Rheumatoid Arthritis: Moutsopoulos HM

Zintzaras E, Dahabreh IJ, Giannouli S, Voulgarelis M, Moutsopoulos HM. · Department of Biomathematics, University of Thessaly School of Medicine, Larissa, Greece. · Clin Ther. · Pubmed #19108784 No free full text.

Abstract: BACKGROUND: Because of its long-term effectiveness in clinical practice, methotrexate (MTX) is currently the preferred disease-modifying antirheumatic drug (DMARD) for patients with active rheumatoid arthritis (RRA). However, many patients do not experience remission and continue to have signs and symptoms of active disease while receiving a maximally tolerated dose. OBJECTIVES: The aims of this meta-analysis were to estimate the efficacy and tolerability of the various dosage schemes of infliximab versus MTX for the treatment of active RA, to eliminate size-related uncertainty of effects, and to identify subgroups of patients who benefit most from infliximab + MTX therapy. METHODS: Using the MEDLINE online database (inception through November 2006) and the Cochrane Database of Systematic Reviews (Issue 4, 2006), we identified English-language articles on randomized controlled clinical trials. Studies investigating infliximab + MTX regimens versus a control group receiving MTX alone to assess efficacy in active RA, using the American College of Rheumatology (ACR) criteria for 20% improvement (ACR20), 50% improvement (ACR50), and 70% improvement (ACR70), were considered eligible for the meta-analysis. Pooled odds ratios (ORs) and 95% CIs were calculated to compare the relative risks and benefits of adding infliximab to MTX. RESULTS: From a total of 78 initially identified studies, 42 were considered potentially eligible for this review and 12 were considered eligible for the meta-analysis. Overall, 4899 patients were randomized to either infliximab + MTX (3919 patients) or MTX alone (980 patients). Mean patient age ranged from 44.6 to 56 years in the MTX-only arms and from 45.8 to 56 years in the infliximab + MTX arms. The proportion of female patients ranged from 66.6% to 100% in the MTX arms and from 68% to 100% in the infliximab arms. Infliximab 3 mg/kkg + MTX was more effective than MTX alone (OR = 3.52 [2.14-5.79] for reaching ACR20; 2.87 [2.228-3.61] for ACR50; and 2.42 [1.87-3.13] for ACR70). Infliximab 10 mg/kkg + MTX was also more effective than MTX alone (OR = 5.06 [3.88-6.59] for reaching ACR20; 5.72 [4.05-8.08] for ACR50; and 7.32 [2.28-23.50] for ACR70). Infliximab 10-mm/kg regimens appeared to be more effective than infliximab 3-mg/kg regimens (P = NS, P = 0.001, and P = NS for reaching ACR20, ACR50, and ACR70, respectively), without being associated with an increased risk for adverse events. Infliximab 10 mg/kg appeared to be more effective in trials of longer duration (> or = 54 weeks) compared with those of shorter duration (P = 0.03, P = 0.02, and P = 0.01 for reaching ACR20, ACR50, and ACR70, respectively) and in those that enrolled patients with severe disease activity (P = 0.05, P = 0.05, and P = NS for reaching ACR20, ACR50, and ACR70, respectively). Steroid coadministration (P < 0.001, P < 0.001, and P = NS for reaching ACR20, ACR50, and ACR70, respectively), previous DMARD exposure (P < 0.001, P < 0.001, and P = 0.04 for reaching ACR20, ACR50, and ACR70, respectively), and MTX naivete (P = NS, P < 0.001, and P =0.013 for reaching ACR20, ACR50, and ACR70, respectively) correlated with higher infliximab efficacy. CONCLUSIONS: Based on this meta-analysis, higher dose infliximab (10 mg/kg) in combination with MTX appeared to be more effective than the standard 3 mg/kg dose, particularly for patients with severe disease activity.The benefits of high-dose treatment appeared to accrue over time, and patients who received higher doses of infliximab did not experience a higher incidence of severe adverse events. The addition of oral low-dose steroids significantly enhanced infliximab efficacy.

