Objectives
To determine the effects of dental implant surface chemistry and energy on macrophage activation in vitro.

Materials and Methods
Disks made from two clinically used implant materials (titanium [Ti], titanium zirconium alloy [TiZr]) were produced with two different surface treatments (sandblast/acid-etch [SLA], hydrophilic-SLA [modSLA]). Surface roughness, energy, and chemistry were characterized. Primary murine macrophages were isolated from 6- to 8-week-old male C57Bl/6 mice and cultured on test surfaces (Ti SLA, TiZr SLA, Ti modSLA, TiZr modSLA) or control tissue culture polystyrene. mRNA was quantified by quantitative polymerase chain reaction after 24 h of culture. Pro- (IL-1β, IL-6, and TNF-α) and anti-inflammatory (IL-4, IL-10) protein levels were measured by ELISA after 1 or 3 days of culture.

Results
Quantitatively, microroughness was similar on all surfaces. Qualitatively, nanostructures were present on modSLA surfaces that were denser on Ti than on TiZr. modSLA surfaces were determined hydrophilic (high-energy surface) while SLA surfaces were hydrophobic (low-energy surface). Cells on high-energy surfaces had higher levels of mRNA from anti-inflammatory markers characteristic of M2 activation compared to cells on low-energy surfaces. This effect was enhanced on the TiZr surfaces when compared to cells on Ti SLA and Ti modSLA. Macrophages cultured on TiZr SLA and modSLA surfaces released more anti-inflammatory cytokines.

Conclusions
The combination of high-energy and altered surface chemistry present on TiZr modSLA was able to influence macrophages to produce the greatest anti-inflammatory microenvironment and reduce extended pro-inflammatory factor release.

Dental implant surface chemistry and energy alter macrophage activation in vitro

IgG4-related disease is a rare immune-mediated systemic disease with the capability of involving essentially any organ. Although the presenting clinical features vary substantially according to the speciality to which patients present first, perhaps the most common clinical presentation is that of single or multiple organ enlargement, arousing suspicion of cancer. The disease is frequently diagnosed unexpectedly in pathological specimens or on imaging studies. The diagnostic approach is complex and includes not only IgG4-related tests (serum levels, circulating plasmablasts, and specific immunohistochemical studies), but also clinical, laboratory, and imaging tests as well as the typical histopathological features (lymphocytic infiltration, storiform fibrosis, eosinophilic infiltration, and obliterative phlebitis). IgG4-related tests should not be considered as diagnostic in the absence of an appropriate clinical scenario. Therapeutic approaches reported to date pertain primarily to glucocorticoids, but the use of these medications has not been studied in a controlled or prospective manner. The most current investigational treatment approaches have focused on targeting cells of the B-cell lineage, including B-cell-depleting agents (rituximab) and a non-depleting homodimer monoclonal antibody targeting CD19 and Fc-gamma RIIIb.

IgG4-related disease: Advances in the diagnosis and treatment.

Objectives To study the impact of sex on the clinical presentation of IgG4-related disease (IgG4-RD). Methods We prospectively enrolled 403 newly diagnosed IgG4-RD patients. We compared the demographic features, clinical manifestations, organ involvement, laboratory tests and treatment outcomes between female and male patients. The organs involved were divided into superficial organs (salivary glands, lacrimal glands, orbit, sinus and skin) and internal organs (all the other organs). The patients treated with glucocorticoids with or without additional immunosuppressants were included in the assessment of treatment outcomes, and potential confounding factors were corrected by propensity score matching or multivariate Cox regression analysis. Results Female patients showed younger age at both symptom onset and diagnosis, and a longer interval between symptom onset and diagnosis. Allergy history, Mikulicz's disease and thyroiditis were more common in female patients, while autoimmune pancreatitis, sclerosing cholangitis and retroperitoneal fibrosis were more common in male patients. In accordance, female patients more frequently presented with superficial organ involvement, while male patients more frequently had internal organ involvement, and the discrepancy was more prominent in the patients with older age. Male sex was associated with higher peripheral eosinophils, CRP and IgG4 levels at baseline. In response to glucocorticoid-based therapies, male sex was associated with a higher IgG4-RD responder index during follow-up as well as a greater risk of relapse (hazard ratio 3.14, P = 0.003). Conclusion Our study revealed the sex disparities in clinical characteristics of IgG4-RD, and indicated that male sex was independently associated with worse prognosis in response to glucocorticoid-based therapies.

Sex disparities in clinical characteristics and prognosis of immunoglobulin G4-related disease: a prospective study of 403 patients.

