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Abstracts

Sjögren's Syndrome

ABSTRACTS

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Myelopoisis induction on human bone marrow precursor cells by a calf thymic derivative (Thymomodulin); in vitro comparison with exogenous CSF.

Andolina, M., Dobrinz, M.G., Meraviglia, L., Agosti, E., Cazzola, P.

Int. J. Immunother. 1987; 3: 139.

No abstract available.

Nutritional Formulas for the Right Body Chemistry (undated teaching lecture).

Anon.

Philpot, KY: Rolling Press Publications (P.O. Box 70).

Sjogren's Syndrome: Early Detection 2002.

BCD.

College Station, TX: Baylor College of Dentistry/Texas A&M University System Health Science Center (http://www.tambcd.edu/cedental/sjogrens.htm).

Long-term follow-up of patients treated with acupuncture for xerostomia and the influence of additional treatment.

Blom M, Lundeberg T Department of Clinical Oral Physiology, School of Dentistry, Karolinska Institute, Huddinge, Sweden.

Oral Dis 2000 Jan;6(1):15-24

OBJECTIVE: To determine the long-term effects of acupuncture in patients with xerostomia of different etiologies and the influence of additional treatment.

DESIGN: Retrospective study. SUBJECTS: Seventy patients, between the ages of 33 and 82, with xerostomia due to primary and secondary Sjogren's syndrome, irradiation and other causes were included. The median duration of xerostomia was 32 months.

METHODS: Salivary flow rates (SFR) for whole unstimulated and stimulated saliva were used as indicators of effects of treatment. Data from 67/70 patients were analyzed 6 months following a baseline course of 24 acupuncture treatments using two-way ANOVA. Patients data up to 3 years were also compared by those who chose to receive additional acupuncture treatment vs those who did not. These data were analyzed descriptively.

RESULTS: Statistically significant differences in unstimulated and stimulated salivary flow rates (P < 0.01) were found in all etiological groups after 24 acupuncture treatments and up to 6 months follow-up compared to baseline. Three years observation of these patients showed that patients receiving additional acupuncture treatment had a consistently higher median SFR in both unstimulated and stimulated saliva compared to patients who chose not to continue acupuncture. The upper limits of the interquartile range were also higher

CONCLUSIONS: This study shows that acupuncture treatment results in statistically significant improvements in SFR in patients with xerostomia up to 6 months. It suggests that additional acupuncture therapy can maintain this improvement in SFR for up to 3 years. Oral Diseases (2000) 6, 15-24

Dr. Braly's Optimum Health Program 1985.

Braly, J.

New York: Time Books/Random House.

The New Sjogren's Syndrome Handbook 1998.

Carsons, S.

New York: Oxford University Press.

Inflammatory Bowel Disease 2002

DeNoon, D.

(http://content.health.msm.com/content/article/1820.50236).

Beneficial effects of oral zinc supplementation on the immune response of old people.

Duchateau J, Delepesse G, Vrijens R, Collet H

Am J Med 1981 May;70(5):1001-4

Zinc is known to have beneficial effects on the immune response. In an attempt to modify age-associated immune dysfunction, supplemental zinc was administered to 15 subjects over 70 years of age (220 mg zinc sulfate twice daily for a month). As compared to 15 controls, matched for age and sex, there was a significant improvement in the following immune parameters in the treated group: (1) number of circulating T lymphocytes; (2) delayed cutaneous hypersensitivity reactions to purified protein derivative, Candidin and streptokinase-streptodornase; (3) immunoglobulin G (IgG) antibody response to tetanus vaccine. Zinc treatment had no influence on the number of total circulating leukocytes or lymphocytes, or on the in vitro lymphocyte response to three mitogens: phytohemagglutinin (PHA), concanavalin A (Con A) and pokeweed mitogen (PWM). The data suggest that the addition of zinc to the diet of old persons could be an effective and simple way to improve their immune function.

Cevimeline for the treatment of xerostomia in patients with Sjogren syndrome: a randomized trial.

Fife RS, Chase WF, Dore RK, Wiesenhutter CW, Lockhart PB, Tindall E, Suen JY. Department of Medicine, Indiana University School of Medicine, 535 Barnhill Dr, Room 150, Indianapolis, IN 46202, USA.

Arch Intern Med. 2002 Jun 10;162(11):1293-300.

BACKGROUND: Cevimeline hydrochloride is a cholinergic agent with muscarinic agonist activity prominently affecting the M1 and M3 receptors prevalent in exocrine glands. We evaluated the safety and efficacy of cevimeline in the treatment of xerostomia in patients with Sjogren syndrome.

METHODS: Seventy-five patients with Sjogren syndrome and associated salivary gland dysfunction were enrolled in a double-blind, randomized, placebo-controlled trial at 8 university- and office-based outpatient clinical facilities in the United States. Eligible study participants were randomized to receive 30 mg of cevimeline 3 times daily, 60 mg of cevimeline 3 times daily, or placebo for 6 weeks. Subjective responses were determined using global patient evaluation and visual analog scales. Salivary flow was measured objectively.

RESULTS: Sixty-one participants completed the study. Patients in both cevimeline groups had significant improvements in dry mouth, as indicated by symptoms, salivary flow, and use of artificial saliva, compared with the placebo group. The drug was generally well tolerated, with expected adverse events resulting from the drug's muscarinic agonist action. Fourteen patients withdrew from the study because of adverse events, the most frequent being nausea.

CONCLUSIONS: Therapy with cevimeline, 30 mg 3 times daily, seems to be well tolerated and to provide substantive relief of xerostomia symptoms. Although both dosages of cevimeline provided symptomatic improvement, 60 mg 3 times daily was associated with an increase in the occurrence of adverse events, particularly gastrointestinal tract disorders. Use of 30 mg of cevimeline provides a new option for the treatment of xerostomia in Sjogren syndrome.

Anti-CD3 and anti-CD2-induced T-cell activation in primary Sjogren's syndrome.

Gerli R, Bertotto A, Cernetti C, Agea E, Crupi S, Arcangeli C, Spinozzi F, Galandrini R, Rambotti P. Department of Internal Medicine, University of Perugia, Italy.