Voulgarelis M, Tzioufas AG, Moutsopoulos HM. · Department of Pathophysiology, Medical School, National University of Athens, Greece. · Clin Exp Rheumatol. · Pubmed #19026146 No free full text.

Abstract: Sjögren's syndrome (SS) is a chronic autoimmune disease that involves primarily the exocrine glands and results in their functional impairment. The disease may occur alone (primary SS, pSS) or in association with other autoimmune diseases, such as rheumatoid arthritis (secondary SS, sSS). Although the clinical manifestations of pSS patients are mainly those of an autoimmune exocrinopathy, 40% to 50% of patients develop extraglandular disease, which may be manifested either by epithelial lymphocytic invasion of lung, liver, or kidney (resulting in interstitial nephritis) or by skin vasculitis, peripheral neuropathy, glomerulonephritis, and low C4 levels, conditions which represent an immune-complex mediated disease. Patients belonging to the latter category, inferring a high risk for development of non-Hodgkin's lymphoma, by default have a worse prognosis with higher mortality rates. In this review, the role of several factors involved in mortality of pSS, as well as markers predictive for lymphoma development are discussed.

Voulgarelis M, Moutsopoulos HM. · Department of Pathophysiology, Medical School, National University of Athens, 75 Mikras Asias Street, 11527 Athens, Greece. · Rheum Dis Clin North Am. · Pubmed #18984412 No free full text.

Abstract: Sjögren's syndrome is a chronic inflammatory disease primarily affecting the exocrine glands. Its association with lymphoma is well documented, with salivary extranodal marginal zone lymphomas of the mucosa-associated lymphoid tissue type being the most common and constituting a major disease complication. These neoplasms are antigen-stimulated B-cell lymphomas characterized by localized stage, indolent clinical course, and recurrence in other extranodal sites. This article presents a review of the literature and discusses the clinical, histopathologic, therapeutic, and prognostic aspects of these tumors in Sjögren's syndrome. In addition, it highlights the predictor markers of lymphoma development.

Tzioufas AG, Tsonis J, Moutsopoulos HM. · Department of Pathophysiology, School of Medicine, University of Athens, Athens, Greece. · Neuroimmunomodulation. · Pubmed #18667798 No free full text.

Abstract: Interactions among the immune, nervous and endocrine systems, which are mediated by hormones, neuropeptides, neurotransmitters, cytokines and their receptors, appear to play an important role in modulating host susceptibility and resistance to inflammatory disease. The neuroendocrine system has two main components: the central and the peripheral. The central compartment is located in the locus ceruleus, the brainstem centers of the autonomic system and the paraventricular nucleus; the peripheral mainly consists of the sympathetic/adrenomedullary system, the hypothalamic-pituitary-adrenal axis (HPA), the hypothalamic-pituitary-gonadal (HPG) axis, and the neuroendocrine tissue located in several organs throughout the body. Hormones and neuropeptides may influence the activities of lymphoid organs and cells via endocrine and local autocrine/paracrine pathways or alter the function of different cell types in target organs. Recent studies highlighted alterations of the neuroendocrine system in systemic autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus and Sjogren's syndrome (SS). SS, a prototype autoimmune disorder, has a wide clinical spectrum, extending from organ involvement (autoimmune exocrinopathy) to systemic disease and B cell lymphoma. In SS, several functions of the neuroendocrine system are impaired. First, the HPA axis appears to be disturbed, since significantly lower basal ACTH and cortisol levels were found in patients with SS and were associated with a blunted pituitary and adrenal response to ovine corticotropin-releasing factor compared to normal controls. Second, HPG axis is also involved, since lack of estrogens is associated with human disease and the development of autoimmune exocrinopathy in several experimental models. Finally, exocrine glands are enriched with neuroendocrine-related molecules, adjacent to local autoimmune lesions. Certain clinical manifestations of the disease, including the sicca manifestations, easy fatigue, fibromyalgia and psychological disturbances can be very well explained by mechanisms directly related to disturbances of the neuroendocrine axis. On the other hand, the molecular and biochemical effects of the inflammatory molecules or cell-to-cell interaction, observed during the local or systemic autoimmune injury with cells and mediators of the neuroendocrine system, are largely unexplored.

