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Objectives The study systematically reviewed the existing literature on the management of autoimmune inner ear disease (AIED). Study Design Systematic review. Methods We performed a literature search of Embase, NCBI, Cochrane, and Web of Science databases from April 1990 to April 2020. Inclusion criteria included studies that were retrospective or prospective in nature evaluating the treatment of AIED with audiometric data measuring hearing outcomes during treatment. Hearing improvement was the primary study outcome and improvement in vestibular symptoms was the secondary study outcome. Results Sixteen of 412 candidate articles were included in our study. Systemic steroid treatment is most commonly described. Alternative treatment modalities included intratympanic steroid treatment, methotrexate, cyclophosphamide, azathioprine, infliximab, etanercept, adalimumab, golimumab, methylprednisolone, rituximab, and anakinra. Conclusion Systemic corticosteroids are the first line treatment of AIED. Intratympanic steroids are a potential adjuvant or alternative treatment for patients who cannot tolerate or become refractory to steroid treatment. Steroid nonresponders may benefit from biologic therapy. Alternative treatment modalities including nonsteroidal immunosuppressants and biologics have been studied in small cohorts of patients with varying results. Prospective studies investigating the efficacy of biologic and nonsteroidal therapy are warranted. Level of Evidence 2., Autoimmune inner ear disease is an uncommon inner ear disorder characterized by progressive and often fluctuating sensorineural hearing loss. Currently, there are no consensus treatment recommendations for management of AIED. In this systematic review, we review published treatment paradigms, and create a novel treatment protocol based on existing evidence.

BackgroundMonitoring of mycophenolic acid (MPA) levels may be useful for effective mycophenolate mofetil (MMF) dosing. However, whether commonly obtained trough levels are an acceptable method of surveillance remains debatable. We hypothesized that trough levels of MPA would be a poor predictor of area under the curve (AUC) for MPA.MethodsA total of 51 patients with lupus nephritis who were on MMF 1500 mg twice a day and had a 4-h AUC done were included in this study. MPA levels were measured prior to (C0) and at 1 (C1), 2 (C2) and 4 (C4) h, followed by 1500 mg of MMF. The MPA AUC values were calculated using the linear trapezoidal rule. Regression analysis was used to examine the relationship between the MPA trough and AUC. Differences in the MPA trough and AUC between different clinical and demographic categories were compared using t-tests.ResultsWhen grouped by tertiles there was significant overlap in MPA, AUC 0-4 and MPA trough in all tertiles. Although there was a statistically significant correlation between MPA trough levels and AUC, this association was weak and accounted for only 30% of the variability in MPA trough levels. This relationship might be even more unreliable in men than women. The use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was associated with increased MPA trough levels and AUC at 0-4 h (AUC0–4).ConclusionTrough levels of MPA do not show a strong correlation with AUC. In clinical situations where MPA levels are essential to guide therapy, an AUC0–4 would be a better indicator of the adequacy of treatment.

Objective In vitro studies suggest that the type I interferon (IFN) signature seen in most lupus patients results from Fcγ receptor–mediated uptake of nucleic acid–containing immune complexes by plasmacytoid dendritic cells and engagement of endosomal Toll-like receptors. The aim of this study was to reexamine the pathogenesis of the IFN signature in vivo. Methods Lupus was induced in mice by injecting pristane. Some mice were treated with normal immunoglobulin or with cobra venom factor to deplete complement. The IFN signature was evaluated by polymerase chain reaction. The IFN signature also was determined in C4-deficient patients and control subjects. Results Wild-type C57BL/6 mice with pristane-induced lupus developed a strong IFN signature, which was absent in immunoglobulin-deficient (μMT), C3−/−, and CD18−/− mice. Intravenous infusion of normal IgM, but not IgG, restored the IFN signature in μMT mice, and the IFN signature in wild-type mice was inhibited by depleting complement, suggesting that opsonization by IgM and complement is involved in IFN production. Consistent with that possibility, the levels of “natural” IgM antibodies reactive with dead cells were increased in pristane-treated wild-type mice compared with untreated controls, and in vivo phagocytosis of dead cells was impaired in C3-deficient mice. To examine the clinical relevance of these findings, we identified 10 C4-deficient patients with lupus-like disease and compared them with 152 C4-intact patients and 21 healthy controls. In comparison with C4-intact patients, C4-deficient patients had a different clinical/serologic phenotype and lacked the IFN signature. Conclusion These studies define previously unrecognized roles of natural IgM, complement, and complement receptors in generating the IFN signature in lupus.