Clin Exp Rheumatol 1989 Sep-Oct;7 Suppl 3:S129-34

Because T-cell dysfunctions have been reported in patients with primary Sjogren's syndrome (SS), peripheral blood mononuclear cell (PBMC) proliferation obtained with anti-CD3 and anti-CD2 monoclonal antibodies was evaluated in these patients. Anti-CD3-induced mitogenesis, which varied widely among the patients, was lower in subjects with evidence of anti-SSA and anti-SSB antibodies than in controls. Moreover, the anti-CD2-induced response was depressed in about half the patients and the nonresponders were mainly those with anti-SSA and anti-SSB antibodies. Phorbol myristate acetate, a protein kinase C activator, used alone or added to anti-CD3, induced greater proliferation in patients than in control PBMC. In contrast, exogenous recombinant interleukin 2 (rIL-2) did not significantly enhance the anti-CD2-induced response of patients' PBMC, as it did in normal PBMC. Peripheral blood and parotid T cells from a patient with well-defined primary SS and parotid enlargement also responded poorly to anti-CD2 stimulation. Exogenous rIL-2 restored T-cell proliferation only in the salivary gland cultures of this patient. The present findings suggest that there is a T-cell activation defect in subjects with primary SS, particularly in those with circulating anti-SSA and anti-SSB antibodies. In addition, the difference in the response to IL-2 of peripheral blood and parotid-infiltrating T cells would seem to indicate that T-cell subsets are differently distributed in the blood and inflammation site.

Invisible Drug Terrorist That May Take Your Immune System Hostage 2000

Gilbere, G.

(http://www.needs.com/vitalityarchive/winter02.asp).

Stress-induced immunomodulation: implications for infectious diseases?

Glaser, R., Rabin, B., Chesney, M., Cohen, S., Natelson, B.

JAMA 1999 Jun 23-30; 281(24): 2268-70.

No abstract available.

Therapy of secondary T-cell immunodeficiencies with biological substances and drugs.

Hadden, J.W., Hadden, E.M.

Med. Oncol. Tumor Pharmacother. 1989; 6(1): 11.

Dietary n-6 and n-3 fatty acids in immunity and autoimmune disease.

Harbige LS School of Chemical and Life Sciences, University of Greenwich, London, UK. Harbige@greenwich.ac.uk

Proc Nutr Soc 1998 Nov;57(4):555-62

Clearly there is much evidence to show that under well-controlled laboratory and dietary conditions fatty acid intake can have profound effects on animal models of autoimmune disease. Studies in human autoimmune disease have been less dramatic; however, human trials have been subject to uncontrolled dietary and genetic backgrounds, infection and other environmental influences, and basic trial designs have been inadequate. The impact of dietary fatty acids on animal autoimmune disease models appears to depend on the animal model and the type and amount of fatty acids fed. Diets low in fat, essential fatty acid-deficient, or high in n-3 fatty acids from fish oils increase the survival and reduce disease severity in spontaneous autoantibody-mediated disease, whilst linoleic acid-rich diets appear to increase disease severity. In experimentally-induced T-cell-mediated autoimmune disease, essential fatty acid-deficient diets or diets supplemented with n-3 fatty acids appear to augment disease, whereas n-6 fatty acids prevent or reduce the severity. In contrast, in both T-cell and antibody-mediated auto-immune disease the desaturated and elongated metabolites of linoleic acid are protective. Suppression of autoantibody and T lymphocyte proliferation, apoptosis of autoreactive lymphocytes, and reduced pro-inflammatory cytokine production by high-dose fish oils are all likely mechanisms by which n-3 fatty acids ameliorate autoimmune disease. However, these could be undesirable long-term effects of high-dose fish oil which may compromise host immunity. The protective mechanism(s) of n-6 fatty acids in T-cell- mediated autoimmune disease are less clear, but may include dihomo-gamma-linolenic acid- and arachidonic acid-sensitive immunoregulatory circuits such as Th1 responses, TGF beta 1-mediated effects and Th3-like responses. It is often claimed that n-6 fatty acids promote autoimmune and inflammatory disease based on results obtained with linoleic acid only. It should be appreciated that linoleic acid does not reflect the functions of dihomo-gamma-linolenic and arachidonic acid, and that the endogenous rate of conversion of linoleic to arachidonic acid is slow (Hassam et al. 1975, 1977; Phylactos et al. 1994; Harbige et al. 1995). In addition to effects of dietary fatty acids on immunoregulation, inflammation as a consequence of immune activation in autoimmune disease may also be an important mechanism of action whereby dietary fatty acids modulate disease activity. In conclusion, regulation of gene expression, signal transduction pathways, production of eicosanoids and cytokines, and the action of antioxidant enzymes are all mechanisms by which dietary n-6 and n-3 fatty acids may exert effects on the immune system and autoimmune disease. Probably the most significant of these mechanisms in relation to our current understanding of immunoregulation and inflammation would appear to be via fatty acid effects on cytokines. The amount, type and balance of dietary fatty acids and associated antioxidant nutrients appear to impact on the immune system to produce immune-deviation or immunosuppressive effects, and to reduce immune-mediated inflammation which will in turn affect the susceptibility to, or severity of, autoimmune disease.

Non-steroidal anti-inflammatory drug gastropathy: causes and treatment.

Hawkey CJ. Division of Gastroenterology, University Hospital, Nottingham, UK.

Scand J Gastroenterol Suppl. 1996;220:124-7.