Mavragani CP, Moutsopoulos HM. · Hospital for Special Surgery, New York, NY, USA. · Clin Rev Allergy Immunol. · Pubmed #17992595 No free full text.

Abstract: Sjogren's syndrome (SS) is a chronic autoimmune disorder affecting mainly middle-aged women. It is characterized by lymphocytic infiltration and destruction of the exocrine glands (mainly the salivary and lacrimal glands), resulting in dry mouth and eyes. Symptoms of SS are chronic and sometimes devastating, compromising the quality of life at a major extent. Despite its autoimmune nature, evidence for the use of immunosuppressive agents, which are the mainstay of therapy of diseases of autoimmune origin, is limited. Keratoconjunctivitis sicca (KCS), the main ocular manifestation of SS, is managed with tear substitutes, as well as local and systemic stimulators of tear secretion and supportive surgical procedures. Management of oral manifestations includes intense oral hygiene, prevention and treatment of oral infections, use of saliva substitutes, and local and systematic stimulation of salivary secretion. Cholinergic agents, such as pilocarpine and cevimeline are the cornerstone of current therapy in SS. Corticosteroids, cyclophoshamide, and nucleoside analogues are reserved for severe extraglandular manifestations of SS. The role of anti-B-cell therapy is a promising option for glandular and extraglandular manifestations of the disease, as well as for the management of SS-associated lymphoma.

Papiris SA, Tsonis IA, Moutsopoulos HM. · 2nd Pulmonary Department, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. · Semin Respir Crit Care Med. · Pubmed #17764063 No free full text.

Abstract: Sjögren's syndrome (SS) is a chronic, slowly progressive, inflammatory, autoimmune disease characterized by (1) lymphocytic infiltration of the exocrine glands leading to diminished or absent glandular secretion, and (2) marked B-lymphocytic cell hyperreactivity manifested initially by a variety of serum autoantibodies, including those against the Ro(SSA) and La(SSB) ribonucleoproteins, ending in the development of B cell non-Hodgkin's lymphoma in a substantial number of patients. Most patients with SS present only with keratoconjunctivitis sicca and xerostomia. However, approximately 40% develop extraglandular manifestations that present in two ways: (1) the development of lymphoepithelial lesions in several extra-exocrine gland tissues (i.e., bronchi, renal tubules, or biliary ducts), and (2) vasculitis related to the deposition of immune complexes due to B cell hyperreactivity. Pulmonary manifestations develop in some patients and may present as (1) bronchitis sicca; (2) a wide spectrum of lymphoproliferative diseases, ranging from bronchus-associated lymphoid tissue (BALT) hyperplasia, lymphoid interstitial pneumonia, and B cell non-Hodgkin's lymphoma mainly of the extranodal marginal zone B-cell lymphoma of BALT-type or rarely of higher-grade malignancy; and (3) other interstitial pneumonias. Pleuritis can be seen in SS patients with associated systemic lupus erythematosus or rheumatoid arthritis.

Johnson EO, Kostandi M, Moutsopoulos HM. · Department of Anatomy-Histology-Embryology, University of Ioannina, School of Medicine, Ioannina 45-110, Greece. · Ann N Y Acad Sci. · Pubmed #17192555 No free full text.

