Successful treatment of relapsing autoimmune pancreatitis in primary Sj?gren’s syndrome with Rituximab: report of a case and review of the literature

Autoimmune pancreatitis (AIP) is a rare disorder often associated with multiple autoimmune diseases like rheumatoid arthritis, inflammatory bowel disease and Sjögren’s syndrome (SS). Although knowledge of AIP has grown over the last few years, little is certain about its cause and pathogenesis. Positive immunologic markers like antinuclear antibodies (ANA) or elevated serum levels of IgG4, systemic autoimmune disease association and positive response to oral steroid therapy strongly supports the idea of autoimmune mechanisms involved in the pathogenesis of AIP. We describe the first case reported on the literature of a patient with primary SS who developed relapsing AIP to steroids but responded successfully to Rituximab (RTX) therapy. New theories about the role of B-cells activity in SS and other autoimmune diseases has encourage the use of RTX, proving tolerance and efficacy especially in extra-glandular manifestations.     

A case of a flare-up of systemic lupus erythematosus and Sjögren’s syndrome manifesting with cholecystitis secondary to pregnancy

a 30-year- old had a 2 year history of systemic lupus erythematosus (SLE) was transferred to our hospital by her gynecologist because of a low-grade fever and dyspnea after delivery. Since a blood culture performed upon admission showed the presence ofBacteroides caccae, she was diagnosed with sepsis. Antibiotic therapy did not resolve her symptoms and she further developed an acute abdomen with marked cholecystitis. This was believed to be due to a flare-up of SLE after the pregnancy, overlapped with Sjögren’s syndrome which was evidenced by sialaden biopsy. She showed a good response to combination therapy with steroids and antibiotics.     

Polymyalgia rheumatica in primary Sjögren’s syndrome

The aim of the study was to describe the clinical and laboratory aspects of primary Sjögren’s syndrome (pSS) associated with polymyalgia rheumatica (PMR). The retrospective study compares the clinical and laboratory aspects of patients with pSS associated with PMR on a relatively large cohort of patients (n=16) and pSS patients without PMR (n=531). The prevalence of PMR among pSS patients was 3%, while in the average population, the prevalence of PMR is only 0.75%. PMR developed 8.7 years after the diagnosis of pSS in the older female pSS population (over 50 years of age), and in those with only glandular features. Interestingly the pSS/PMR patients had hypo gammaglobuline levels, while in the pSS patient group hypergammaglobulinaemia presented. Furthermore, positive ANA serology was more frequent among pSS/PMR patients. Since the clinical management of pSS/PMR is different from pSS, a better understanding of this clinical entity is essential.     

Autoantibodies to alfa-fodrin in patients with Hashimoto thyroiditis and Sjögren’s syndrome: possible markers for a common secretory disorder

Presence of autoantibodies to alfa-fodrin was investigated in patients with Sjögren’s syndrome (n = 61), Hashimoto thyroiditis (n = 27), Sjögren’s syndrome associated with Hashimoto thyroiditis (n = 31) and in healthy persons (n = 77). In each group, level of alfa-fodrin antibodies was higher than in the controls. There was no significant difference in their presence either between patients with Hashimoto thyroiditis with or without Sjögren’s syndrome, or—in IgA isotype—between Sjögren’s and Hashimoto thyroiditis patients. Correlation was found between the level of IgG alfa-fodrin and anti-thyroglobulin antibodies. Based on these findings, fodrin can be associated with both endocrine and exocrine glandular secretion. Antibodies to alfa-fodrin might have a role in the pathogenesis of Hashimoto thyroiditis concerning the “final common effectory pathway”, secretion. Alfa-fodrin antibodies can be good markers of secretory disorders. Assessment of these autoantibodies might help the diagnosis and follow-up of patients with impaired secretory capability of not only autoimmune origin.     