Immunoglobulin G4-related disease (IgG4-RD) is a newly recognized fibro-inflammatory condition. Forty-two cases with immunoglobulin G4-related sialadenitis (IgG4-RS) confirmed by histopathological and immunohistochemical assessment were studied to clarify the clinicopathologic characteristics of the salivary glands involved in IgG4-RS, especially the relationship between the histopathologic features and function of salivary glands or serum levels of IgG4. Clinical, serologic, imaging and histopathological data of these cases were analyzed. CT volumes of submandibular, parotid, and lacrimal glands were calculated. The saliva flow rate was measured. Scintigraphy with 99mTc-pertechnetate was undertaken in 31 cases, and the concentration index (CI) and secretion index (SI) was calculated. Relationships between fibrosis severity and salivary gland function or serum IgG4 levels were analyzed. The first symptom was swelling of bilateral submandibular or lacrimal glands. Physical examination showed multiple bilateral major salivary glands (including sublingual and accessory parotid glands) and lacrimal glands were enlarged in IgG4 RS. Multiple enlarged cervical lymph nodes were noted in 30 patients. Saliva flow at rest was lower than normal in 34 cases; stimulated saliva flow was lower than normal in 15 cases. Secretory function was reduced more severely in the submandibular glands than in the parotid glands. Serum levels of IgG4 were elevated in 95.2% of cases and 78.6% patients had increased IgE levels. Serum IgG4 level was higher and saliva secretion lower as glandular fibrosis increased. Prominent changes in the morphology, histology, immunohistochemistry and secretion of the major salivary glands of IgG4-RS patients were accompanied by involvement of the lacrimal glands and cervical lymph nodes. Elevated IgE, allergic history, eosinophil infiltration suggest allergic reactions as a potential pathogenesis of IgG4-RS. Severity of glandular fibrosis correlated with salivary function and serum levels of IgG4.

/pdf/clinicopathological-characteristics-of-immunoglobulin-g4-36yh1ed4ra.pdf

Clinicopathological characteristics of immunoglobulin G4-related sialadenitis

Novel in vitro comparative model of osteogenic and inflammatory cell response to dental implants.

Immunoglobulin G4-related sialadenitis (IgG4-RS) is a newly recognized immune-mediated systemic disease. Despite its good response to steroid therapy, its treatment protocol is not standardized and the long-term outcome is controversial. The study was conducted to determine the short-term and long-term outcomes of IgG4-RS patients treated with glucocorticoids and steroid-sparing immunosuppressive agents, to analyze secretory function, serological and radiological changes in salivary glands and to assess the usefulness of serum IgG4 level as an indicator of disease activity. IgG4-RS patients who were treated for more than 3 months were enrolled. Serological tests, salivary gland function assessment and computed tomography (CT) were performed before treatment and during follow up. The treatment outcomes in the short and the long term were evaluated, and the relationship between serum IgG4 level and salivary gland volume was analyzed. Glucocorticoids were used in all 43 patients and steroid-sparing immunosuppressive agents in 38 patients (88.4%). The follow-up period was 24.6 ± 14.9 months. Clinical remission was achieved in all patients after induction therapy. During short-term observation, salivary gland secretion significantly increased, and the serum IgG4 levels, the volumes and CT values of submandibular and parotid gland decreased significantly (P < 0.001). For long term, relapse occurred in 32.5% patients within 55 months in the regularly treated group, while all seven irregularly treated patients relapsed. However, the relapse-free survival curves were not significantly different between the steroid monotherapy and the combination therapy groups (P = 0.566). Submandibular glands, lacrimal glands, sublingual glands, nasal and paranasal cavity were commonly relapsing organs. In clinically stable patients, a serologically unstable condition occurred in 54.9% patients within 55 months and medication adjustment was performed accordingly. Volume changes in the submandibular and parotid glands were associated with serum IgG4 levels and time of follow up (R2adjusted = 0.905, P < 0.0001 and R2adjusted = 0.9334, P < 0.0001, respectively). The combination of glucocorticoid and steroid-sparing agents could be effective for treating IgG4-RS, and restoring salivary gland function. Serum IgG4 levels could predict disease activity.

/pdf/treatment-of-immunoglobulin-g4-related-sialadenitis-outcomes-2ph2uc5gxg.pdf

Treatment of immunoglobulin G4-related sialadenitis: outcomes of glucocorticoid therapy combined with steroid-sparing agents

Objectives/Hypothesis

To further recognize the comorbid diseases of immunoglobulin G4-related sialadenitis (IgG4-RS) in the head and neck region and to observe the response of these conditions to immunomodulatory therapy.



Study Design

Retrospective review.



Methods

The symptoms of comorbid diseases and medical histories in 51 patients (24 men, 27 women; median age, 55 years) diagnosed with IgG4-RS were analyzed. Thirty-six patients received immunomodulatory therapy and were followed up for 10.4 ± 5.9 months. Computed tomography (CT) examination was performed before and after therapy.