Abstract: To date, evidence suggests that rheumatic diseases are associated with hypofunctioning of the hypothalamic-pituitary-adrenal (HPA) axis. Sjögren's syndrome (SS), the second most common autoimmune disorder, is characterized by diminished lacrimal and salivary gland secretion. To examine HPA axis activity in SS patients, the adrenocorticotropin (ACTH) response to ovine corticotropin-releasing factor (oCRH) was used as a direct measure of corticotrophic function, and the plasma cortisol response to the ACTH released during oCRH stimulation as an indirect measure of adrenal function. Significantly lower basal ACTH and cortisol levels were found in patients with SS and were associated with a blunted pituitary and adrenal response to oCRH compared to normal controls. Fibromyalgia (FM) patients demonstrated elevated evening basal ACTH and cortisol levels and a somewhat exaggerated peak, delta, and net integrated ACTH response to oCRH. A subgroup of SS patients also met the diagnostic criteria for FM and demonstrated a pituitary-adrenal response that was intermediate to SS and FM. These findings suggest not only adrenal axis hypoactivity in SS and FM patients, but also that varying patterns of adrenal and thyroid axes dysfunction may exist in patients with different rheumatic diseases.

Mitsias DI, Kapsogeorgou EK, Moutsopoulos HM. · Department of Pathophysiology, School of Medicine, National University of Athens, Athens, Greece. · Oral Dis. · Pubmed #17054763 No free full text.

Abstract: The expression 'autoimmune epithelitis' has been proposed as an alternative for Sjögren's syndrome (SS) based on data pointing out the central role of the epithelial cell in the pathogenesis of the syndrome. Clinically, apart from exocrine glands that are the main target, the epithelial component of the other organs such as kidneys, liver, lungs or thyroid is commonly affected resulting in various extraglandular manifestations. On the other hand, at the molecular and cellular level, the epithelial cell plays a major role in the initiation and perpetuation of the autoimmune lesion. Mechanisms such as antigen presentation, apoptosis, chemokine production or germinal center formation lie in the center of SS pathogenesis and the epithelial cell has a very important role. Herein, we present both aspects, review the data that support the proposed terminology and finally, suggest a unifying theory for the pathogenesis of SS.

Mavragani CP, Moutsopoulos NM, Moutsopoulos HM. · Hospital for Special Surgery, New York, NY, USA. · Nat Clin Pract Rheumatol. · Pubmed #16932698 No free full text.

Abstract: Sjögren's syndrome is a chronic autoimmune disorder, characterized by lymphocytic infiltration and malfunction of the exocrine glands, resulting in dry mouth and eyes. The syndrome can present either alone (primary Sjögren's syndrome) or in the context of an underlying connective tissue disease (secondary Sjögren's syndrome). Systemic features, resulting from cutaneous, respiratory, renal, hepatic, neurologic, and vascular involvement, often occur. Two types of primary Sjögren's syndrome are currently recognized: a benign disease that affects quality of life, and a systemic syndrome associated with increased morbidity and mortality owing to a high risk of malignant transformation, and that requires close follow-up. Ocular involvement, manifested as keratoconjunctivitis sicca, is managed with local and systemic stimulators of tear secretion and supportive surgical procedures. Treatment of oral manifestations includes intense oral hygiene, prevention and treatment of oral infections, use of saliva substitutes, and local and systematic stimulation of salivary secretion. Cholinergic agents, such as pilocarpine and cevimeline, are helpful in patients with residual salivary function, and ciclosporin ocular drops seem to be of some benefit. Systemic immunosuppressives are reserved for treatment of severe extraglandular manifestations of Sjögren's syndrome. Anti-B-cell therapy is a new potential therapy for the glandular and extraglandular manifestations, such as glomerulonephritis or vasculitis, in addition to the management of lymphoma associated with Sjögren's syndrome. Induction of oral tolerance and gene-transfer modalities were recently attempted in animal models, with promising results.

Mitsias DI, Kapsogeorgou EK, Moutsopoulos HM. · Department of Pathophysiology, School of Medicine, National University of Athens, Athens, Greece. · Lupus. · Pubmed #16761498 No free full text.