Aspirin and non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) almost invariably cause acute gastroduodenal injury and probably account for approximately 12,000 ulcer bleeding episodes and 1200 deaths per annum in the United Kingdom. Clinically significant intestinal toxicity is also recognized but less clearly defined. The main risk factors for NSAID-related peptic ulcer complications are age, past history, use of higher risk individual NSAIDs, drug dose, concurrent use of warfarin or corticosteroids. The underlying reason for NSAID use and Helicobacter pylori status is not clearly associated with increased risk. Whether NSAIDs cause drug-induced non-ulcer dyspepsia is also controversial. Acute injury occurs more readily with aspirin than with non-aspirin NSAIDs, and the spectrum of acute injury is of little value in predicting clinically significant end points in comparison with different NSAIDs. However, acute studies of co-prescribed protective agents are highly predictive of performance in clinical practice. Gastric mucosal integrity is maintained by the interplay of three protective networks: prostaglandin synthesis, nitric oxide synthesis and the activity of the enteric nervous system. Aspirin and NSAIDs act by inhibiting prostaglandin synthesis catalysed by two cyclooxygenase enzymes. Most existing NSAIDs are unselective and inhibit the activity of the constitutive cyclooxygenase (COX) 1 enzyme in the stomach as much as the cyclooxygenase (COX) 2 enzyme which is induced at sites of inflammation such as joint disease. There are, however, prospects for selective cyclooxygenase 2 inhibitors. Some NSAIDs, particularly aspirin, have additional topical toxicity, which may in part reflect mucosal trapping. Some data favor an effect of NSAIDs in inhibiting mitochondrial oxidative phosphorylation. The principal physiological mechanisms which are compromised by NSAID use are mucosal blood flow, secretion of mucus and bicarbonate and maintenance of a hydrophobic mucosal surface. Animal data suggest that polymorphonuclear leukocytes (PMNs) are important for acute damage though the relevance to humans has yet to be established. As well as damaging the mucosa, NSAIDs impair ulcer healing and are associated with reduced epithelial proliferation and evidence of diminished angiogenesis. An interaction between prostaglandins and growth factors, as well as the synthesis of antiproliferative products of arachidonic acid metabolism may be involved. Healing of NSAID ulcers by conventional doses of H2 antagonists is slow and H2 antagonists are poor at preventing gastric ulcer development or recurrence. These problems can be overcome by the use of more potent acid suppression. Misoprostol heals NSAID-associated ulcers, though whether healing is as fast as with non-NSAID ulcers has not been formally established. Misoprostol is effective prophylactic treatment but has a significant incidence of adverse events, particularly diarrhoea. Misoprostol has been reported to prevent ulcer complications, and in endoscopic studies has been superior as prophylaxis to standard dose ranitidine. Results of its efficacy compared to proton-pump inhibitors are awaited. For many patients appropriate management is avoidance of NSAIDs or use of less potent/toxic alternatives such as ibuprofen. Reductions in prescribing arising from a prior authorization scheme show that this can be achieved. For high-risk patients requiring continuing NSAID use co-prescription of omeprazole or misoprostol should be considered.

Fluoride Toxicity 2001.

HSRI.

aytona Beach, FL: Health & Science Research Institute

(http://www.health-science.com/index.htm?page=/fluoride_toxicity.html).

Loss of delta-6-desaturase activity as a key factor in aging.

Horrobin DF.

Med Hypotheses. 1981 Sep;7(9):1211-20.

Aging is characterized by a wide variety of defects, particularly in the cardiovascular and immune systems. Cyclic AMP levels fall, especially in lymphocytes. Delta-6-desaturase (D6D) levels have been found to fall rapidly in the testes and more slowly in the liver in aging rats. D6D is an enzyme which converts cis-linoleic acid to gamma-linolenic acid (GLA). Other factors which inhibit D6D activity are diabetes, alcohol and radiation, all of which may be associated with accelerated aging. In meat eaters or omnivores which can acquire arachidonic acid from food, the main consequences of D6D loss will be deficiencies of GLA, dihomogamma-linolenic acid (DGLA) and prostaglandin (PG) E1. PGE1 activates T lymphocytes, inhibits smooth muscle proliferation and thrombosis, is important in gonadal function and raises cyclic AMP levels in many tissues. It is a good candidate for a key factor lost in aging. Moderate food restriction, the only manoeuvre which consistently slows aging in homoiotherms, raises D6D activity by 300%. Other factors important in regulating D6D and the conversion of GLA to PGE1 are zinc, pyridoxine, ascorbic acid, the pineal hormone, melatonin, and possibly vitamin B3. GLA administration to humans has been found to lower blood pressure and cholesterol, and to cause clinical improvement in patients with Sjogren's syndrome, scleroderma and alcoholism. These diseases are associated with some features of accelerated aging. The proposition that D6D loss is not only a marker of aging but a cause of some of its major manifestations is amenable to experimental test even in humans. The blocked enzyme can be by-passed by giving GLA directly.

Essential fatty acid metabolism in diseases of connective tissue with special reference to scleroderma and to Sjogren's syndrome.

Horrobin DF

Med Hypotheses 1984 Jul;14(3):233-47

Drugs which modify the conversion of essential fatty acids to prostaglandins and leukotrienes are the mainstays of treatment in rheumatology. Yet these drugs have little or no action in scleroderma or Sjogren's syndrome and under some circumstances may have adverse effects. Patients with scleroderma have been shown to have very high levels of circulating prostaglandins, coupled with depletion of the prostaglandin precursors, dihomogammalinolenic acid and arachidonic acid. Levels of the metabolites of arachidonic acid, 22:4n-6 and 22:5n-6, which have major roles in maintaining normal cell membrane characteristics were exceptionally low in both plasma and red cell membranes. Others have observed that various functions are highly resistant to normal actions of PGs in scleroderma. This raises the possibility that the high rate of PG formation in scleroderma may be beneficial, in compensation, and that clinical symptoms develop when PG precursors begin to be depleted. Red cell membrane fatty acids patterns in Sjogren's syndrome are almost identical to those in scleroderma. Placebo-controlled trials of supplementation with essential fatty acids have been found to be beneficial in both scleroderma and Sjogren's syndrome.

Essential fatty acid and prostaglandin metabolism in Sjogren's syndrome, systemic sclerosis and rheumatoid arthritis.

Horrobin DF

Scand J Rheumatol Suppl 1986;61:242-5

Evidence from biochemical studies and from experimental animals indicates that abnormalities of essential fatty acid (EFA) and eicosanoid metabolism could lead to salivary and lacrimal gland atrophy and to immunological and cardio-vascular defects. Measurements of EFA levels in erythrocytes from patients with primary Sjogren's syndrome have shown that abnormalities are indeed present. Controlled clinical trials of supplementation with gamma-linolenic acid (GLA) as evening primrose oil (Efamol) in both primary Sjogren's syndrome and systemic sclerosis have given positive results. There are strong arguments to indicate that sophisticated manipulation of EFA metabolism may have a role to play, not only in Sjogren's syndrome but also in other rheumatological disorders.

