Multifocal nodular AL amyloidosis in primary Sjögren's syndrome

Primary Sj?gren's syndrome (primary SS) is characterized by lymphocytic and plasma cell infiltration of the lacrimal and salivary glands, sometimes extending to extraglandular sites. An increased incidence of B-cell lymphoproliferative disorders has been observed in patients with primary SS. We recently studied an unusual case of primary SS associated with multifocal nodular AL amyloidosis (amyloidomas), located in the lower respiratory tract and oral mucosa. A 66-year-old woman with primary Sj?gren's syndrome since 1966 was hospitalized in 1996 because of multifocal nodular shadows on a chest radiograph. An open lung biopsy specimen was obtained, revealing a large mass of amorphous eosinophilic material with green birefringence when stained with Congo red. Numerous plasma cells surrounded the amyloid deposits, aggregated in nodules and around blood vessels. The cytoplasm of these cells stained monotypically with anti-lambda light chain, using a peroxidase technique. Amyloid material did not stain with antibodies directed against kappa and lambda light chains, or against IgG, IgA and IgM heavy chains. Immunofixation of the serum and concentrated urine did not demonstrate monoclonal immunoglobulins. AL-amyloidomas might be a manifestation of local immunoglobulin production and amyloid formation within extramedullary plasmacytoma. This plasmacytoma might be burned out, namely, overcome by the deposits and no longer recognizable.     

Early rheumatoid arthritis in a patient with Sjögren's syndrome and pulmonary nodular amyloidosis: clinical implication of early limited use of infliximab

Infliximab, an anti-tumor necrosis factor α antibody, is among the most effective therapies for rheumatoid arthritis (RA). In this study, we report a patient with early RA of 6 months who has Sjögren's syndrome and pulmonary nodular lesions concomitantly. The patient did not respond to methotrexate (MTX, 6^Smg per week) for 3 months. When introduction of infliximab therapy is considered, we need to exclude the possibility of pulmonary granulomatous infection and malignancy. With the use of computed tomography-guided percutaneous needle biopsy and subsequent histological examinations, this case was rapidly and confidently diagnosed as localized pulmonary nodular amyloidosis. Immunochemical staining showed light chain type nodular amyloidosis by a deposition of immunoglobulin κ light chains, which is a rare condition in a patient with Sjögren's syndrome. We started combination therapy of infliximab (200^Smg per infusion) and MTX (6^Smg per week). Because of severe systemic eruption, this therapy was stopped halfway through the third infusion of infliximab, and MTX monotherapy was continued. Despite the withdrawal of infliximab therapy, the C-reactive protein values were decreased to an undetectable level at week 14, and the disease activity score for 28 joints was 3.1 at week 22. Clinical remission has been maintained more than 14 months with MTX alone. Infliximab has been used only for patients with recalcitrant RA, because the cost of its lifelong use would be an economic burden in most cases. An optimal and affordable strategy for the treatment of early RA should be developed. Our findings may support the idea that the combination therapy of infliximab and MTX for early RA alters the course of the disease.     

Early rheumatoid arthritis in a patient with Sjögren's syndrome and pulmonary nodular amyloidosis: clinical implication of early limited use of infliximab

Abstract

Infliximab, an anti-tumor necrosis factor α antibody, is among the most effective therapies for rheumatoid arthritis (RA). In this study, we report a patient with early RA of 6 months who has Sjögren's syndrome and pulmonary nodular lesions concomitantly. The patient did not respond to methotrexate (MTX, 6^Smg per week) for 3 months. When introduction of infliximab therapy is considered, we need to exclude the possibility of pulmonary granulomatous infection and malignancy. With the use of computed tomography-guided percutaneous needle biopsy and subsequent histological examinations, this case was rapidly and confidently diagnosed as localized pulmonary nodular amyloidosis. Immunochemical staining showed light chain type nodular amyloidosis by a deposition of immunoglobulin κ light chains, which is a rare condition in a patient with Sjögren's syndrome. We started combination therapy of infliximab (200^Smg per infusion) and MTX (6^Smg per week). Because of severe systemic eruption, this therapy was stopped halfway through the third infusion of infliximab, and MTX monotherapy was continued. Despite the withdrawal of infliximab therapy, the C-reactive protein values were decreased to an undetectable level at week 14, and the disease activity score for 28 joints was 3.1 at week 22. Clinical remission has been maintained more than 14 months with MTX alone. Infliximab has been used only for patients with recalcitrant RA, because the cost of its lifelong use would be an economic burden in most cases. An optimal and affordable strategy for the treatment of early RA should be developed. Our findings may support the idea that the combination therapy of infliximab and MTX for early RA alters the course of the disease.     

Sjögren's syndrome and localized nodular cutaneous amyloidosis: coincidence or a distinct clinical entity?