Unusual presentation of triple A syndrome mimicking Sj?gren’s syndrome

Triple A syndrome is a rare autosomal recessive disorder characterized by alacrima, achalasia, and adrenal insufficiency. Sj?gren’s syndrome (SS) is a chronic inflammatory disorder manifested primarily by diminished lacrimal and salivary gland secretions, resulting in symptoms of dry eyes and dry mouth, the so-called “sicca complex”. However, a variety of other manifestations also can occur, which can be termed “nonexocrine manifestations”. One of the frequent nonexocrine manifestations is dysphagia. In this paper, we present an unusual form of Triple A disease mimicking Sj?gren’s syndrome, which leads to a challenging diagnosis. An erratum to this article can be found at     

Bronchus-associated lymphoid tissue lymphoma in a patient with primary Sjögren’s syndrome

Despite its infrequent occurrence, the possible development of lymphoma or lymphoid lung disease in patients with Sjögren’s syndrome should always be borne in mind. We describe a case of bronchus-associated lymphoid tissue (BALT) lymphoma in a patient with Sjögren’s syndrome that clearly exemplifies the wide-ranging problems of diagnosing, treating and following such patients. This difficulty is due to the fact that the clinical and radiological findings suggest interstitial lung disease, and histological assays are required for a correct diagnosis. A precise knowledge of the various histological and radiological patterns of lung involvement can aid patient management.     

Hodgkin lymphoma as a complication of primary Sjögren’s syndrome

Sjögren’s syndrome (SS) is a chronic autoimmune disease that is characterized by lymphocytic infiltration of the exocrine glands, mainly the salivary and lachrymal glands, usually manifesting with xerostomia and xerophthalmia. Around 50% of patients with primary SS develop systemic complications, lymphoma being the most feared of these. The majority of these neoplasias originate from B cells and are of the non-Hodgkin type. We describe here a rare case of SS in which the patient developed a Hodgkin lymphoma. We also review the literature on this subject.     

Acquired hypophosphatemia osteomalacia associated with Fanconi’s syndrome in Sjögren’s syndrome

Sjögren’s syndrome is an autoimmune disorder involving exocrine glands that occurs alone or in association with various autoimmune and connective tissue diseases. The severity of Sjögren’s syndrome ranges from isolated sicca syndrome to severe complications such as vasculitis, lung and renal involvement. Overt or latent renal tubular acidosis caused by autoimmune tubulointerstitial nephritis, is a common extraglandular manifestation in Sjögren’s syndrome. Osteomalacia is a rare complication of renal tubular acidosis, and it was reported to be associated with distal renal tubular acidosis in Sjögren’s syndrome. We report a 60-year-old woman who presented with multiple bone deformity and general muscle weakness. Osteomalacia was secondary to Fanconi’s syndrome, and the Fanconi’s syndrome was a result of renal involvement in Sjögren’s syndrome. Fanconi’s syndrome is a rare kidney manifestation in Sjögren’s syndrome. It may be latent and may precede the subjective sicca symptoms. These findings suggest that evidence for Sjögren’s syndrome should be sought in adult patients with unexplained osteomalacia and renal tubular acidosis, even in the absence of subjective sicca syndrome. Conversely, in patients with Sjögren’s syndrome, early investigation and treatment of renal tubular dysfunction may prevent future complications, such as osteomalacia.     

Interstitial lung disease and Sjögren’s syndrome in primary biliary cirrhosis: a causal or casual association?

Interstitial lung disease (ILD) has been reported in patients with primary biliary cirrhosis (PBC); however, its frequency and pathogenesis are still poorly documented. Sjogren's syndrome (SS) is fairly common among patients with PBC, but the relationship between SS and PBC also remains controversial. To determine whether ILD and SS in PBC is a causal or casual association, whether SS accompanying PBC, could be considered secondary to or associated with PBC. One hundred and nine consecutive PBC cases were analyzed, and the differences of clinical features, histological stages, and serum autoantibodies between the PBC patients with and without SS were compared. There were 46 PBC patients with SS and 63 without SS, and 11 patients met the criteria of ILD. SS is associated with PBC in the form of secondary SS. The frequency of ILD in PBC patients with SS was 21.7% while only 1.6% in PBC patients without SS (P < 0.0001). ILD in PBC was related to SS, with Spearman's rank coefficient of 0.330 (P = 0.000). The association of SS with PBC, significantly higher in patients with than without ILD, which supports the hypothesis that ILD and SS in PBC, may be a causal, not casual, association.     