Estrogen deficiency accelerates autoimmune exocrinopathy in murine Sjogren's syndrome through fas-mediated apoptosis.

Ishimaru N, Saegusa K, Yanagi K, Haneji N, Saito I, Hayashi Y Departments of Pathology and Pediatric Dentistry, Tokushima University School of Dentistry, Tokushima, Japan.

Am J Pathol 1999 Jul;155(1):173-81

Estrogenic action has been suggested to be responsible for the strong female preponderance of autoimmune diseases, but the role of estrogens in the female has not been well characterized. We evaluated the effects of estrogen deficiency in a murine model for autoimmune exocrinopathy of Sjogren's syndrome (SS). Severe destructive autoimmune lesions developed in the salivary and lacrimal glands in estrogen-deficient mice, and these lesions were recovered by estrogen administration. We detected an intense estrogen receptor in splenic CD8(+) T cells compared with that in CD4(+) T cells, and concanavalin-A-stimulated blastogenesis of splenic CD8(+) T cells with estrogens was much higher than that of CD4(+) T cells. We found a significant increase in serum autoantibody production against the organ-specific autoantigen alpha-fodrin. Moreover, an increased proportion of TUNEL+ apoptotic epithelial duct cells was observed in estrogen-deficient mice. It was demonstrated that Fas-mediated apoptosis in cultured salivary gland cells was clearly inhibited by estrogens in vitro. These results indicate that dysfunction of regulatory T cells by estrogen deficiency may play a crucial role on acceleration of organ-specific autoimmune lesions, and estrogenic action further influences target epithelial cells through Fas-mediated apoptosis in a murine model for SS.

Sjogren's Syndrome and Lupus 2001

Klassen, S.

(http://www.lupus.org/education/brochures/sjogren.html).

Oral glutamine accelerates healing of the small intestine and improves outcome after whole abdominal radiation.

Klimberg VS, Salloum RM, Kasper M, Plumley DA, Dolson DJ, Hautamaki RD, Mendenhall WR, Bova FC, Bland KI, Copeland EM 3rd, et al. Department of Surgery, University of Florida College of Medicine, Gainesville 32610.

Arch Surg. 1990 Aug;125(8):1040-5.

The healing effects of glutamine given orally for 8 days as a single amino acid nutrient after treatment with whole abdominal radiation (10 Gy) were studied. Rats received isonitrogenous and isovolumic diets containing 3% glutamine or 3% glycine. Control rats were not irradiated but were given identical diets. In irradiated animals, survival was 100% in animals receiving glutamine compared with 45% in animals receiving glycine. Glutamine ingestion diminished bloody diarrhea and the incidence of bowel perforation. Arterial glutamine level was higher in animals receiving glutamine in the diet, as were gut glutamine extraction (35% +/- 8% vs 12% +/- 7%) and intestinal glutaminase activity. These metabolic improvements were associated with a marked increase in villous height, villous number, and the number of mitoses per crypt in rats receiving glutamine. Glutamine was not beneficial in control nonirradiated animals. The data demonstrated that provision of oral glutamine after abdominal radiation supported gut glutamine metabolism, improved mucosal morphometrics, and decreased the morbidity and mortality associated with this abdominal radiation model.

Thymomodulin: biological properties and clinical applications.

Kouttab NM, Prada M, Cazzola P. Dept of Pathology, Roger Williams General Hospital, Providence, Rhode Island.

Med Oncol Tumor Pharmacother. 1989;6(1):5-9.

Thymomodulin (Ellem Industria Farmaceutica s.p.a., Milan, Italy) is a calf thymus acid lysate derivative, composed of several peptides with a molecular weight range of 1-10 kD. Thymomodulin did not exhibit any mutagenic effect. Furthermore, thymomodulin used in animal studies showed no toxicity even when used at high concentrations. Of major significance are the observations in murine and human systems that thymomodulin remains active when administered orally. In vitro and in vivo administered thymomodulin was able to induce the maturation of T-lymphocytes. Additionally, studies in vitro showed that this thymic derivative can enhance the functions of mature T-lymphocytes with cascading effects on B-cell and macrophage functions. Extensive human clinical trials with thymomodulin showed that this agent can improve the clinical symptoms observed with various disease processes, including infections, allergies and malignancies, and can improve immunological functions during ageing.

Interferon gamma and tumor necrosis factor alpha induce Fas expression and anti-Fas mediated apoptosis in a salivary ductal cell line.

Matsumura R, Umemiya K, Goto T, Nakazawa T, Ochiai K, Kagami M, Tomioka H, Tanabe E, Sugiyama T, Sueishi M. Department of Internal Medicine, Toho University School of Medicine, Sakura Hospital, Japan.

Clin Exp Rheumatol. 2000 May-Jun;18(3):311-8.

BACKGROUND: We previously reported that Fas antigen was strongly expressed on salivary duct epithelial cells and that some salivary infiltrating cells showed the Fas ligand in patients with severe sialoadenitis due to Sjogren's syndrome (SS). Apoptotic changes were observed in ductal epithelial cells and some infiltrating cells by DNA nick end labeling methods. These findings suggest that the Fas-Fas ligand system may play a role in the pathogenesis of sialoadenitis in SS.

OBJECTIVE: To elucidate the mechanism of the de novo expression of ductal Fas antigen in sialoadenitis associated with SS, we investigated the induction of Fas antigen and apoptosis by cytokines in a human salivary duct cell line.

METHODS: Human salivary duct cell line (HSG) was cultured with interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta), interleukin 2 (IL-2), interleukin 4 (IL-4), and granulocyte monocyte colony stimulating factor (GM-CSF). The expression of Fas antigen in HSG was examined by immunoperoxidase cell ELISA. The appearance of DNA strand breaks during apoptosis induced by anti-Fas antibody was detected by DNA nick end labeling methods.

RESULTS: Unstimulated HSG cells constitutively expressed low levels of Fas antigen. IFN-gamma and TNF-alpha consistently upregulated constitutive levels of Fas. In contrast, IL-1 beta, IL-2, IL-4, and GM-CSF had no effect on Fas levels. HSG cells expressing Fas antigen in response to IFN-gamma or TNF-alpha were susceptible to apoptosis by anti-Fas antibody.

