IgA immunoglobulin isotype of rheumatoid factor in primary Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is an autoimmune disease with autoantibodies overproduction, including rheumatoid factors (RF). RF-IgA, IgG immunoglobulin classes are suggested as potential biomarkers of pSS. We studied 76 patients with pSS (ACR/Eular 2017); laboratory tests included ESR, C-reactive protein, concentrations of gamma globulins, RF, Anti-SS-A/Ro, and anti-SS-B/La. Eye dryness and keratoconjunctivitis sicca were confirmed with Schirmer's test, the ocular staining score (OSS) using lissamine green, fluorescein staining and biopsy of minor salivary gland with the histopathological evaluation. Differences between groups were analyzed with U Mann-Whitney test. Correlations between quantitative variables were assessed with the Spearman correlation coefficient.. The best diagnostic values of immunoglobulin concentration for discriminating pSS patients and healthy individuals are for RF-IgA. With cut-off of 21.5 EU/mL, the sensitivity is 72% and specificity is 100%. Very high specificity (100%) is also obtained for RF-IgM concentration of 74.1 EU/mL. Sensitivity is, however, smaller than that for RF-IgA and amounted to 61%. The RF-IgG is the poorest indicator of pSS with 51% of sensitivity and 95% of specificity. To summarize RF-IgA strongly associate with anti-SS-A and anti-SS-B autoantibodies. Both RF-IgA and RF-IgM may be used as diagnostic tools for pSS. Conclusions: among the three studied rheumatoid factor subtypes, RF-IgA showed the best diagnostic accuracy for pSS. RF-IgA correlated with anti-SS-A/Ro and anti-SS-B antibodies even more closely than RF-IgM. The assessment of the RF-IgA serum concentration may be helpful in the process of establishing pSS diagnosis.

Clinicopathologic significance of in vivo antinuclear autoantibodies in oral mucosal biopsies.

OBJECTIVE: Although antinuclear autoantibody (ANA) staining of oral biopsy specimens is indicative of chronic ulcerative stomatitis, it is not known whether this staining is characteristic of other autoimmune diseases. Our study was undertaken to characterize the various in vivo ANA patterns detected in the oral mucosa by direct immunofluorescence to describe the associated hematoxylin and eosin findings, and determine whether patients with these findings had a coexisting systemic connective tissue disease. STUDY DESIGN: This was a retrospective analysis of oral biopsy specimens submitted from 2013 to 2016. RESULTS: In vivo ANA staining was present in 72 of the 2019 cases examined. Immunoglobulin G was the most common immunoreactant (71 of 72 cases), and speckled nuclear staining was the most frequent in vivo ANA pattern (52 of 72). In most cases, hematoxylin and eosin staining of biopsy specimens showed mucositis (24 of 34). Detailed clinical information was available for 10 patients, and all of them had an autoimmune disease. CONCLUSIONS: We found similar prevalence of ANA staining with direct immunofluorescence in oral epithelial biopsy specimens as reported for those of skin. In vivo ANA in the oral epithelium may indicate the presence of an immune-mediated disease. Patients who show ANA deposits in oral mucosal biopsy specimens should be investigated for systemic connective tissue disease as well as for chronic ulcerative stomatitis.

Multicentric Squamous Odontogenic Tumor: A Case Report and Review of the Literature.

Squamous odontogenic tumor (SOT) is a rare benign epithelial odontogenic neoplasm of the jaws. Both intraosseous and peripheral SOTs have been described in the English language literature. While most intraosseous SOTs occur as solitary lesions, a multicentric variant has also been previously described. Although the radiographic and microscopic features are identical for both solitary and multicentric clinical presentations, there are three significant differences between them. More specifically, multicentric SOT presents at an earlier age (third decade of life), has a slightly higher male to female ratio than the solitary type and has a marked predilection for African-Americans. Here we document the eighth reported case of multicentric SOT, which was diagnosed in a 43-year-old African-American male. In addition, we feature focal sebaceous metaplasia, a heretofore unknown microscopic feature of SOT. Clinical, radiological, and histopathological findings are discussed. The differential diagnosis, biological behavior and management modalities for SOT are also addressed.

Multiple Roles for B-Lymphocytes in Sjogren's Syndrome.

Sjogren's syndrome (SS) is a complex heterogeneous autoimmune disease resulting in loss of salivary gland and lacrimal gland function that may include multiple systemic manifestations including lymphoma. Multiple cell types participate in disease pathogenesis. This review discusses evidence for abnormal B cell subpopulations in patients with SS, critical roles of B cells in SS and the status of B cell-directed therapies in the management of patients with SS.