Objective This study performed an integrated analysis of the cellular and transcriptional differences in peripheral immune cells between patients with Systemic Lupus Erythematosus (SLE) and healthy controls (HC). Methods Peripheral blood was analyzed using standardized flow cytometry panels. Transcriptional analysis of CD4+ T cells was performed by microarrays and Nanostring assays. Results SLE CD4+ T cells showed an increased expression of oxidative phosphorylation and immunoregulatory genes. SLE patients presented higher frequencies of activated CD38+HLA-DR+ T cells than HC. Hierarchical clustering identified a group of SLE patients among which African Americans were overrepresented, with highly activated T cells, and higher frequencies of Th1, Tfh, and plasmablast cells. T cell activation was positively correlated with metabolic gene expression in SLE patients but not in HC. Conclusions SLE subjects presenting with activated T cells and a hyperactive metabolic signature may represent an opportunity to correct aberrant immune activation through targeted metabolic inhibitors.

Anti-RNA polymerase III (RNAP III) antibodies are highly specific for scleroderma (SSc) and associated with diffuse SSc and renal crisis. Coexistence of anti-RNAP III and other SSc autoantibodies is rarely documented. We report three cases with coexisting anti-RNAP III and anti-U1RNP. Autoantibodies in 3829 sera from rheumatology clinics were screened by immunoprecipitation. Anti-RNAP III-positive sera were also examined by immunofluorescence and anti-RNAP III ELISA. In total, 35 anti-RNAP III-positive sera were identified by immunoprecipitation, in which three had coexisting anti-U1RNP. All three were anti-RNAP III ELISA positive. Two had anti-RNAP I dominant (vs. RNAP III) reactivity and showed strong nucleolar staining. A case with anti-U1/U2RNP (U2RNP dominant) had systemic lupus erythematosus (SLE)–SSc overlap syndrome; however, the remaining two cases had SLE without signs of SSc. All three cases of anti-RNAP III + U1RNP fulfilled ACR SLE criteria but none in the group with anti-RNAP III alone ( p = 0.0002). In contrast, only one case in the former group had sclerodermatous skin changes and Raynaud's phenomenon, vs. 92% with scleroderma in the latter ( p

Purpose: The purpose of this pilot clinical study is to assess three-dimensional (3-D) quantitative photoacoustic tomography (qPAT) for in vivo detection of osteoarthritis (OA) in the finger joints.Methods: All subject data were handled in compliance with the rules and regulations concerning the privacy and security of protected health information under HIPAA. Seven female subjects (two OA patients and five healthy controls) entered the study and their distal interphalangeal (DIP) joints were examined by a 3-D photoacoustic scanner. 3-D optical absorption coefficient images of all the photoacoustically examined joints were recovered using a 3-D qPAT reconstruction algorithm.Results: The recovered quantitative photoacousticimages revealed obvious difference in the optical absorption coefficient of the joint cavity (cartilage and synovial fluid) between the OA and healthy joints. Quantitative analysis of the joints also indicated an apparent difference in the recovered joint spacing between the OA and healthy subjects.Conclusion: This initial clinical evaluation suggests that it is feasible to detect osteoarthritis in the finger joints with our 3-D qPAT approach, which has paved the way to further statistically evaluate the diagnostic performance of the 3-D qPAT approach in comparison with radiography or magnetic resonance imaging (MRI) on a sample of hand osteoarthritis.

Autoantibodies to topoisomerase I (topo I), RNA polymerase III (RNAPIII), centromere, U3RNP/fibrillarin, Th, PM-Scl, and U1RNP found in scleroderma (SSc) are associated with unique clinical subsets. The effects of race and gender on autoantibody prevalence and clinical manifestations were examined. Autoantibodies in sera from 105 SSc (include 75 Caucasian, 24 African-American, 6 others; 89 females and 16 males) were analyzed by immunofluorescence and immunoprecipitation. Clinical information was from database. SSc-related autoantibodies seldom coexist except for anti-topo I and anti-U1RNP. Anti-topo I (35% vs 15%), anti-U3RNP (30% vs 3%, p = 0.0005), and anti-U1RNP (30% vs 13%) were more common in African-Americans vs Caucasians. Anti-centromere (17%) and anti-PM-Scl (only in 8% of female) were found only in Caucasians. In race/gender combination, all three African-American males had anti-topo I (p = 0.04). Anti-U3RNP (35% vs 3%, p = 0.0005) and anti-U1RNP were common in African-American females. In African-American, all nucleolar dominant staining sera had anti-U3RNP; nuclear pattern was topo I (50%), U1RNP (19%), and RNAPIII (13%). In Caucasian, nucleolar was anti-Th (43%) and PM-Scl (29%); nuclear pattern was RNAPIII (29%), topo I (24%), and U1RNP (18%). Anti-topo I, anti-RNAPIII, and anti-U3RNP were associated with diffuse SSc while anti-centromere, anti-Th, and anti-U1 with limited disease. Proximal scleroderma was less common in African-American with anti-topo I (38% vs 91% in Caucasian, p = 0.04). The production of SSc-related autoantibodies is gender and race dependent, and this can be highly relevant in understanding their clinical significance.