CONCLUSION: Our findings suggest that IFN-gamma or TNF-alpha secreted by infiltrating lymphocytes induces ductal Fas expression and ductal apoptosis in sialoadenitis associated with SS.

Sjogren's Syndrome Clinic 2000.

NIDCR.

Bethesda, MD: Division of Intramural Research/National Institute of Dental and

Craniofacial Research/National Institutes of Health

(http://wwwdir.nidcr.nih.gov/sjogrens/SjogrenMain.htm).

The use of oral pilocarpine in xerostomia and Sjogren's syndrome.

Nusair S, Rubinow A Division of Medicine, the Hadassah University Hospital and Hebrew University-Hadassah School of Medicine, Jerusalem, Israel. samjack@shani.net

Semin Arthritis Rheum 1999 Jun;28(6):360-7

OBJECTIVES: To analyze the role of oral pilocarpine in the treatment of xerostomia of Sjogren's syndrome (SS).

METHODS: The medical literature was reviewed for all studies using oral pilocarpine to treat xerostomia caused by SS or radiotherapy registered in the MedLine Silver Platter database from 1966 to 1998.

RESULTS: All the studies identified excluded elderly individuals with cardiac or pulmonary disease. Patients with postradiation xerostomia and incomplete resection of the salivary glands were more likely to benefit from oral pilocarpine when there was sufficient residual glandular function than patients with radical surgery for head and neck cancer (HNC). However, patients with SS and other inflammatory disorders seemed to benefit from oral pilocarpine, when compared with patients with postradiation xerostomia. The optimal dose of oral pilocarpine, which was less likely to cause side effects, was 5 mg four times daily. A recent multi-center study in SS patients suggests that oral pilocarpine is effective and safe for long-term administration. Although some studies did not show evidence for increased salivary gland secretion rate as measured by sialometry, symptoms improved, perhaps because of increased secretion from the minor salivary glands or better conditioning of the oral mucosa.

CONCLUSIONS: Oral pilocarpine is likely to benefit patients with SS by reducing the symptoms of xerostomia, even if the salivary gland secretion rate does not increase. Further controlled studies are needed in patients with SS and should include elderly patients with cardiovascular disease treated with moderate doses of oral pilocarpine.

Fas-induced apoptosis is a rare event in Sjogren's syndrome.

Ohlsson M, Skarstein K, Bolstad AI, Johannessen AC, Jonsson R. Broegelmann Research Laboratory, University of Bergen, Norway. Maria.Ohlsson@gades.uib.no

Lab Invest. 2001 Jan;81(1):95-105.

The aim of this study was to perform a controlled in situ analysis on the incidence of apoptosis, investigate the expression of apoptosis-mediating proteins, and determine the frequency of apoptotic CD4+ and CD8+ T cells in Sjogren's syndrome (SS). The study was extended to patients with atrophy-fibrosis (AF) not related to SS, as well as to a control group. Immunohistochemistry and the terminal deoxynucleotidyl transferase mediated dUTP digoxigenin nick end labeling (TUNEL) method were applied to study the Fas and FasL expression and the incidence of apoptosis in salivary glands (SG) from patients with primary and secondary SS, AF, and controls. These methods were also combined to enable simultaneous detection of apoptotic and CD4+ or CD8+ T cells. Despite abundant expression of Fas and FasL in SS SG, apoptotic cells were not exceeding 1% in the foci of infiltrating mononuclear cells (IMC). Double staining showed that the frequency of apoptosis was low among both CD4+ and CD8+ T cells. Only a few TUNEL+ epithelial cells were found in all patient groups. Fas was expressed predominantly on SS IMC, single SS epithelial cells, and a few normal acinar cells, but not in AF SG. Although FasL was present on SS and AF IMC and epithelial cells, it was rarely detected in normal tissue. Consequently we demonstrate that Fas-induced apoptosis among SS SG is a rare event. Our findings support an earlier hypothesis indicating that IMC seem to be able to escape apoptosis, resulting in foci of inflammatory cells. Notably, however, no obvious correlation can be drawn to previous studies where a high incidence of apoptosis of epithelial cells was proposed as an important mechanism leading to decreased glandular function, which is a hallmark of SS.

Patients with primary Sjogren's syndrome treated for two months with evening primrose oil.

Oxholm P, Manthorpe R, Prause JU, Horrobin D

Scand J Rheumatol 1986;15(2):103-8

Twenty-four female and 4 male patients, all fulfilling the Copenhagen criteria for primary Sjogren's syndrome (primary SS), were treated for 8 weeks with evening primrose oil (Efamol). Efamol is a seed oil which consists primarily of the n-6 essential fatty acids (EFA): cis-linoleic acid and gammalinolenic acid (GLA). The investigation was carried out as a randomized, double-blind, placebo-controlled, cross-over trial in order to determine whether long-term treatment of patients with primary SS with Efamol would improve the ocular and oral clinical status, and whether the levels of EFA in plasma and erythrocytes increase during Efamol treatment. The objective ocular status, evaluated by a combined ocular score, including the results from Schirmer-I test, break-up time and van Bijsterveld score, improved significantly during Efamol treatment when compared with Efamol start-values (p less than 0.05), but not when compared with placebo values (p less than 0.2). The GLA metabolite and prostaglandin-E1 (PGE1) precursor dihomogammalinolenic acid (20: 3n6, DGLA) increased both in plasma (p less than 0.001) and in erythrocytes (p less than 0.001) during treatment with Efamol. No correlations between objective ocular and oral status and DGLA values in plasma or erythrocytes were found.

Essential fatty acid status in cell membranes and plasma of patients with primary Sjogren's syndrome. Correlations to clinical and immunologic variables using a new model for classification and assessment of disease manifestations.

