
Dehydroepiandrosterone (DHEA) not effective for treating Sjögrens syndrome
Sjögren's Syndrome; as listed in the Merck Manual
Sjögren's Syndrome
Infliximab Shows Promise Against Active Primary Sjogren's Syndrome

Sjögren's Syndrome Robert I. Fox, MD, PhD  Key findings on  Sjögren's syndrome (SS) were presented at this year's American College of Rheumatology (ACR) 66th annual meeting in New Orleans, Louisiana.

The reports on SS this year largely represented a "consolidation" of observations that had been made in past years based on reevaluation of the data from patient cohorts using the proposed new American-European consensus criteria for SS. These new criteria require either a characteristic biopsy specimen or characteristic autoantibody (ie, SS-A, Ro) in addition to significant objective findings of oral and ocular dryness. The new criteria exclude hepatitis C and other causes of dryness.

Terenzi and coworkers[14] from New York compared patients classified under the European system (EEC) and the new consensus system and found that a main difference was that patients with dryness and fibromyalgia were no longer included in the new consensus criteria. The implementation of new methods to define disease activity and response to therapy is being developed based on scales used in SLE and previous measures called "oral health quality-of-life impact measures."

Using the revised criteria, Witte and coworkers[15] from Germany found an increased frequency of IgA anti-fodrin antibodies (as well as in SLE patients), whereas a separate study of SS patients by Sibilia and colleagues[16] failed to find a significant association with antibodies directed against the fodrin 120-kd fragment that plays a critical role in one murine model of SS (the NFS/sld mouse after thymectomy).

Patients with SS may develop antibodies to a novel centromeric antigen (cen-C), and these patients also recognize SS-A (52 kd) and SS-B (45 kd), according to Pillemer and coworkers[17] of Bethesda. This novel reactivity with a centromeric antigen is distinct from the cen A/cen B, which appears to be an antigenic target in scleroderma patients and helps explain the coexistence of some patients with antibodies to SS-A and yet having an anti-centromeric pattern on their ANA test results. Anti-citrulline antibodies may be present in some SS patients (who are ANA positive and RF negative) and were associated with synovitis previously termed rheumatoid arthritis (RA).

Jonnson and colleagues[18] from Norway reported on the expression of B-cell activating factor (BAFF) in salivary glands, as well as expression of E-cadherin and its integrin ligand aEb7 on the glandular vascular cells and cells infiltrating glandular epithelial cells, respectively. An increased level of Fas and Fas L were again noted, although the level of apoptotic cells was not increased. This activation of early steps of apoptosis appears to lead to glandular dysfunction, as measured by decreased response to muscarinic agonists, even in the absence of apoptotic changes of nuclear fragmentation and cellular blebbing.

Beutler[19] (San Diego) reviewed the important role of cell signaling through TOLL-like receptors to generate apoptotic products. These pathways involve CARD and NOD motif proteins, initially recognized as important elements in the response to lipopolysacharide and now considered as potential agents in the generation of autoantigens that maintain autoimmune T cells (as discussed above). Although distinct from SS, it was also noted that Blau's syndrome (granulomatous uveitis that simulates sarcoidosis) results from mutations in the nod sequences and that familial Mediterranean fever derives from interleukin 1 liberated in unopposed fashion due to mutations in the pyrin gene (Kaster and coworkers,[20] Bethesda), which normally serves as a break on this inflammatory cascade.

Kapsogeorgou and colleagues[21] from Athens reported that glandular cells could release exosomal vesicles that contain potential autoantigens and thus present additional methods to maintain autoimmune T cells similar to those described above for SLE. Lavie and coworkers[22] from France reported that rank and rank ligand, members of the tumor necrosis factor (TNF) superfamily usually associated with bone remodeling, were expressed in the SS salivary gland and could potentially lead to stimulation of T cells and B cells by salivary gland ductal epithelial cells.

Grandis and colleagues[23] from Minnesota reported analysis of complementary DNA made from SS peripheral blood using a microarray of oligonucleotides corresponding to a wide spectrum of inflammatory-related markers. They found at least 2-fold differences in more than 80 genes, including those associated with FAS, protein kinase C, BAFF, and ubiquitin. During the discussion period, the limitations of using blood (a heterogeneous population) to detect small changes in transcription and assay reliability for small changes in transcription were mentioned, but this technology may be useful in monitoring clinical response in particular patients.

Depression as measured by the Center for Epidemiologic Studies--Depression scale was more common in a cohort of SS patients than in age-matched RA patients, according to Reisine and Parke[24] in Connecticut. The dryness symptoms may be further exacerbated by certain antidepressive medications, and the symptoms of dryness (in comparison to objective findings) are further exaggerated by the depression. This creates a vicious cycle for the patient with sleep deprivation and fatigue, as well as a diagnostic and therapeutic difficulty for the rheumatologist.