Abstract: Sjögren's syndrome (SS) is a chronic autoimmune disease affecting epithelial tissues. Exocrine glands are the primary target and their functional impairment comes as a result of immune attack of epithelial cells of the affected organs (autoimmune epithelitis). In this interplay, the role of the epithelial cell is pivotal. Extensive data point to an intrinsically activated status. Moreover, the epithelial cells possess all the features needed in order to act as non-professional antigen presenting cells. Through apoptosis and exosomes release endocellular antigens contributing to tolerance breakdown. In addition, produce cytokines and chemokines that recruit lymphocytes in the immunopathogenic lesion. Herein, we review all the aforementioned aspects of the epithelial activity that lead to the perpetuation of the lesion as well as the probable viral factors for the intrinsic activation. Finally, we propose a model for SS pathogenesis that integrates the knowledge accumulated during the last decade.

Zintzaras E, Voulgarelis M, Moutsopoulos HM. · Department of Biomathematics, University of Thessaly School of Medicine, Larissa, Greece. · Arch Intern Med. · Pubmed #16287762 links to  free full text

Abstract: BACKGROUND: The risk of development of non-Hodgkin lymphoma (NHL) in autoimmune patients has been investigated in several cohort studies. These studies revealed inconclusive results. To shed some light on this controversy, we conducted a meta-analysis of all available cohort studies linking systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and primary Sjögren syndrome (pSS) to the risk of NHL development. METHODS: We searched the PubMed database (1974 to April 2005) for English-language cohort studies using the key words systemic lupus erythematosus, SLE, rheumatoid arthritis, RA, Sjögren syndrome, or SS; non-Hodgkin lymphoma; and relative risk, RR, standardized incidence rate, or SIR. All cohort studies that used established diagnostic criteria for SLE, RA, and pSS; had histologic confirmation of NHL; and provided standardized incidence rates (SIRs) were included in the meta-analysis. RESULTS: The 20 studies chosen for the analysis included 6 for SLE, 9 for RA, and 5 for pSS. Overall, the meta-analysis suggested extreme heterogeneity among the studies (P < .01; I2 > 70%), high risk of NHL development for pSS (random effects SIR, 18.8; 95% confidence interval [CI], 9.5-37.3); moderate risk for SLE (random effects SIR, 7.4; 95% CI, 3.3-17.0); and lower risk for RA (random effects SIR, 3.9; 95% CI, 2.5-5.9). In RA, the random effects SIRs of NHL with conventional antirheumatic treatment, cytotoxic treatment, and treatment with a biological agent were 2.5 (95% CI, 0.7-9.0), 5.1 (95% CI, 0.9-28.6), and 11.5 (95% CI, 3.7-26.9), respectively. CONCLUSIONS: Rheumatic disease may present a potential risk factor for development of NHL. In this regard, we focused on the underlying pathophysiologic mechanisms related to lymphomagenesis in pSS, SLE, and RA, to justify the varying potential for and background of NHL development.

Triantafyllopoulou A, Moutsopoulos HM. · Department of Pathophysiology, National University of Athens Medical School, M. Asias 75, Goudi, Athens 11527, Greece. · Ann N Y Acad Sci. · Pubmed #16014556 No free full text.

Abstract: Exocrine gland epithelial cells are the target of autoimmune pathology in primary Sjögren's syndrome (pSS). Their activated phenotype has incited the notion that they are infected by a virus. We recently presented evidence that coxsackieviruses may persistently infect the salivary glands of pSS patients. We hypothesize that coxsackieviruses may play a permissive role for the perpetuation and possibly the induction of autoimmune disease in pSS.

Samarkos M, Moutsopoulos HM. · Department of Pathophysiology, University of Athens School of Medicine, 25 Mikras Asias street, 115 27, Athens, Greece. · Curr Allergy Asthma Rep. · Pubmed #15967078 No free full text.