Humoral Responses to Diverse Autoimmune Disease-Associated Antigens in Multiple Sclerosis.

UNLABELLED: To compare frequencies of autoreactive antibody responses to endogenous disease-associated antigens in healthy controls (HC), relapsing and progressive MS and to assess their associations with clinical and MRI measures of MS disease progression. METHODS: The study analyzed 969 serum samples from 315 HC, 411 relapsing remitting MS (RR-MS), 128 secondary progressive MS (SP-MS), 33 primary progressive MS (PP-MS) and 82 patients with other neurological diseases for autoantibodies against two putative MS antigens CSF114(Glc) and KIR4.1a and KIR4.1b and against 24 key endogenous antigens linked to diseases such as vasculitis, systemic sclerosis, rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus, polymyositis, scleroderma, polymyositis, dermatomyositis, mixed connective tissue disease and primary biliary cirrhosis. Associations with disability and MRI measures of lesional injury and neurodegeneration were assessed. RESULTS: The frequencies of anti-KIR4.1a and anti-KIR4.1b peptide IgG positivity were 9.8% and 11.4% in HC compared to 4.9% and 7.5% in RR-MS, 8.6% for both peptides in SP-MS and 6.1% for both peptides in PP-MS (p = 0.13 for KIR4.1a and p = 0.34 for KIR4.1b), respectively. Antibodies against CSF114(Glc), KIR4.1a and KIR4.1b peptides were not associated with MS compared to HC, or with MS disease progression. HLA DRB1*15:01 positivity and anti-Epstein Barr virus antibodies, which are MS risk factors, were not associated with these putative MS antibodies. CONCLUSIONS: Antibody responses to KIR4.1a and KIR4.1b peptides are not increased in MS compared to HC nor associated with MS disease progression. The frequencies of the diverse autoreactive antibodies investigated are similar in MS and HC.

Indications and procedures for direct immunofluorescence biopsies of the oral mucosa.

A definitive diagnosis is crucial for management of any oral mucosal disease. Direct immunofluorescence (DIF) is a valuable diagnostic aid for immune-mediated blistering diseases and systemic connective tissue diseases of the skin and the mucosa. This paper gives an overview of the DIF biopsy technique for oral lesions and provides a background for the clinician to optimize the utilization of DIF biopsy. The key characteristic diagnostic findings of DIF of specific mucosal diseases are also discussed.

Evaluation of salivary gland protein 1 antibodies in patients with primary and secondary Sjogren's syndrome.

Sjogren's syndrome (SS) has been associated with the expression of anti-Ro and anti-La antibodies. Anti-salivary gland protein 1 (SP1) antibodies have recently been identified in patients with SS. The current work involved a cross sectional study to determine whether anti-SP1 antibodies were identified in particular subgroups of patients with SS. The results of this study revealed that anti-SP1 antibodies were present in the sera of 52% of SS patients while anti-Ro/anti-La was present in 63% of patients. 19% of patients had anti-SP1 without anti-Ro/anti-La. Patients with SS and lymphoma expressed anti-Ro, anti-La and anti-SP1 together. In SS associated with RA, 50% had antibodies anti-SP1 while 40% had anti-Ro/anti-La. In conclusion, anti-SP1 antibodies are commonly seen in both primary and secondary SS and rarely in normal controls. Future studies are needed to determine the roles and timing of expression of anti-SP1 antibodies in Sjogren's syndrome.

Anti-salivary gland protein 1 antibodies in two patients with Sjogren's syndrome: two case reports.

INTRODUCTION: Current diagnostic criteria for Sjogren's syndrome developed by the American College of Rheumatology include the presence of antinuclear antibodies, rheumatoid factor, anti-Ro or anti-La autoantibodies. The purpose of this report is to describe two patients with biopsy-proven Sjogren's syndrome lacking these autoantibodies but identified by antibodies to salivary gland protein 1. Diagnosis was delayed until salivary gland tumors developed in these patients because of the lack of the classic autoantibodies. This report emphasizes the existence of patients with primary Sjogren's syndrome who lack autoantibodies anti-Ro or anti-La and may therefore be misdiagnosed. Antibodies to salivary gland protein 1 identify some of these patients. CASE PRESENTATION: Two patients are described and were seen in the autoimmune disease clinics of the State University of New York (SUNY) at the Buffalo School of Medicine. In both patients, chronic dry mouth and dry eye had been dismissed as idiopathic because test results for autoantibodies anti-Ro and anti-La were negative. Both patients had swelling of major salivary glands that prompted biopsies. Biopsies of major salivary glands from both cases demonstrated salivary gland tumors and existence of inflammation consistent with Sjogren's syndrome. Serologic testing revealed antibodies to salivary gland protein 1. CONCLUSIONS: Patients presenting with classic clinical symptoms of dry mouth and eyes do not always show the current serologic markers of Sjogren's syndrome, anti-Ro and anti-La. In these cases, investigation for antibodies to salivary gland protein 1 is of importance to make the diagnosis of Sjogren's syndrome. Early diagnosis of Sjogren's syndrome is necessary for improved management as well as for vigilance regarding potential complications, such as salivary gland tumors as were seen in the described cases.