Sankar and colleagues[25] from Bethesda found that an elevation in serum IgM levels at presentation was associated with a serial decline in salivary gland function as measured by decreased saliva production that occurred in about half of a cohort of 46 patients followed up for 2 years, whereas surprisingly, no association was found with erythrocyte sedimentation rate or IgG levels at presentation. In long-term follow-up studies of SS patients, Quemeneur and coworkers[26] from France found progression of mild interstitial lung disease, which may have been due to aging, as measured by serial pulmonary function tests in 12 patients, for a mean of 10 years.

In a cohort of 110 patients, Ramos-Casals and colleagues[27] from Mexico found a circulating monoclonal protein in 24 patients. Although these patients had extraglandular manifestations such as purpura and pneumonitis, they did not find lymphoproliferative disease (although the length of follow-up of one patient for lymphoproliferative disease was short). In a long-term follow-up of a Greek cohort of patients by Ionnakis and coworkers,[28] purpura and low complement as well as parotid swelling at time of initial evaluation were significant predictors of development of lymphoma at 10-year follow-up.

Different aspects of therapy were presented. Dehydroepiandrosterone was not found to have significant benefit, according to Pillemer and colleagues[29] from Bethesda. Steinfeld and coworkers[30] (Amsterdam) presented favorable results from an open-label trial using infliximab (3 mg/kg) at 0.2 and 6 weeks followed by every 12 weeks in patients with at least one extraglandular manifestation (usually arthritis). These patients were not receiving concurrent methotrexate and had not previously been taking methotrexate.

With the exception of infusion reactions, Steinfeld and colleagues thought that the results were encouraging and noted that the study had now been extended to almost 100 patients with few toxic effects. However, the discussion noted that a safer medication (methotrexate) had not previously failed and that the patients showed wide variation in response (unlike the dramatic response of RA patients to infliximab). Also, the discussion pointed out the potential risks of lymphoma (increased in SS) and potential difficulty in detecting TBC (due to increased frequency of pneumonitis in this population), as well as increased risk of demyelinating disease in this population that could be exacerbated by TNF inhibitors. Other biologic agents that may undergo trial in SS would be targeted toward B cells, including anti-CD20 (rituximab) for the hemolytic anemia or thrombocytopenia, as well as CTLA-4 Ig or anti-BAFF antibody.

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Infliximab Shows Promise Against Active Primary Sjogren's Syndrome

NEW YORK (Reuters Health) Jan 07 - In patients with active primary Sjogren's syndrome, treatment with infliximab, a tumor necrosis factor (TNF) antagonist, may provide lasting relief, Brussels, Belgium-based researchers report.

In an initial 3-month pilot study of 16 such patients, infliximab (3 mg/kg) given in three separate infusions at weeks 0, 2, and 6, was safe and led to rapid and sustained improvement in all clinical and functional parameters.

These successful results led Dr. Serge D. Steinfeld and colleagues from Erasme University Hospital to extend the protocol to test the safety and efficacy of infliximab as a maintenance regimen. They administered additional infusions of infliximab approximately every 12 weeks for 1 year
to 10 of the original 16 subjects.

In the December issue of Arthritis and Rheumatism, the team reports that the clinical improvements induced by the three original infusions lasted 9 weeks before the first symptoms of Sjogren's reemerged. The most common recurrent symptom was dry mouth.

Three patients remained completely free of symptoms for 1 year after the initial infliximab treatment regimen. With a median age of 37.3 years, these patients were younger than the other patients and had shorter disease duration (<3 years).

The maintenance regimen was generally well tolerated. The main side effect was mild self-limited infusion reactions. After 1 year, all 10 patients experienced a "statistically significant decrease in global and local disease manifestations," Dr. Steinfeld's team reports. "Interestingly," they
write, "retreatment induced an improvement that was comparable with the
response seen at week 14 of the pilot study."

The team adds that a controlled trial is needed to define the optimal
reinfusion regimen. Arthritis Rheum 2002;46:3301-3303.

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Sjögren's Syndrome

Sjögren's syndrome is characterized by excessive dryness of the eyes, mouth, and other mucous membranes.

Sjögren's syndrome is thought to be an autoimmune disorder, but its cause is not known. It is more common in women than in men.