Abstract: Sjögren's syndrome (SS) is an autoimmune disorder, the principal ocular manifestation of which is decreased tear production leading to chronic irritation and damage to the corneal and conjunctival epithelium. The most important advance in the treatment of ocular manifestations of SS is the introduction of topical anti-inflammatory agents such as cyclosporine A, which increases tear production and decreases symptoms without any significant side effect. Stimulators of tear secretion, both topical, such as diquafosol, and systemic, such as pilocarpine and cevimeline, are also effective, although they have been associated with frequent side effects. Topical use of autologous serum is another new and effective form of treatment, but problems in the preparations prevent their widespread use. Additionally, nonpharmacologic treatments, such as insertion of punctal plugs, are beneficial in the dry eye of SS, whereas several other modalities, such as anti-CD4 monoclonal antibody eye drops and gene transfer, are still in experimental phases.

Soliotis FC, Moutsopoulos HM. · Department of Pathophysiology, School of Medicine, University of Athens, 75 M. Asias, 115 27, Athens, Greece. · Autoimmunity. · Pubmed #15518047 No free full text.

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Kassan SS, Moutsopoulos HM. · University of Colorado Health Sciences Center, Denver, USA. · Arch Intern Med. · Pubmed #15226160 links to  free full text

Abstract: Sjögren syndrome (SS) is a common autoimmune disease evidenced by broad organ-specific and systemic manifestations, the most prevalent being diminished lacrimal and salivary gland function, xerostomia, keratoconjunctivitis sicca, and parotid gland enlargement. Primary SS presents alone, and secondary SS occurs in connection with autoimmune rheumatic diseases. In addition, symptoms do not always present concurrently. This diversity of symptomatic expression adds to the difficulty in initial diagnosis. Armed with the recently refined criteria for diagnosis, specialists, such as rheumatologists, primary care physicians, ophthalmologists, and dentists, who would otherwise focus only on those symptoms that encompass their areas of expertise, can get a comprehensive image of the presenting patient, leading to earlier identification and treatment of SS.

Voulgarelis M, Moutsopoulos HM. · Department of Pathophysiology, Medical School, National University of Athens, M. Asias 75, Goudi 11527, Athens, Greece. · Curr Rheumatol Rep. · Pubmed #14531960 No free full text.

Abstract: Sjögren's syndrome is a chronic inflammatory process involving primarily the exocrine glands. Its association with lymphoma is well documented. A low-grade marginal-zone lymphoma related to mucosa-associated lymphoid tissue is the most common lymphoid neoplasia in Sjögren's syndrome. Among all autoimmune diseases, Sjögren's syndrome is the best tool to clarify the multiple components of autoimmunity and lymphomatogenesis. Herewith, the authors review the literature and discuss the molecular, clinical, histopathologic, and therapeutic aspects of these tumors in Sjögren's syndrome.

Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, Daniels TE, Fox PC, Fox RI, Kassan SS, Pillemer SR, Talal N, Weisman MH, Anonymous00126. · Department of Internal Medicine and Rheumatology, Ospedale Villamaria, Piombino, LI, Italy. · Ann Rheum Dis. · Pubmed #12006334 links to  free full text

Abstract: Classification criteria for Sjögren's syndrome (SS) were developed and validated between 1989 and 1996 by the European Study Group on Classification Criteria for SS, and broadly accepted. These have been re-examined by consensus group members, who have introduced some modifications, more clearly defined the rules for classifying patients with primary or secondary SS, and provided more precise exclusion criteria.

Manoussakis MN, Moutsopoulos HM. · Department of Pathophysiology, School of Medicine, National University of Athens, Greece. · Adv Intern Med. · Pubmed #11795075 No free full text.

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Voulgarelis M, Moutsopoulos HM. · Department of Pathophysiology, Medical School, National University of Athens, Athens, Greece. · Isr Med Assoc J. · Pubmed #11692552 links to  free full text

Abstract: Sjogren's syndrome is a chronic inflammatory process involving primarily the exocrine glands. Its association with lymphoma is well documented. A low grade marginal-zone lymphoma related to mucosa-associated lymphoid tissue is the commonest lymphoid neoplasia in Sjogren's syndrome. We review the literature and comment on the molecular, clinical, histopathologic and therapeutic aspects of these tumors in Sjogren's syndrome.