Different stages of primary Sjogren's syndrome involving lymphotoxin and type 1 IFN.

Primary Sjögren's syndrome (pSS) is a complex autoimmune disease starting in the salivary and lacrimal glands and continuing to involve the lungs and kidneys with the eventual development of lymphoma. Many studies have emphasized the role of type 1 IFN (IFN-α) and lymphotoxin α (LTα) in the pathogenesis of the disease. The present studies were designed to delineate the role of IFN-α in pSS using an animal model, the IL-14α (IL14αTG) transgenic mouse. IL14αTG mice lacking the type 1 IFNR (IL14αTG.IFNR(-/-)) had the same submandibular gland and lacrimal gland injury as did the IL14αTG mice, but they lacked the later parotid gland and lung injury. Development of lymphoma was delayed in IL14αTG.IFNR(-/-) mice. The switch from IgM to IgG autoantibodies as well as the increase in serum IgG2a seen is IL14αTG mice was inhibited in IL14αTG.IFNR(-/-) mice. Production of LTα was identified in both IL14αTG mice and IL14αTG.IFNR(-/-) mice at the time that salivary gland injury was occurring. These and previous studies suggest a model for pSS that separates the disease into several stages: 1) initial injury to the submandibular and lacrimal glands via an environmental insult and LTα; 2) amplification of local injury via the production of type 1 IFN; injury to the parotid glands, lungs, and kidneys is seen; 3) progression of systemic inflammation with the eventual development of large B cell lymphoma. Understanding these different stages will help to develop strategies for treatment of patients with pSS based on the status of their disease.

Definitive and differential diagnosis of desquamative gingivitis through direct immunofluorescence studies.

BACKGROUND: Desquamative gingivitis (DG) is a common clinical manifestation of oral autoimmune vesiculobullous diseases (VBDs). Their polymorphous clinical presentations coupled with similar histologic features make diagnosis indistinguishable among the different VBDs. Direct immunofluorescence (IF) studies are valuable gold-standard diagnostic tests that allow for discrimination among the various VBDs that present with DG. There have been no recent detailed analyses done that have used conventional light microscopy and direct IF in diagnosis to document the clinical associations of DG with various autoimmune oral diseases. The aim of this study is to examine retrospectively a large cohort of patients with DG for associated diseases and to determine the utility of direct IF and conventional light microscopy in establishing a definitive diagnosis. METHODS: During a 14-month period, our laboratory in Buffalo, New York, received 239 consecutive archival cases of gingival biopsy with a clinical diagnosis of DG. These specimens were submitted to establish or rule out a diagnosis of a direct IF-positive VBD. The demographic, clinical, and microscopic findings were tabulated using established inclusion and diagnostic criteria. RESULTS: Approximately half the number (48.1%) of biopsies received for direct IF studies were submitted by periodontists. Slightly more than half of the patients (53%) previously had biopsies submitted for both hematoxylin and eosin (H & E) and direct IF testing. There was a female predilection for all the diseases studied except for pemphigus and linear immunoglobulin A disease. Oral lichen planus was the most common disease presenting as DG, followed by pemphigoid. The clinical diagnosis of lichen planus correlated with the biopsy findings in 80% of the cases and with pemphigoid in 60%. Definitive diagnosis was rendered to ≈80% of the gingival biopsies submitted. Negative cases of direct IF presenting as DG had significant pathology, such as dysplasia and carcinoma, which would have been otherwise missed if H & E studies had not been performed. CONCLUSIONS: This study has the largest cohort of patients with DG suspected of VBD reported in the literature. The patients were predominantly females who had most often been seen by a periodontist. The definitive diagnosis of DG was most accurately achieved when H & E along with two biopsies for direct IF studies were submitted for testing. H & E studies were particularly important for definitive diagnosis of negative cases. Oral lichen planus was the most common disease presenting as DG, which is consistent with recent studies. Systemic connective tissue disorders that present as DG at initial clinical examination require direct IF and serum studies for a conclusive diagnosis. Clinical pathologic correlation, including history, presentation, H & E, and direct IF studies, are essential in establishing a definitive and differential diagnosis for cases presenting with DG.