Oxholm P, Asmussen K, Wiik A, Horrobin DF Copenhagen Sjogren's Syndrome Research Centre, Department of Rheumatology U, Copenhagen County Hospital in Gentofte, Hellerup, Denmark. peter.oxholm@dadlnet.dk

Prostaglandins Leukot Essent Fatty Acids 1998 Oct;59(4):239-45

In 41 primary Sjogren's syndrome patients we compared fatty acid levels within erythrocyte phospholipids, plasma phospholipids, plasma triglycerides and plasma cholesterol esters, with the immunopathological and clinical disease status. Docosahexaenoic acid was the essential fatty acid (EFA), the levels of which correlated (inversely) most closely with the clinical disease status (r=-0.33 to -0.50). Levels of dihomogammalinolenic acid and eicosapentaenoic acid correlated inversely to levels of IgM rheumatoid factors (r=-0.33) and anti-SSA/Ro antibodies (r=-0.40) respectively. Moreover, levels of anti-SSA/Ro antibodies (r=-0.34-0.40) correlated with levels of the proinflammatory arachidonic acid. Sigma n-3 EFA/sigma n-6 EFA ratios correlated significantly to the quantitative estimates of immunopathological and clinical disease status. Our data are in agreement with current understanding of pro- and anti-immunoinflammatory roles within EFA metabolism, and support the rationale for intervention studies.

Oral pilocarpine HCl stimulates labial (minor) salivary gland flow in patients with Sjogren's syndrome.

Rhodus NL Department of Diagnostic and Surgical Sciences, University of Minnesota, Minneapolis, USA.

Oral Dis 1997 Jun;3(2):93-8

Pilocarpine HCl has been shown to stimulate parotid and submandibular gland salivary flow. The purpose of this study was to determine whether this cholinergic-muscarinic drug also stimulates labial (minor) salivary gland (LSG) flow and to relate that with whole unstimulated salivary (WUS) flow rates. Subjects diagnosed with primary Sjogren's syndrome (SS-1; n = 9) or secondary Sjogren's syndrome (SS-2; n = 9) were enrolled in this study after meeting stringent enrollment criteria. An age-gender matched control group was also enrolled. The labial saliva was collected in a standardized manner on Periopaper for 5 min and the volume was analysed by the Periotron. Whole unstimulated salivary samples were collected for 5 min by the method of Mandel and Wotman (1976). Each subject was dosed with pilocarpine HCl (5 mg; tablets; p.o.). After 60 min the LSG flow as well as the WUS flow was determined again as previously. The results indicated a significant (> 180%) increase in both labial salivary gland flow as well as whole salivary flow in the SS-1 and SS-2 subjects (mean s.e.m.): [SS-1: WUS = 0.1080 0.03 vs 0.2242 0.03 ml per 5 min; LSG = 93.1 22.2 vs 167.8 15.9 microliters/5 min; P < 0.001; SS-2: WUS = 0.1384 0.02 vs 0.2775 0.09 ml per 5 min; LSG = 97.7 20.2 vs 182.8 17.9 microliters per 5 min; P < 0.001]. These results indicate a significant increase in labial salivary gland flow as well as whole salivary flow as stimulated by pilocarpine HCl in Sjogren's syndrome patients.

Altered Immunity and the Leaky Gut Syndrome (undated)

Rona Z.

Childhood Illness and the Allergy Connection: A Nutritional Approach to Overcoming and Preventing Childhood Illness 1996.

Roseville, CA: Prima Publishing/Random House.

(http://www.health-n-energy.com/ronagut.htm)

Treatment of primary Sjogren's syndrome with low-dose natural human interferon-alpha administered by the oral mucosal route: a phase II clinical trial. IFN Protocol Study Group.

Ship JA, Fox PC, Michalek JE, Cummins MJ, Richards AB Department of Oral Medicine/Pathology/Oncology, University of Michigan School of Dentistry, Ann Arbor 48109-1078, USA. jship@umich.edu

J Interferon Cytokine Res 1999 Aug;19(8):943-51

The purpose of this investigation was to examine the safety and efficacy of four dosages of natural human interferon-alpha (nHuIFN-alpha) delivered over a 12-week period orally in lozenges (150 IU and 450 IU, once [QD] or three times [TID] daily) compared to placebo in subjects with primary Sjogren's syndrome. This randomized, double-blinded clinical trial demonstrated that nHuIFN-alpha at a dose of 150 IU administered TID by oral lozenge significantly improved stimulated whole saliva output compared to placebo after 12 weeks of treatment. The 150 IU TID dose also was suggestive of benefit for 5 of 7 subjective measures of oral and ocular comfort. IFN lozenges demonstrated a good safety profile, with no serious adverse events found in any treatment group. There were no significant differences between the placebo and the four doses of IFN for adverse events by total number, organ system, severity, dropouts, and number judged to be related to treatment. In conclusion, these results demonstrated that the use of 150 IU IFN lozenges TID for 12 weeks in subjects with primary Sjogren's syndrome improved salivary output and decreased complaints of xerostomia without causing significant adverse medical events.

The effect of calf thymus extract TFX-Polfa on clinical and laboratory parameters in patients with rheumatoid arthritis.

Skotnicki, A.B., Hoszowska, B., Szerla, J., Biedowa, E.

Abstracts of the Sixth International Congress of Immunology, Toronto, 1986, p. 679.

The initial results of TFX-Polfa application in patients with chronic recurrent infections of upper respiratory tract.

Stankiewiez-Szymezak, W., Moszynski, B., Dabrowski, M.P., Dabrowski-Bernzstein, B.K., Stasiak, A.

Pol. J. Otolaryngol. 1986; 2: 350.

Plaquenil: a possible treatment for Sjogren's syndrome.

Stecher, V. et al.

Moisture Seekers Newsletter 1990 May-Jun (article based on a presentation made by Drs. Stecher, Bernstein, and Carsons).

Jericho, NY: Moisture Seekers Newsletter.

The Right Time to Die 1993

Talal, N.

(http://www.cosmos-club.org/journals/1995/talal.html).

Allergic disorders in primary Sjogren's syndrome.

Tishler M, Paran D, Yaron M. Department of Rheumatology, Tel Aviv-Sourasky Medical Center, and the Tel Aviv University Sackler School of Medicine, Israel.

Scand J Rheumatol. 1998;27(3):166-9.