Decreased levels of soluble receptor for advanced glycation end products in patients with primary Sjögren’s syndrome

The purpose of this study was to evaluate the levels of sRAGE in primary Sjögren’s syndrome (SS), and to assess whether there is an association between sRAGE levels and disease characteristics. Thirteen patients were randomly selected from three subgroups: primary SS, (n = 6), secondary Sjögren’s, (n = 4), and ANA(+) but lacking criteria for further disease classification (n = 3). Levels of serum sRAGE were measured in triplicate using an enzyme-linked immunosorbent assay kit. Mean sRAGE levels were significantly lower in the primary Sjögren’s group. Logistic regression analysis indicated that plasma sRAGE level was a significant predictor of diagnostic status. Analyses using routine serological tests for diagnosing autoimmune disorders failed to reach statistical significance. This preliminary study supports the hypothesis that the RAGE system might participate in the disease pathway of primary SS, and that sRAGE may be a potential biomarker to aid in the diagnosis of primary SS.     

Successful treatment of a patient with primary Sjögren's syndrome with Rituximab

We report the course of a 55-year-old woman, the first patient with primary Sjögren's syndrome and distal renal tubular acidosis but without lymphoma to be treated with B-cell depletion using Rituximab. Rapidly after B-cell depletion, remarkable improvement in xerostomia occurred, while serological findings and tubular acidosis have been unchanged. In labial salivary gland biopsy, lymphocyte infiltration and particularly CD20-positive cells decreased strikingly. Aquaporin 1 (AQP-1) expression in myoepithelial cells was very low before treatment and increased noticeably. Apical AQP-5 in acinus cells likewise increased following Rituximab. In contrast, basolateral NKCC1 was expressed at unchanged intensity before and following Rituximab. The improvement has been sustained and still is most gratifying 10 months after treatment. B-cell depletion may be effective treatment in Sjögren's syndrome. Likewise, it may now be possible to separate the immunologic phenomena in Sjögren's syndrome from the consequences of prolonged hyposalivation when studying the pathophysiology of xerostomia.     

The potential utility of B cell-directed biologic therapy in autoimmune diseases

Increasing awareness of the importance of aberrant B cell regulation in autoimmunity has driven the clinical development of novel B cell-directed biologic therapies with the potential to treat a range of autoimmune disorders. The first of these drugs-rituximab, a chimeric monoclonal antibody against the B cell-specific surface marker CD20-was recently approved for treating rheumatoid arthritis in patients with an inadequate response to other biologic therapies. The aim of this review is to discuss the potential use of rituximab in the management of other autoimmune disorders. Results from early phase clinical trials indicate that rituximab may provide clinical benefit in systemic lupus erythematosus, Sj?gren's syndrome, vasculitis, and thrombocytopenic purpura. Numerous case reports and several small pilot studies have also been published reporting the use of rituximab in conditions such as myositis, antiphospholipid syndrome, Still's disease, and multiple sclerosis. In general, the results from these preliminary studies encourage further testing of rituximab therapy in formalized clinical trials. Based on results published to date, it is concluded that rituximab, together with other B cell-directed therapies currently under clinical development, is likely to provide an important new treatment option for a number of these difficult-to-treat autoimmune disorders.     

Primary rheumatic diseases of secondary Sjögren’s syndrome

The study aims to find out the distribution of the primary rheumatic diseases of secondary Sjögren’s syndrome (SS) in an unselected in-patient population. Patients with primary and secondary SS were collected from the Finnish hospitals’ National Discharge Registry during 1970–1991. In total, 676 cases with primary SS and 709 cases with secondary SS were found. Several rheumatic diseases may be associated with SS, but their figures vary a lot. Rheumatoid arthritis (RA) was the most common primary diagnosis in cases of secondary SS, but systemic connective tissue diseases were as frequent as primary diseases when the figures were compared with the incidences of the diseases. Ankylosing spondylitis (AS), juvenile RA (JRA) and psoriatic arthritis (PA) were less frequently associated with SS. There are major differences between the association figures of SS to other rheumatic diseases. The dysfunction of exocrine cells is probably part of the clinical picture of RA and some systemic connective tissue diseases. but not typically of AS, JRA or PA. Thus the term secondary SS may describe the clinical manifestation of the primary disease and no true combination of two diseases exists.     