Moutsopoulos NM, Moutsopoulos HM. · Oral Infection and Immunity Branch, National Institute of Dental Craniofacial Research, National Institutes of Health, BL. 30, Room 327, 30 Convent Dr., Bethesda, MD 20892, USA. · Springer Semin Immunopathol. · Pubmed #11455852 No free full text.

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Johnson EO, Moutsopoulos HM. · Department of Anatomy, School of Medicine, University of Ioannina, Ioannina 45110, Greece. · Ann N Y Acad Sci. · Pubmed #11268409 No free full text.

Abstract: Evidence suggests that autoimmune rheumatic diseases are associated with neuroendocrine dysfunction. Sjögren's syndrome (SS) is proposed as an ideal model to study perturbations in the neuroimmune axis, since patients tend to be medication free and studies are not confounded by the effects of chronic immunosuppressive therapy. The functional integrity of the adrenal, gonadal, and thyroid axes was assessed in SS. Pituitary function of the HPA axis was evaluated directly by determining the ACTH released during oCRH stimulation, while adrenal function was assessed indirectly by endogenous ACTH released during oCRH stimulation. Low basal activity of the HPA axis was associated with pituitary hyporesponsiveness to exogenous CRH, as well as hyporesponsiveness of the adrenal glands to endogenous ACTH. These findings are compatible with a central deficiency of the adrenal axis. An overall attenuated and delayed LH and FSH response to LHRH stimulation was also indicative of central dysfunction of the gonadal axis in SS. SS patients demonstrated elevated basal TSH levels and evidence of mild hypothyroidism. Basal prolactin concentrations were also elevated in SS, and both TSH and PRL showed relatively increased responses to TRH stimulation. The data suggest a central deficiency in all three neuroendocrine axes: adrenal, gonadal, and thyroid. It is not clear if any one system plays a primary role in the expression of the disease. Rather, it is likely that the net effect involves the synergistic and antagonistic effects of multiple hormones. Taken together, adrenal and gondadal steroid hormone deficiency, plus elevated PRL levels, probably greatly affect immune function in SS patients.

Johnson EO, Skopouli FN, Moutsopoulos HM. · Department of Anatomy, School of Medicine, University of Ioannina, Greece. · Rheum Dis Clin North Am. · Pubmed #11084952 No free full text.

Abstract: Molecular biology has had a major impact on our concepts of the immune system and its relation to neuroendocrine axes, in particular, the adrenal, gonadal, and thyroid axes. It is now well established that not only are the biosynthetic and catabolic pathways of glucocorticoids and sex hormones (estrogen, progesterone, and testosterone) closely related but that the receptors for these hormones are part of a supergene family of receptors which include (in addition to these hormone receptors) the mineralocorticoid receptor, thyroid hormone receptor, retinoic acid receptors, and vitamin D receptors. This suggests a complex network of steroid hormones and receptors for the control and integration of a multitude of physiologic functions at a systemic level. The immune system seems to be tightly integrated into this homeostatic neuroendocrine regulatory network. The neurophysiologic and biochemical events that promote successful adaptation during stressful situations are now identified for illnesses that seem to occur as a result of or are associated with dysregulation of the stress response. One difficulty in interpreting the mechanisms of HPA axis dysfunction in autoimmune-inflammatory syndromes arises from the plasticity of the hormonal systems involved. Levels of hormones produced and receptors reset rapidly with changes in the hormonal milieu (deficiency or excess) and have likely changed during the course of the chronic immune disorder. This, in turn, is further confounded by the pleomorphic natural history of most autoimmune-inflammatory diseases such as SS. The levels of sex hormones and their receptors are tightly linked to HPA axis function. It may be that significant changes in the estrogen-to-androgen ratio or the ratio of their receptors alter the activity of steroid-sensitive cells such as the individual immune cells or epithelial cells, thus providing a means for endocrine regulation of the immune response in SS. Studies in the closely related disorder RA support this hypothesis. Taken together, adrenal and gonadal steroid hormone deficiency plus elevated PRL levels probably greatly facilitate cellular immunity in SS patients. This hypothesis in SS is supported by a growing body of data indicating that RA develops as a consequence of a deficiency in adrenal and gonadal steroid hormone production. It is noteworthy that the findings in female SS patients indicated a central deficiency in all three neuroendocrine axes: adrenal, gonadal, and thyroid. At present, it is not clear if any one system plays a primary role in the expression of the disease. Rather, it is likely that the net effect involves the synergistic and antagonistic effects of multiple hormones, making the specific effects of individual hormones difficult to discern.