Allergic disorders have been described in a variety of connective tissue disorders. Although an association between allergy and primary Sjogren's syndrome has been suggested, it has not been well documented. The purpose of this study was to analyze the prevalence of several types of allergic disorders in a cohort of primary Sjogren's syndrome patients. The presence of an allergic disorder was evaluated by a specific questionnaire in 65 randomly selected primary Sjogren's syndrome patients and was compared to control groups of 67 rheumatoid arthritis patients, 53 patients with rheumatoid arthritis and sicca symptoms, and 31 patients with osteoarthritis. At least one type of allergic manifestation was reported by 42 of the 65 Sjogren's syndrome patients (65%). This rate was significantly higher than each of the three control groups (p < 0.01). Only drug allergy and skin contact allergy were found to be more prevalent in Sjogren's syndrome patients than in the control groups (p< 0.05). Allergic reactions were more common in Sjogren's syndrome patients who were anti-Ro positive (p < 0.05). As drug and skin contact allergies are a frequent finding in Sjogren's syndrome patients, obtaining a careful history is needed before prescribing drugs in these patients.

Food Toxins, Molecular Mimicry, Leaky Gut, and the MS Connection 2002

Toohey, L., Smith, M.

(http://www.positivehealth.com/permit/Articles/Nutrition/toohey 18.htm).

New treatment of dry eye: the effect of calcium ointment through eyelid skin delivery.

Tsubota K, Monden Y, Yagi Y, Goto E, Shimmura S Department of Ophthalmology, Tokyo Dental College, Chiba, Japan.

Br J Ophthalmol 1999 Jul;83(7):767-70

AIM: To demonstrate the efficacy of a petrolatum based calcium ointment applied to the lower lid skin in the management of dry eye.

METHODS: In a controlled double masked study, the effects of water free petrolatum ointment containing calcium carbonate (10% w/w) on tear functional factors and ocular surface vital staining in dry eye patients were observed. Petrolatum without calcium carbonate served as control. Patients were instructed to place ointment to the lower lid skin twice a day. Evaluation of subjective complaints, fluorescein and rose bengal staining patterns, blink rate, tear evaporation and tear break up time (BUT) were performed before and 3 months after treatment. In order to demonstrate the movement of petrolatum from the skin to the tear film, petrolatum containing 1% sodium fluorescein was placed on the lower lid of four healthy volunteers, and the concentration of fluorescein in the tear film was followed up to 6 hours using an anterior fluorometer.

RESULTS: Subjective symptoms significantly improved in both the calcium group (p=0.001) and control (p=0.012), while only the calcium group demonstrated a significant improvement in fluorescein (p=0.043), rose bengal (p=0.021) scores, and blink rate (p=0.004). Tear evaporation also significantly decreased in both the calcium group (p=0.0004) and control (0.043). BUT did not improve in either group.

CONCLUSION: Petrolatum based calcium ointment significantly improved symptoms, tear dynamics, and ocular surface staining in dry eye patients. However, some of the therapeutic effects may be due to lipids in the petrolatum vehicle. Petrolatum applied to the lower lid skin is an effective drug delivery system for slowly releasing drugs to the ocular surface.

Selected phenotypic induction of null lymphocytes from mice with thymic and nonthymic agents.

Twomey, J.J., Koutab, N.M.

Cell Immun.1982; 72: 186.

No abstract available.

Low serum dehydroepiandrosterone sulfate in women with primary Sjogren's syndrome as an isolated sign of impaired HPA axis function.

Valtysdottir ST, Wide L, Hallgren R. Units of Rheumatology and Clinical Chemistry, Department of Medical Sciences, University Hospital, SE-751 85 Uppsala, Sweden. sigridur.valtysdottir@medicin.uu.se

J Rheumatol. 2001 Jun;28(6):1259-65.

OBJECTIVE: To assess the hypothalamic-pituitary-adrenal (HPA) and thyroid axes in women with primary Sjogren's syndrome (pSS). METHODS: In 10 women with pSS and 10 age matched female controls, we evaluated serum dehydroepiandrosterone sulfate (DHEA-S), testosterone, androstenedione, follicle stimulating hormone, luteinizing hormone, thyroid stimulating hormone, prolactin, growth hormone, sex hormone binding globulin, cortisol, and adrenocorticotropin hormone (ACTH), in both basal condition and after stimulation with corticotropin releasing hormone, thyrotropin releasing hormone, and luteinizing hormone releasing hormone intravenously. Patients had not previously been treated with glucocorticoids.

RESULTS: Patients with pSS had significantly lower basal mean DHEA-S values compared with healthy controls (2.4 +/- 0.4 vs 3.9 +/- 0.3 mumol/l; p < 0.05) and significantly lower DHEA-S values after stimulation. The cortisol/DHEA-S ratio in the patient group was higher than in controls (171 +/- 39 vs 76 +/- 5; p < 0.05). A correlation was found between basal ACTH and DHEA-S values in the patients (r = 0.650; p = 0.05). No correlation was seen between disease activity or age and the serum concentration of DHEA-S. The levels of other hormones both at baseline and after stimulation were similar in patients and controls.

CONCLUSION: The results show that women with pSS have intact cortisol synthesis but decreased serum concentrations of DHEA-S and increased cortisol/DHEA-S ratio compared with healthy controls. The findings may reflect a constitutional or disease mediated influence on adrenal steroid synthesis. The thyroid axis and gonadotropin secretion were similar in patients and controls.

Pilocarpine tablets for the treatment of dry mouth and dry eye symptoms in patients with Sjogren syndrome: a randomized, placebo-controlled, fixed-dose, multicenter trial. P92-01 Study Group.

Vivino FB, Al-Hashimi I, Khan Z, LeVeque FG, Salisbury PL 3rd, Tran-Johnson TK, Muscoplat CC, Trivedi M, Goldlust B, Gallagher SC Division of Rheumatology, University of Pennsylvania Health System, Philadelphia, USA.

Arch Intern Med 1999 Jan 25;159(2):174-81

BACKGROUND: Patients with Sjogren syndrome (SS) experience slowly progressive infiltration of lacrimal and salivary glands by mononuclear cells. This leads to diminished secretions, with resultant symptoms of xerostomia and xerophthalmia. Although pilocarpine hydrochloride tablets are currently indicated for the treatment of radiation-induced xerostomia, their effects on dry mouth or dry eyes in patients with SS are unclear.