Results

Rhinosinusitis occurred in 58.8% patients, and manifested with the symptoms of nasal obstruction, nasal xerosis, and hyposmia. In addition, 43.1% patients had allergic rhinitis. Lymphadenopathy was identified in 74.5% patients. Lacrimal gland swelling occurred in 78.4% patients. Extraocular muscles, otologic organs, skin and superficial soft tissue, and cranial nerves were also involved. All of the lesions were relieved after immunomodulatory therapy. The Lund-Mackay scores decreased (9.6 ± 5.6 to 1.0 ± 2.2) according to CT analyses (P < .05). Mean CT volumes of the swollen lymph nodes and lacrimal glands decreased from 1.21 ± 0.61 cm3 to 0.59 ± 0.35 cm3 and from 2.25 ± 1.35 cm3 to 0.70 ± 0.32 cm3, respectively (P < .05) after treatment.



Conclusions

IgG4-RS could potentially develop with involvement of ocular adnexa, sinonasal cavities, ears, lymph nodes, skin and superficial soft tissue, and cranial nerves in the head and neck region. Immunomodulatory therapy could be effective in controlling both the comorbid diseases of IgG4-RS and sialadenitis of the major salivary glands.



Level of Evidence

4 Laryngoscope, 125:2113–2118, 2015

Comorbid diseases of IgG4‐related sialadenitis in the head and neck region

The aim of this study was to determine the role of ultrasonography in the diagnosis and follow-up evaluation of immunoglobulin G4-related sialadenitis. In this study, 42 patients with immunoglobulin G4-related sialadenitis underwent ultrasonography of the parotid and submandibular glands, and the sonographic appearance was compared with the pathologic findings. Post-treatment ultrasonographic appearance was compared with the pre-treatment findings in 30 patients who received immunomodulatory therapy. The ultrasonographic appearance of the affected glands was divided into five patterns: superficial hypo-echoic, multiple hypo-echoic foci, whole-gland heterogeneity, space occupying and normal echo. Histopathologic examination revealed marked lymphoplasmacytic inflammation and inter-lobular fibrosis, which were more severe in the superficial than deep portion of the affected glands. After treatment, the volume of the affected gland decreased significantly, the internal echo became more homogeneous and the superficial hypo-echoic area disappeared or was reduced. In conclusion, ultrasonography may play an important role in the diagnosis and follow-up evaluation of immunoglobulin G4-related sialadenitis.

Ultrasonographic Features of Immunoglobulin G4-Related Sialadenitis.

Objective To accurately measure the volume of normal human parotid and submandibular glands, establish the normal values of the volumes of the glands, and apply the technique in the diagnosis of swollen salivary glands of the patients with IgG4-related sialadenitis. Methods Two hundred and forty cases with normal parotid and submandibular glands who received CT examination were divided into 4 groups according to the age standards raised by the Society of Geriatrics Chinese Medical Association and WHO (2000) age standards . 3D CT images of parotid and submandibular glands were reconstructed by technique of volume rendering. Volumes of normal parotid and submandibular glands were measured and their normal values were analyzed. The volumes of swollen parotid and submandibular glands from 30 cases with IgG4-related sialadenitis were compared with the normal values. Results 3D images of parotid and submandibular glands were well established by volume rendering. The normal values(95%confidence interval, 95%CI) of CT volume of parotid gland were as follows: adolescent group of males: 16.993-20.975 cm(3), females: 13.908-16.696 cm(3); young group of males: 20.015-24.359 cm(3), females: 18.089-21.135 cm(3); middle-aged group of males: 28.638-35.122 cm(3), females: 19.588-22.474 cm(3); young elderly and elderly group of males: 28.792-35.082 cm(3), females: 28.783-34.909 cm(3). The normal values (95%CI) of submandibular gland were as follows: adolescent group of males: 7.202-8.852 cm(3), females: 6.494-8.126 cm(3); young group of males: 7.759-9.523 cm(3), females: 7.285-8.605 cm(3); middle-aged group of males: 8.423-10.177 cm(3), females: 7.905-9.309 cm(3); young elderly and elderly group of males: 8.310-10.510 cm(3), females: 7.003-8.203 cm(3). The volumes of parotid glands increased with age. but no significant change was found in those of submandibular glands. The volumes of the swollen glands from the patients with IgG4-related sialadenitis were significantly larger than those of the normal glands. Conclusion Volumes of the parotid and submandibular glands could be definitely and quantitively measured by CT volume rendering. The established normal values in this study could be taken as the reference for the diagnosis of parotid and submandibular gland enlargement .

Wei Li

Papers

Clinicopathological characteristics of immunoglobulin G4-related sialadenitis

Treatment of immunoglobulin G4-related sialadenitis: outcomes of glucocorticoid therapy combined with steroid-sparing agents

Comorbid diseases of IgG4‐related sialadenitis in the head and neck region

Ultrasonographic Features of Immunoglobulin G4-Related Sialadenitis.

Volume measurements of human parotid and submandibular glands