OBJECTIVE: To report 8 patients with Sj?gren's syndrome (SS) and localized nodular cutaneous amyloidosis and to examine serologic and immunohistologic findings that may link the 2 diseases. METHODS: The databases for 3 amyloidosis centers were searched for patients with localized nodular cutaneous amyloidosis and SS. Eight patients with this combination were identified, and clinical, serologic, and histologic parameters were retrospectively evaluated. RESULTS: Among the 8 patients with a clinical diagnosis of SS, 6 fulfilled the American-European Consensus Group criteria for SS. All of the patients were women in whom SS had been diagnosed at a median age of 47 years (range 30-61 years) and amyloid had been diagnosed at a median age of 60 years (range 42-79 years). The presence of the immunoglobulin light chain type of amyloid (AL amyloid) was confirmed in 4 patients. In 3 of these 4 patients as well as 2 other patients, a light chain-restricted plasma cell population was observed near the amyloid deposits. Progression to systemic amyloidosis was not observed in any patient during a median followup of 3.5 years. CONCLUSION: SS should be considered in patients with cutaneous amyloidosis. The combination of cutaneous amyloidosis and SS appears to be a distinct disease entity reflecting a particular and benign part of the polymorphic spectrum of lymphoproliferative diseases related to SS.     

Is Sj?gren's syndrome involved in the formation of localised nodular amyloidosis?

The case of a patient who presented with Sj?gren's syndrome complicated by localised cutaneous nodular amyloidosis is reported. We discuss the possible link between these two diseases.     

Pathophysiology of Sjögren's syndrome

Sj?gren's syndrome (SS) is an excellent model for understanding the pathophysiology of autoimmune diseases and the relationships between autoimmunity and lymphoma. Recently discovered new elements probably play a role in the pathogenesis of this multifactorial disease: genetic predisposition remains largely unknown, but there isa link between certain HLA molecules and the type of autoantibodies secreted; sometimes called autoimmune epithelitis, SS is associated with abnormal apoptosis activity in epithelial cells leading to an abnormal accumulation of degradation products of the cytoskeleton proteins such as alpha- and beta-fordrine and also to the presentation of numerous antinuclear autoantigens to the immune system; significant polyclonal activation of B lymphocytes is probably mediated, at least in part, by a major increase in molecules of the TNF family (e.g. BlyS or BAFF) which play an important role in the production of autoantibodies; cytokine inhibition of healthy glands or anti-muscarin receptor antibodies and abnormal function of certain water pumps such as aquaporine could explain the perturbed function of the remaining healthy glands; permanent stimulation of autoreactive B cells favors oncogenic events and could lead to the development of B lymphoma with autoantibody activity. The links between these different elements are progressively falling into place. A better understanding of the pathophysiology of SS can be expected to lead to the development of much needed new therapeutic tools.     

Immunopathology of Sjögren's syndrome

Sj?gren's syndrome is a chronic autoimmune disorder characterized by mononuclear cell infiltration around epithelial cells of exocrine glands. In recent years, several studies have tried to elucidate the components of the immunopathologic interaction in Sj?gren's syndrome as well as the function of these components. 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 Sj?gren's syndrome express several cytokines (IL-1 beta, IL-6, NO), protooncogenes (c-myc), autoantigens (Ro, La, Fodrin) and costimulatory molecules (B71, B72). The characteristic destruction of epithelial cells of Sj?gren'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 Perforin and Granzymes. Finally epithelial cells seem to exert a regenerative effort since they express trefoil proteins (pS2). The above mentioned properties give epithelial cells the leading role in the pathophysiology of the syndrome but the exact causative agent which drives the immune system towards an autoimmune reaction still remains obscure.     

Genes and Sjögren's syndrome

The evidence for a strong genetic component conferring susceptibility to primary Sj?gren's syndrome (SS) is mounting. Several associations with SS have been reported and provide evidence that the HLA region harbors important susceptibility loci and that multiple genes outside the HLA region play a role. Genetic discovery lags behind success observed in related autoimmune diseases. Identifying genetic factors that cause SS will allow more precise definition of pathogenic mechanisms leading to the overall SS phenotype and clinically heterogeneous subsets of patients. Critical opportunities are certain to follow for translation into improved diagnosis and therapies for SS and its spectrum diseases.     

Immunogenetics of Sjögren's syndrome

The etiology for SS remains unknown where multifactorial influences contribute to the pathogenesis of subsequent development of the disease. The genetic influence is also multifactorial and the data suggests a familial component indicative of autosomal-dominant genes as well as genetic contributions associated with class-I and class-II HLA alleles. Various auto-antibodies found with increased frequency in SS (anti-Ro and anti-La) were shown to be associated with HLA class-II alleles at the DQA1 and DQB1 loci that were also found to have in common specific amino acid residues (10). Ethnic groups have also been studied and show varying HLA associations with primary SS. Multiple ethnic groups, however, share a DQ allele supporting the idea that the majority of SS patients carry a common allele which may predispose to primary SS. In some cases, the HLA-DR antigen may be induced and cause to appear on epithelial cells where they present antigen to CD 4+ T-cells, which then go on to aid in the destruction of salivary gland epithelial cells specifically. The further elucidation of disease associations as well as possible immunogenetic pathogenic mechanisms may help to explain the causes for the development of various autoimmune diseases such as Sj?gren's Syndrome. This may eventually result in the ability to immunomodulate these abnormal immune responses. In so doing, an approach to treatment by genetic engineering may also be possible once a further understanding of the genetic influences and mechanisms in the causation of autoimmune disease is further elucidated.     