Mavragani CP, Tzioufas AG, Moutsopoulos HM. · Department of Pathophysiology, School of Medicine, National University of Athens, Greece. · Int Arch Allergy Immunol. · Pubmed #11014971 No free full text.

Abstract: Autoantibodies to cellular autoantigens are usually found in sera of patients with systemic autoimmune rheumatic diseases. Patients with Sjögren's syndrome (SS) frequently present autoantibodies to both organ and non-organ-specific autoantigens. The most commonly detected autoantibodies are those directed against the ribonucleoproteins Ro/SSA and La/SSB. The presence of the antibodies in SS is associated with early disease onset, longer disease duration, parotid gland enlargement, higher frequency of extraglandular manifestations and more intense lymphocytic infiltration of the minor salivary glands. Over the past several years, the structure and function of these autoantigens have been extensively studied. Several centers, using different techniques, have investigated the B cell epitopes on the protein components Ro 60 kD, Ro 52kD, and La 48 kD. Finally, increased evidence of direct involvement of anti-Ro/SSA and anti-La/SSB autoantibodies in the pathogenesis of tissue injury has been contributed by several studies.

Tapinos NI, Polihronis M, Tzioufas AG, Moutsopoulos HM. · Department of Pathophysiology, Medical School, National University of Athens, Greece. · Adv Exp Med Biol. · Pubmed #10599333 No free full text.

Abstract: Sjögren's syndrome is a chronic autoimmune disorder characterized by mononuclear cell infiltration proximally to epithelial cells of exocrine glands. In recent years, several studies have tried to address the function of the components of the immunopathologic lesion in Sjögren's syndrome. The majority of the mononuclear infiltrating cells are CD4 positive T lymphocytes (60-70%) whereas B cells constitute one fourth of the infiltrating cells. Macrophages and natural killer cells are poorly represented in the lesion. Epithelial cells of minor salivary glands of patients with Sjögren's syndrome express proinflammatory cytokines (IL-1 beta, IL-6), protooncogenes (c-myc) and costimulatory molecules (B71, B72). The destruction of epithelial cells of Sjögren's syndrome patients is probably due to activation of several apoptotic pathways since epithelial cells express different apoptosis related molecules such as Fas, FasL, Bax, while mononuclear cells express Bcl-2, Perforin and Granzymes. Finally epithelial cells seem to exert a regenerative effort since they express trefoil proteins (pS2). The above properties give epithelial cells a significant role in the pathophysiology of the syndrome but the exact events which drive the immune system towards an autoimmune reaction remain obscure.

Manoussakis MN, Moutsopoulos HM. · Department of Pathophysiology, National University of Athens School of Medicine, Athens, Greece. · Otolaryngol Clin North Am. · Pubmed #10477791 No free full text.

Abstract: Sjögren's syndrome is a rather common autoimmune disease primarily characterized by the dysfunction and destruction of exocrine glands associated with lymphocytic infiltrations. The disorder has a quite broad clinical presentation, ranging from glandular disease to systemic involvement and to the development of lymphoid malignancy. This article reviews the current aspects in clinical diagnosis and management and the immunopathogenesis of the disorder.