White blood cells infiltrate the glands that secrete fluids, such as the salivary glands in the mouth and the tear glands in the eyes. The white blood cells injure the glands, resulting in a dry mouth and dry eyes--the hallmark symptoms of this syndrome.
Symptoms

In some people, only the mouth or eyes are dry (a condition called sicca complex or sicca syndrome). Dryness of the eyes may severely damage the cornea, resulting in a scratchy or irritated sensation, and a lack of tears can cause permanent eye damage. Insufficient saliva in the mouth can dull taste and smell, make eating and swallowing painful, and cause cavities. The salivary glands in the cheeks (parotids) become enlarged and slightly tender in about one third of people. The mouth may also burn, which may sometimes indicate a complicating yeast infection.

In other people, many organs are affected. Sjögren's syndrome can dry out the mucous membranes lining the digestive tract, windpipe (trachea), vulva, and vagina. Dryness of the trachea and lungs can make these organs more susceptible to infection, leading to pneumonia. Dryness of the vulva and vagina can make sexual intercourse difficult. The protective sac surrounding the heart (pericardium) may be inflamed--a condition called pericarditis. Nerve, lung tissue, and other tissues may be damaged by the inflammation.

Joint inflammation (arthritis) occurs in about one third of people, affecting the same joints that rheumatoid arthritis affects, but the joint inflammation of Sjögren's syndrome tends to be milder and is usually not destructive. Some people also have severe rheumatoid arthritis or systemic lupus erythematosus.

Lymphoma, a cancer of the lymphatic system, is much more common in people who have Sjögren's syndrome than in the general population.
Diagnosis

Although a sensation of dry mouth or dry eyes is fairly common, a sensation of dry mouth and dry eyes accompanied by joint inflammation probably indicates that the person has Sjögren's syndrome. Various tests can help a doctor diagnose this disorder and differentiate it from other connective tissue disorders that can produce similar symptoms.

The amount of tears produced can be estimated by placing a filter paper strip under each lower eyelid and observing how much of the strip is moistened (Schirmer test). A person who has Sjögren's syndrome may produce less than one third of the normal amount. An ophthalmologist can test for damage to the eye's surface. More sophisticated tests to evaluate salivary gland secretion may be performed, and a doctor may order scans or a biopsy of the salivary glands.

Blood tests can detect abnormal antibodies, including SS-B, an antibody that is highly specific for Sjögren's syndrome. Often, people with Sjögren's syndrome also have antibodies that are more characteristic of rheumatoid arthritis or lupus. The erythrocyte sedimentation rate (ESR), a test that measures the rate at which red blood cells settle to the bottom of a test tube containing blood, is elevated in about 7 of 10 people. About 1 of 3 people has a decreased number of red blood cells (anemia) or of certain types of white blood cells (leukopenia).
Prognosis and Treatment

The prognosis is generally good. However, if the lungs, kidneys, or lymph nodes are damaged by the antibodies, pneumonia, kidney failure, or lymphoma may result.

No cure for Sjögren's syndrome is available, but symptoms can be relieved. Dry eyes can be treated with artificial tear drops. A dry mouth can be moistened by continuously sipping liquids, chewing sugarless gum, or using a mouth rinse. Drugs that reduce the amount of saliva, such as decongestants, antidepressants, and antihistamines, should be avoided because they can worsen the dryness. The drug pilocarpine may help stimulate the production of saliva if the salivary glands are not too severely damaged.

Fastidious dental hygiene and frequent dental visits can minimize tooth decay and loss. Painful, swollen salivary glands can be treated with analgesics. Because joint symptoms are usually mild, treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) and rest is often sufficient. When symptoms resulting from damage to internal organs are severe, corticosteroids such as prednisone given by mouth can be useful.

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Pilot clinical trial concludes Dehydroepiandrosterone (DHEA) not effective for treating Sjögrens syndrome

Researchers studied the effect of the non-prescription hormone DHEA on 28 Sjögrens patients. A positive response was considered to be a 20% improvement in at least two of three domains: ocular, oral and laboratory.

Fourteen subjects received DHEA and 14 a placebo. Only two subjects met response criteria in the DHEA group, and three met the criteria in the placebo group. No significant differences were noted between the DHEA and placebo groups for: changes in dry mouth or dry eye symptoms; ocular dryness (Schirmer I test; van Bijsterveld scores); stimulated salivary flow; IgG or ESR. Four DHEA and one placebo group patient dropped out of the study because of adverse effects. In conclusion, DHEA showed no evidence of efficacy as a treatment for Sjögrens syndrome. Without evidence for efficacy, Sjögrens syndrome patients should be discouraged from using unregulated DHEA supplements, since long-term adverse consequences of exposure to this hormone are unknown.