OBJECTIVE: To assess the safety and efficacy of pilocarpine (Salagen) tablets as symptomatic treatment for dry mouth and dry eyes caused by SS in a multicenter, doubleblind, placebo-controlled trial.

METHODS: After providing written informed consent, 373 patients with primary or secondary SS and clinically significant dry mouth and dry eyes were randomized to receive 2.5-mg pilocarpine, 5-mg pilocarpine, or placebo tablets 4 times daily for 12 weeks. Symptoms were assessed by questionnaires with visual analog scales or categorical checkboxes. Whole-mouth salivary flow rates were measured.

RESULTS: A significantly greater proportion of patients in the 5-mg pilocarpine group showed improvement compared with the placebo group (P< or =.01) in global assessments of dry mouth, dry eyes, and other symptoms of dryness (P< or =.05). Salivary flow was significantly increased 2- to 3-fold (P<.001) after administration of the first dose and was maintained throughout the 12-week study. The most common adverse effect was sweating, and no serious drug-related adverse experiences were reported.

CONCLUSION: Administration of 5-mg pilocarpine tablets 4 times daily (20 mg/d) was well tolerated and produced significant improvement in symptoms of dry mouth and dry eyes and other xeroses in patients with SS.

Increased production of interleukin-6 and autoantibodies in patients with Sjogren's syndrome.

Wen CL, Wang CR, Chuang CY, Chen CY. Department of Internal Medicine, Lo-Tong Poh Ai Hospital, I Lan, Taiwan, R.O.C.

Zhonghua Min Guo Wei Sheng Wu Ji Mian Yi Xue Za Zhi. 1992 Aug;25(3):189-95.

The occurrence of autoantibodies including antinuclear antibody, anti-nDNA, anti-Sm, anti-RNP, anti-SSA, anti-SSB, anticardiolipin (aCL) antibody, M-Proteins, and interleukin-6 (IL-6) and circulating immune complex (CIC) were studied in 18 patients with primary Sjogren's syndrome (SS) and 20 patients with secondary SS. Another 15 healthy individuals were served as a control group. The differences between primary and secondary SS in these autoantibodies, IL-6 and M-protein were also compared. The result showed a high incidence of autoantibodies and CIC in patients with SS. Higher frequencies of anti-nDNA and anti-Sm antibodies were noted in patients with secondary SS. There were also elevated levels of IL-6, much higher in primary than in secondary SS. In addition, higher frequencies of M-protein were detected in patients with primary SS. In conclusion, through immune dysregulations, higher levels of IL-6 were found in patients with SS. Autoantibodies produced in these patients might be derived from IL-6 stimulated B cells.

Primary Sjogren's syndrome after infectious mononucleosis.

Whittingham S, McNeilage J, Mackay IR.

Ann Intern Med 1985 Apr;102(4):490-3

A healthy young woman developed primary Sjogren's syndrome after protracted infectious mononucleosis. The diagnosis of primary Sjogren's syndrome was supported by histologic evidence of sialadenitis in labial salivary glands, rheumatoid factor, hypergammaglobulinemia, the HLA-B8 phenotype, and a high titer antibody to the anti-La (SS-B) nucleoprotein that co-precipitated the small ribonucleic acids encoded by Epstein-Barr virus, EBER 1 and EBER 2, as well as "host" RNA. There was strong humoral immunity to the Epstein-Barr nuclear and capsid antigens, but weak T-lymphocyte-mediated cytotoxicity to Epstein-Barr-transformed lymphoblasts, anergy to antigens used to elicit delayed-type hypersensitivity, and a low T-helper/T-suppressor cell ratio. The series of events initiated by infectious mononucleosis was attributed to a genetic defect in the immune response. Association of viral RNA with the La nucleoprotein resulted in a break in immunologic tolerance via a T-cell bypass effect with induction of anti-La (SS-B) by polyclonally activated B lymphocytes leading to autoimmune sialadenitis.

Epstein-Barr virus (types 1 and 2) in the tear film in Sjogren's syndrome and HIV infection.

Willoughby CE, Baker K, Kaye SB, Carey P, O'Donnell N, Field A, Longman L, Bucknall R, Hart CA. St. Paul's Eye Unit, Royal Liverpool University Hospital, Liverpool, United Kingdom.

J Med Virol. 2002 Nov;68(3):378-83.

Evidence of Epstein-Barr virus (EBV) shedding in the saliva and tear film has been sought to explain the pathogenesis of the oral and ocular features of Sjogren's syndrome. Patients with human immunodeficiency virus (HIV) infection are purported to have a higher incidence of keratoconjunctivitis sicca. Twenty patients with definite Sjogren's syndrome (primary and secondary), 19 with HIV infection, and 15 normal controls were recruited and studied. Human herpes viruses (EBV 1 and 2, CMV, HZV, and HSV-1) in tear film were detected by polymerase chain reaction of DNA extracted from Schirmer strips. HSV-1, VZV, and CMV were not detected in any tear samples. EBV-1 DNA was found in the tear film of 4 patients with Sjogren's syndrome, which was not significantly different from the control group (P = 0.18). Twelve patients with HIV infection had evidence of EBV-1 in their tears, which was significantly different from controls (P = 0.0002) and patients with Sjogren's syndrome (P = 0.014). EBV-2 was found in 3 patients with HIV and in 1 patient with secondary Sjogren's syndrome, and was always found as a co-infection with EBV-1 (P = 0.01). This represents the first report examining EBV types 1 and 2 in the tear film and also EBV in the tear film of patients with HIV. Shedding of EBV in the tear film was not related to the presence of keratoconjunctivitis sicca in Sjogren's syndrome. EBV-2 co-infection with EBV-1 has not been previously reported in the tear film. EBV infection is abnormally regulated in Sjogren's syndrome and HIV, and it is likely that the presence of EBV in the tear film is related to the patients' altered immune status. Copyright 2002 Wiley-Liss, Inc.

Thymus Extracts: An International Literature Review of Clinical Studies 1999

Wilson, J.L.

(http://www.hepatitiscfree.com/thymus_article2.html).

Smart Medicine for Healthier Living 1999.

Zand, J., Lavalle, J.B., Spreen, A.

Garden City Park, NY: Avery Publishing Group.