Follicular bronchiolitis in association with connective tissue diseases

Eleven patients with connective tissue diseases were found to have bronchiolar lesions associated with minimal or no alveolar septal thickening. Seven of these patients had rheumatoid arthritis, 3 had Sjögren’s syndrome, and 1 had ankylosing spondylitis. Radiographic studies showed an interstitial pattern in all patients. The patients were nonsmokers and received no treatment prior to biopsy. All lung biopsy specimens showed inflammatory bronchiolar lesions which consisted of bronchiolar and peribronchiolar lymphocytic infiltrates (follicular bronchiolitis). The bronchiolar lesion has been reported previously in patients with connective tissue diseases treated with D-penicillamine; whether it represents a component of the systemic disease or a lack of effect of the therapeutic agent had not been established. The present study shows that several connective tissue diseases can be associated with inflammatory bronchiolar lesions.     

A follow-up study of minimally invasive lip biopsy in the diagnosis of Sjögren’s syndrome

The aims of this study were to characterize a minimally invasive technique of minor salivary gland biopsy of the lower lip and to present a large patient material undergoing this procedure because of a suspicion of Sjögren’s syndrome (SS), as well as to assess the procedure’s short-term and long-term value as a diagnostic test and a prognostic factor. The sample consists of consecutive 191 patients undergoing lower lip biopsy in 1987–1990 in Kanta-Hame Central Hospital, Hameenlinna, Finland. The method used was the retrospective chart review. Only three (1.6%) of the biopsies were uninformative, and only one (0.5%) of the patients had a biopsy complication. In 41% of the cases, biopsy was suggestive of SS. Females and elderly patients were more likely to have a positive biopsy result. Surprisingly, a large diversity between pathologists was observed. With the use of focus score instead of older Chisholm classification as an indicator of SS, the specificity of SS diagnostics improved, and the variability between pathologists diminished. Neither SS diagnosis nor positive lip biopsy for SS predicted patients’ long-term outcome. In only three patients (1.6%) did the histological diagnosis change due to repeated biopsies. The minimal invasive lower lip biopsy technique presented in this study is a reliable and safe aid in SS diagnostics. The currently recommended histological grading system (focus score?≥?1 suggesting SS) is more specific and reproducible than older Chisholm classification. Repeated biopsy very rarely adds new information.     

Autoantibodies to novel membrane and cytosolic antigens of the lachrymal gland in primary Sjögren’s syndrome

Sjögren’s syndrome (SS) is a prototypical systemic autoimmune disease, where autoimmune processes lead to the dysfunction of the exocrine glands. The key feature of the disease is autoimmune exocrinopathy, causing reduced tear secretion and subsequent keratoconjunctivitis sicca (KCS). The aim of this study was to investigate the connection between the presence of autoantibodies to lachrymal gland antigens and the reduced tear production in patients with primary SS. Ninety-nine patients, 90 women and 9 men, were investigated in the study. Twenty healthy young women served as controls. Enzyme-linked immunosorbent assay (ELISA) and Western blotting were applied to detect autoantibodies to antigen fractions prepared from the human lachrymal gland membrane and cytosolic fractions. Autoantibodies of the IgG, IgA and IgM isotypes to the lachrymal membrane and cytosolic fractions were detected in about one third (27%) of the patients with primary SS. IgA antobodies to the membrane and cytosolic fractions occurred most frequently in SS patients. A significant difference was found in the presence of IgA antibodies to the membrane lachrymal fraction between patients and controls given in ELISA indices (1.23?±?0.3 vs 1?±?0.19, p?R?=?0.998; p?=?0.045) with the clinical loss of secretory function (Schirmer’s test values). Positive correlation was found between membrane IgM and anti-SS-A levels (R?=?0.962; p?=?0.038) and also between cytosolic IgM antibodies and anti-SS-A levels (R?=?0.982; p?=?0.018). IgG, IgA and IgM types of autoantibodies may play a role in the development of the impaired lachrymal secretion and therefore may be involved in the pathogenesis of KCS.     