Study conducted by: Stanley R. Pillemer, National Institutes of Health (NIH), Bethesda, MD; Michael Brennan, Carolinas Medical Center, Charlotte, NC; Vidya Sankar, NIH; Rose Anne Leakan, NIH; Margaret Grisius, NIH; Sophie Ligier, Hôpital Maisonneuve-Rosemont, Montreal, PQ, Canada; Marc R. Kok, NIH; Bruce J. Baum, NIH; Philip C. Fox, NIH.

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Researchers identify possible Sjögren's trigger

Next Steps are Further Testing and Clinical Trials

According to the Oct. 5, 2002 issue of the scientific journal The Lancet, researchers at the Hospital for Sick Children, Toronto Western Hospital, and the University of Toronto have found a protein that triggers an allergic reaction in mice with Sjögrens syndrome. When these mice were then immunized against this protein, their Sjögrens went away.

The protein (ICA69) and prototype vaccine were identified by the laboratory of Michael Dosch, MD. By removing the gene that produces the ICA69 protein, mice that normally develop Sjögrens syndrome showed no tear gland disease and a much-reduced salivary disease. The prototype vaccine was able to stop the progression of the disease in the mice.

"Our vaccine was able to stop Sjögrens syndrome even after the disease had fully developed, an unusual finding, since in other autoimmune disorders, it is impossible so far to stop and reverse the disease process once it is fully established," said Dosch, the studys principal investigator and a professor of Paediatrics and Immunology at U of T. "This finding is also exciting because it opens the door to further knowledge about treating selective organ autoimmune diseases, including the possibility of vaccines. In autoimmune diseases such as type 1 diabetes, it is difficult to assess the effectiveness and learn how to use vaccines, since the target organ cannot be examined. With Sjögrens syndrome, the organ attacked by autoimmunity (the exocrine glands) are accessible to study, unlike the pancreas in diabetes, for example."

Doschs research group collaborated with Arthur Bookman, MD, a rheumatologist at Toronto Western Hospital and a member of the SSF Medical and Scientific Advisory Board, to compare the autoimmune response to the ICA69 protein in the mouse model to human patients, which was strikingly similar.

"The blood samples taken from our patients almost uniformly reacted against this same protein in the mice. We plan to extend this research to demonstrate that more patients react against this protein," said Bookman, who co-authored the study. "We are planning a study that will involve at least 100 Sjögrens patients so we can learn more about the connection between this protein and patients autoimmunity in preparation for possible trials of the vaccine in humans."

Bookmans clinic is currently screening patients to see if they will be eligible for our future research studies. However, he cautioned that these studies are an early step in what is often a long process. "Ultimately, of course, we want to see if we can vaccinate human patients against this protein and make their Sjögrens syndrome go away. But that is not going to happen for several years."

Stuart S. Kassan, MD, Chair of the SSF Medical & Scientific Advisory Board, is encouraged by these scientific developments. "The findings are both exciting and extremely important in possibly opening up new avenues for research in the autoimmune diseases and specifically Sjögrens syndrome. Hopefully, the studies conducted at the Hospital for Sick Children in Toronto will stimulate more research efforts into this new frontier of science."

SSF president Ann Race, a Sjögrens patient, expressed great optimism that more research breakthroughs are on the horizon. "Certainly these findings offer yet another step forward in conquering this serious and life-altering disease. The Foundation congratulates the researchers in Toronto on their great success and thanks them for their diligent efforts."

Arthur Grayzel, MD, the SSF's immediate past president, had this to say about the findings: "ICA69 is a cell surface protein of unknown function found in neurons, pancreas (insulin producing beta cells), salivary and lacrimal glands. This paper studied NOD mice which spontaneously develop diabetes and Sjögren's. Both mice and humans with Sjögren's have antibodies to ICA69 in their serum. Mice also have ICA69 specific T lymphocytes in nodes that drain the salivary glands. NOD mice that lack the gene for ICA69 do not develop Sjögren's. NOD mice with established Sjögren's treated with a small immunogenic piece of the ICA69 protein have improvement in their salivary gland inflammation.

"The good news is that if you are a mouse with an autoimmune disease like lupus, diabetes, arthritis and now Sjögren's there is effective treatment. The bad news is that this has not been translated into effective treatment for people. Also researchers studying type one diabetes in mice have had similar data like that described above for over a decade without success in curing humans. Nevertheless the Juvenile Diabetes Society (JDS) believes that they are just one breakthrough away from success and have raised $100 million plus to pursue research in NOD mice and related areas.

"These studies need to be reproduced in other labs and then pursued further. Colonies of NOD mice are expensive. We need to continue our encouragement for NIH to support work in this area. We also can use some of our research funds."

For more information, please visit www.sickkids.ca or www.uhn.on.ca

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