A role for lymphotoxin in primary Sjogren's disease.

The etiology of salivary gland injury in primary Sjögren's disease is not well understood. We have previously described a mouse model of Sjögren's disease, IL-14α transgenic (IL14αTG) mice, which reproduces many of the features of the human disease. We now demonstrate a critical role for lymphotoxin α (LTA) in the pathogenesis of Sjögren's disease in IL14αTG mice. IL14αTG mice express LTA mRNA in their salivary glands and spleen and produce soluble LTA protein in their salivary secretions. When IL14αTG mice were crossed with LTA(-/-) mice, the IL14αTG.LTA(-/-) mice retained normal salivary gland secretions and did not develop either lymphocytic infiltration of their salivary glands or secondary lymphomas. However, both IL14αTG and IL14αTG.LTA(-/-) mice produced similar amounts of IFN-α and had similar deposition of autoantibodies in their salivary glands. Both IL14α and IL14α/LTA(-/-) mice had similar B cell responses to T-dependent and T-independent Ags, L-selectin expression, and expression of RelA, RelB, and NF-κB2 in their spleens. These studies suggest that LTA plays a critical role in the local rather than systemic inflammatory process of Sjögren's disease. Furthermore, local production of soluble LTA in the salivary glands of IL14αTG mice is necessary for the development of overt Sjögren's disease. Autoantibody deposition alone is not sufficient to produce salivary gland dysfunction. We also demonstrate that LTA is increased in the salivary gland secretions and sera of patients with Sjögren's disease, further strengthening the biological relevance of the IL14αTG model to understanding the pathogenesis of human disease.

Desmoplastic fibroma of the anterior mandible. Case report and review of literature.

Desmoplastic fibroma is a rare and locally aggressive lesion that affects the long bone and the jaw bones. Mandibular bone involvement has been mostly reported in the posterior segment; anterior region presentation is rare. This case report highlights the diagnosis, management and treatment of a midline mandibular involvement. It includes a literature review.

IL-14 alpha, the nexus for primary Sjögren's disease in mice and humans.

To evaluate the role of interleukin 14 alpha (IL-14a) in Sjögren's syndrome (SS), we evaluated the expression of IL-14a in the peripheral blood lymphocytes (PBL) of patients with primary and secondary SS and normal controls by quantitative RT-PCR. In addition, transgenic IL-14a mice were analyzed from 6 weeks of age to death for both histological and immunological features of Sjögren's disease. Patients with both primary and secondary Sjögren's syndrome expressed IL-14a at statistically higher levels in their peripheral blood compared to normal controls matched for age, sex and ethnic group. Transgenic mice in which IL-14a expression was increased constitutively were previously demonstrated to develop hypergammaglobulinemia, autoantibodies, infiltration of the parotid glands with lymphocytes, mild immune-complex mediated renal disease and large B cell lymphoma. In this paper we expand these observations to demonstrate that these mice develop all the clinical and immunological features of primary Sjögren's disease in the same relative time frame as patients with primary Sjögren's disease: stage 1-early hypergammaglobulinemia and autoantibody production, stage 2-decreased salivary gland function with early lymphocytic infiltration of the submandibular glands only, but antibody deposition in the submandibular and parotid glands, stage 3-lymphocytic infiltration of the submandibular, parotid and lacrimal glands with B and T lymphocytes and plasma cells along with interstitial lung disease and mild renal disease, and stage 4-large B cell lymphoma. Thus IL-14a is important in the pathophysiology of Sjögren's disease. The IL-14a transgenic mouse is a novel animal model that can be utilized to understand the pathophysiology of Sjögren's disease.

A comparative treatment study of topical tacrolimus and clobetasol in oral lichen planus.

BACKGROUND: Existing clinical trials have shown that topical corticosteroids are often effective in the management of oral lichen planus (OLP). However, tacrolimus has recently been shown to be an effective treatment of OLP. OBJECTIVE: To compare the effectiveness of clobetasol and tacrolimus in the topical management of OLP. STUDY DESIGN: In this randomized comparative double-blind study, 30 consecutive patients with oral lesions consistent clinically and histologically with OLP were recruited. The patients were divided into 2 groups to receive clobetasol 0.05% or tacrolimus 0.1% ointment and were treated for 6 weeks. RESULTS: The profiles of mean lesion sizes and mean pain measures did not differ between the tacrolimus and clobetasol treatment groups. CONCLUSION: We found tacrolimus to be as useful as clobetasol in treatment of OLP. We believe that up-to-date evidence indicates the effectiveness of tacrolimus in treating OLP.