Coexistence of five autoimmune diseases: diagnostic and therapeutic difficulties

We report the case of coexistence of five autoimmune diseases in a 36-year-old woman, who initially developed psoriasis. Several years later, the patient was diagnosed with a mixed connective tissue disease and primary biliary cirrhosis (PBC). On admission to the Department of Rheumatology and Connective Tissue Diseases, the patient fulfilled classification criteria of an overlap syndrome systemic lupus erythematosus (SLE) with secondary antiphospholipid syndrome/systemic sclerosis (SSc)/Sjogren's syndrome (SS) with coexisting PBC and psoriasis. The SLE symptoms included discoid lupus erythematosus, arthritis, pancytopenia, antinuclear antibodies and anticardiolipin antibodies. Moreover, the patient met the criteria of antiphospholipid syndrome diagnosed based on preterm delivery before week 34, and high values of anticardiolipin antibodies were found at repeated determinations. The SSc symptoms included sclerodactyly, pulmonary fibrosis with pulmonary hypertension and esophageal dysfunction. The SS syndrome involved xerostomia, xerophthalmia, the positive Schirmer's test and presence of anti-SS antibodies. The literature reports overlap syndromes in various combinations; however, the coexistence of five autoimmune diseases is extremely rare.     

Ulnar artery vasculopathy in systemic sclerosis

Although digital ulceration frequently occurs in patients with systemic sclerosis, there have been few reports on macrovascular involvement. Macrovascular disease in systemic sclerosis has recently been described. We retrospectively reviewed the medical records and brachial angiographic findings of 19 systemic sclerosis patients, who exhibited Raynaud’s phenomenon and digital ulceration. We found that ulnar artery involvement is frequent in systemic sclerosis, although the precise mechanism is not known. There was no significant difference in risk factors of macrovascular disease between ulnar artery-involved patients and not-involved subjects. Thirteen patients underwent surgical intervention; five of the 13 patients had vascular graft performed due to ulnar artery involvement. We suggest that angiographic screening and early surgical intervention such as revascularization should be considered in patients with systemic sclerosis who manifest a severe form of Raynaud’s phenomenon and/or digital ulceration and especially in patients with diffuse sclerosis.     

Subclinical alveolitis in immunologic systemic disorders

Subclinical alveolitis is a frequent finding in immunologic systemic disorders. However the significance of subclinical alveolar inflammation does not seem to be univocal and varies according to the disease. The fact that pulmonary involvement is rare during the course of extrathoracic granulomatosis like Crohn’s disease or primary cirrhosis and that subclinical alveolitis is frequent suggests that alveolar inflammation may be the expression in the lung of a systemic immune disorder. In contrast subclinical alveolitis in collagen-vascular diseases, particularly progressive systemic sclerosis, is frequently associated with abnormalities of lung parenchyma as assessed by CT scan supporting the hypothesis that subclinical alveolitis is associated with development of ILD. Close follow-up of these patients is needed to better determine whether subclinical alveolitis precedes ILD and whether early detection of subclinical alveolitis in immunologic systemic disorders may identify those patients that are at risk for the development of ILD in the future.     

Efficacy and safety of rebamipide for the treatment of dry mouth symptoms in patients with Sj?gren’s syndrome: a double-blind placebo-controlled multicenter trial

The effects of rebamipide on dry mouth and salivary secretion in Sjögren’s syndrome patients were investigated in a double-blind placebo-controlled study. Rebamipide (100 mg TID) or placebo was administered for eight weeks and patient-assessed improvement of dry mouth and increase in salivary secretion measured by the Saxon test were evaluated. At two, four, and eight weeks, dry mouth improvement rates were, respectively, 26.0, 44.0, and 46.9% for rebamipide and 20.0, 27.1, and 39.1% for placebo, and mean increases in salivary secretion were, respectively, 0.14, 0.24, and 0.35 g for rebamipide and 0.03, 0.09, and 0.17 g for placebo, indicating higher values in the rebamipide group for both parameters at all timepoints but no significant differences between the two groups. Analysis by baseline characteristics suggested a statistically significant salivary secretion increasing effect of rebamipide in cases of primary Sjögren’s syndrome. No difference in the incidence of adverse events was seen between the two groups, confirming the safety of rebamipide. As a salivary secretion increasing effect was strongly suggested in cases of primary Sjögren’s syndrome, further study on the administration of rebamipide for the treatment of dry mouth in patients with Sjögren’s syndrome is required.