Sjögren's syndrome

Sj?gren's syndrome is an autoimmune disease characterized by inflammation of the exocrine glands, leading to impaired function. Here, I review the relatively short history of the syndrome and explain why it is frequently underdiagnosed, undertreated and under-researched. Attempts to provide classification criteria have culminated in the revised American-European Consensus Criteria, which provide a sound basis for both clinical management and research. The recognition that Sj?gren's syndrome is a disease of considerable morbidity has led to a more aggressive approach to therapy ranging from topical therapies to systemic treatment with secretagogues such as pilocarpine and cemiveline, and immunomodulatory drugs such as hydroxychloroquine and interferon-alpha. The central role of the glandular epithelial cell is identified as the key to understanding the pathogenesis of the disease. Hypofunction rather than destruction of these cells is now regarded as the main mechanism of secretory failure in Sj?gren's syndrome.     

Sjögren's syndrome

Sj?gren's syndrome is a chronic autoimmune disorder of the exocrine glands with associated lymphocytic infiltrates of the affected glands. Dryness of the mouth and eyes results from involvement of the salivary and lacrimal glands. The accessibility of these glands to biopsy enables study of the molecular biology of a tissue-specific autoimmune process. The exocrinopathy can be encountered alone (primary Sj?gren's syndrome) or in the presence of another autoimmune disorder such as rheumatoid arthritis, systemic lupus erythematosus, or progressive systemic sclerosis. A new international consensus for diagnosis requires objective signs and symptoms of dryness including a characteristic appearance of a biopsy sample from a minor salivary gland or autoantibody such as anti-SS-A. Exclusions to the diagnosis include infections with HIV, human T-lymphotropic virus type I, or hepatitis C virus. Therapy includes topical agents to improve moisture and decrease inflammation. Systemic therapy includes steroidal and non-steroidal anti-inflammatory agents, disease-modifying agents, and cytotoxic agents to address the extraglandular manifestations involving skin, lung, heart, kidneys, and nervous system (peripheral and central) and haematological and lymphoproliferative disorders. The most difficult challenge in diagnosis and therapy is patients with symptoms of fibromyalgia (arthralgia, myalgia, fatigue) and oral and ocular dryness in the presence of circulating antinuclear antibodies.     

Diagnosis and definition of primary Sjögren's syndrome

During the last years, several sets of criteria for the diagnosis and classification of primary Sj?gren's syndrome (SS) have been promulgated. So far none has achieved universal acceptance. It is conceivable that the lack of pathognomonic features of SS and the frequent coexistence of SS with other connective tissue di-seases partly explain the lack of agreement. Regardless of criteria preference the final diagnosis of SS should reflect the definition of the syndrome, being an inflammatory and autoimmune rheumatic disease. It is therefore suggested that any criteria employed should include a mandatory combination of measurements of exocrine dysfunction. histological confirmation of inflammation, serological evidence of autoimmunity and exclusion or diseases mimicking primary Sj?gren's syndrome.     

Simultaneous presentation of sarcoidosis and Sjögren's syndrome

SIR, A 32-yr-old woman presented with pretibial painful rednodules. She had a 6-month history of migratory pain and swellingof several joints. She complained of daily progressive oraldryness, thirst, impaired swallowing and blurred vision witha feeling of dry eyes for more than 3 h a day. Her medical,family, occupational and environmental histories were non-contributory.She used an oral contraceptive and ibuprofen. Physical examinationshowed oedema of the ankles and erythema nodosum on both legs.Laboratory investigations revealed an erythrocyte sedimentationrate of 44 mm/h (normal value <10) and a     

Sjögren's syndrome and pancreatic affection

Sj?gren's syndrome (SS) is an autoimmune disorder affecting primarily the exocrine glands, leading to keratoconjunctivitis sicca (KCS) and xerostomia, but that can also include extraglandular features(1). Due the anatomical, physiological and pathological similarity between the pancreas and the salivary glands, it has been described that the pancreas it is not exempt from the damage produced by this syndrome. Some authors have assessed pancreatic involvement of SS by analyzing the histopathological changes, evaluating the pancreatic endocrine and exocrine function (serum pancreatic enzymes, elastase, lipase or trypsin determinations, N-benzoyl-L-tyrosyl-para-aminobenzoic acid excretion test, etc), searching specific pancreatic antibodies (antiductal) or performing endoscopic retrograde colangiopancreatography or noninvasive imaging studies such as computed tomography or ultrasound. Herein we review the literature regarding the prevalence and type of pancreatic involvement in the SS and we discuss the differential diagnosis with multiorganic Lymphoproliferative Syndrome.     

The management of Sjögren's syndrome

Sj?gren'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 Sj?gren's syndrome) or in the context of an underlying connective tissue disease (secondary Sj?gren's syndrome). Systemic features, resulting from cutaneous, respiratory, renal, hepatic, neurologic, and vascular involvement, often occur. Two types of primary Sj?gren'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 Sj?gren'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 Sj?gren's syndrome. Induction of oral tolerance and gene-transfer modalities were recently attempted in animal models, with promising results.