Prevalence and clinical significance of elongated calcified styloid processes in panoramic radiographs.

The styloid process refers to a mineralized styloid ligament of the temporal bone that usually appears (in different forms and lengths) on panoramic radiographs. This study sought to evaluate panoramic radiographs to determine the prevalence and clinical significance of elongated calcified styloid processes. For this study, panoramic radiographs from 1,000 dental patients were evaluated. Each styloid process length was measured and its pattern of calcification was assessed as elongated (that is, uninterrupted styloid calcification), pseudoarticulated (a single joint appearing as an articulated styloid process), or segmented (an interrupted calcified styloid process). Calcified styloid processes longer than 30 mm were considered to be elongated and were used for this study; 220 panoramic radiographs (22%) revealed such elongated processes. This retrospective study indicated that there is no clinical significance when elongated styloid processes are found coincidentally.

Significance of IgG4 in the diagnosis of mucous membrane pemphigoid.

OBJECTIVE: To determine the diagnostic value and frequency of tissue deposition of IgG4 in comparison to polyclonal IgG, IgA, IgM, and C3. STUDY DESIGN: Oral mucosal biopsies of 82 patients clinically suspected to have mucous membrane pemphigoid (MMP) were analyzed by direct immunofluorescence (IF) using polyclonal anti-human IgG, IgM, IgA, fibrin, complement C3, and anti-human IgG4 subclass monoclonal antibodies. RESULTS: Based on clinical, hematoxylin and eosin (H & E), and direct IF studies, 34 cases were diagnosed as MMP. The most common antibody deposited was IgG (90%), followed by C3 (82%), and IgG4 (71%). In more than half the cases of MMP, IgG4 deposition was seen in combination with IgG and or C3. Strikingly, IgG4 was the sole antibody detected in 2 cases (6%). CONCLUSION: Our results suggest that the use of monoclonal IgG4 is important in the diagnosis of MMP. We suggest adding monoclonal IgG4 to the routine panel of antibodies used in studies of cases suspected to have MMP to avoid false-negatives.

Intraosseous angiomyoma of the mandible.

Leiomyoma is a benign smooth muscle tumor that usually is found in the uterus, gastrointestinal tract, or skin. It appears infrequently in the oral cavity. Intraosseous leiomyomas are rare; to date, only 14 cases have been reported in the English-language literature. Gnathic leiomyoma occurs more commonly in the posterior mandible as an asymptomatic swelling with variable radiographic appearance. Microscopically, 53% of gnathic leiomyomas have a prominent vascular component that warrants a diagnosis of angiomyoma. Surgical excision is the treatment of choice. This article describes the clinical-pathological features of an exceptional intraosseous angiomyoma of the mandible.

Subacute necrotizing sialadenitis: a clinicopathological study.

OBJECTIVE: To report cases of extra-palatal subacute necrotizing sialadenitis (SANS), an uncommon condition that usually affects palatal minor salivary glands, and to characterize the etiopathogenesis, clinical features, and histology of this lesion. STUDY DESIGN: Retrospective reviews of records for patients with SANS diagnosed between 1999 and 2005; only cases with complete clinical history and histology were included in the study. RESULTS: Five cases (3 women, 2 men) were identified. The majority of patients presented with painful 1.0 to 1.5 cm swellings, with sudden and rapid increase in size. Two cases occurred in the buccal mucosa, 2 on the ventral surface of tongue, and 1 on the upper lip. Histology showed acinar necrosis surrounded by a dense polymorphous inflammatory infiltrate with focal exuberant tissue eosinophilia. Ductal atrophy was seen with minimal squamous metaplasia. In all the cases, healing occurred without any further treatment in 3 weeks. No recurrence was observed. CONCLUSION: SANS is an uncommon, inflammatory condition of unknown etiology affecting minor salivary glands. SANS appears to be a self-limiting process that has distinct characteristic clinical and histologic features. Nevertheless, SANS shares some of the histologic features of early necrotizing sialometaplasia (NS), suggesting a possible relationship between the 2 conditions. Additional reporting of SANS would be helpful in better defining the condition and its delineation from NS.