This study presents a computer-aided classification method to distinguish osteoarthritis finger joints from healthy ones based on the functional images captured by x-ray guided diffuse optical tomography. Three imaging features, joint space width, optical absorption, and scattering coefficients, are employed to train a Least Squares Support Vector Machine (LS-SVM) classifier for osteoarthritis classification. The 10-fold validation results show that all osteoarthritis joints are clearly identified and all healthy joints are ruled out by the LS-SVM classifier. The best sensitivity, specificity, and overall accuracy of the classification by experienced technicians based on manual calculation of optical properties and visual examination of optical images are only 85%, 93%, and 90%, respectively. Therefore, our LS-SVM based computer-aided classification is a considerably improved method for osteoarthritis diagnosis.

Purpose: The aim of this study was to investigate the potential use of multimodality functional imaging techniques to identify the quantitative optical findings that can be used to distinguish between osteoarthritic and normal finger joints. Methods: Between 2006 and 2009, the distal interphalangeal finger joints from 40 female subjects including 22 patients and 18 healthy controls were examined clinically and scanned by a hybrid imaging system. This system integrated x-ray tomosynthetic setup with a diffuse optical imaging system. Optical absorption and scattering images were recovered based on a regularization-based hybrid reconstruction algorithm. A receiver operating characteristic curve was used to calculate the statistical significance of specific optical features obtained from osteoarthritic and healthy joints groups. Results: The three-dimensional optical and x-ray images captured made it possible to quantify optical properties and joint space width of finger joints. Based on the recovered optical absorption and scattering parameters, the authors observed statistically significant differences between healthy and osteoarthritis finger joints. Conclusions: The statistical results revealed that sensitivity and specificity values up to 92% and 100%, respectively, can be achieved when optical properties of joint tissues were used as classifiers. This suggests that these optical imaging parameters are possible indicators for diagnosing osteoarthritis and monitoring its progression.

Objective.Anti-cyclic citrullinated peptide (CCP) antibodies are a serological marker for rheumatoid arthritis (RA); up to 10%–15% of patients with systemic lupus erythematosus (SLE) are also positive. While anti-CCP in RA is citrulline-dependent, anti-CCP in some other diseases is citrulline-independent and reacts with both CCP and the unmodified (arginine-containing) cyclic arginine peptide (CAP). We investigated the citrulline dependence of anti-CCP and its significance in the arthritis of SLE.Methods.IgG anti-CCP was compared by ELISA to anti-CAP in sera from patients with SLE (n = 335) and RA (n = 47) and healthy controls (n = 35). SLE patients were divided into 5 groups based on their joint involvement: subset I: deforming/erosive arthritis (n = 20); II: arthritis fulfilling (or likely fulfilling) American College of Rheumatology criteria for RA but without erosions (n = 18); III: joint swelling but not fulfilling RA criteria (n = 39); IV: arthritis without documented joint swelling (n = 194); and V: no arthritis (n = 58).Results.Anti-CCP (> 1.7 units) was found in 68% (32/47) of patients with RA and 17% (55/329) of those with SLE. It was more common in SLE patients with deforming/erosive arthritis (38%). High anti-CCP (> 10 units) was found in RA (26%) and deforming/erosive SLE (12%). High anti-CCP/CAP ratios (> 2, indicating a selectivity to CCP) were found in 91% of anti-CCP-positive RA and 50% of anti-CCP-positive SLE patients with deforming/erosive arthritis. Patients from subset II did not have high anti-CCP/CAP.Conclusion.Citrulline dependence or high levels (> 10) of anti-CCP were common in SLE patients with deforming/erosive arthritis, while most anti-CCP in SLE patients was citrulline-independent. This may be useful in identifying a subset of SLE patients with high risk for development of deforming/erosive arthritis.

Anti–cyclic citrullinated peptide (anti-CCP) using a peptide of filaggrin has been used extensively as a new serologic marker of rheumatoid arthritis (RA) (1,2). Many studies have confirmed that anti-CCP enzyme-linked immunosorbent assay (ELISA) is as sensitive as rheumatoid factor (RF) and much more specific for RA among various rheumatic diseases (2). However, anti-CCP in other diseases has been less well studied. Patients with certain infectious diseases, such as hepatitis C and tuberculosis (TB), can present with arthritis and frequently also have serum RF, making it difficult to distinguish infectious disease–related arthritis from RA. Thus, the utility of anti-CCP testing under these clinical circumstances is important. Studies in patients with hepatitis C viral infection showed the absence of anti-CCP, in contrast to frequent RF positivity (3). However, a recent study showed the presence of anti-CCP in 32% of patients with active pulmonary TB (4). Patients with TB can exhibit various forms of arthropathy, including tuberculous arthritis and reactive arthritis (5). Some of these patients’ diseases may mimic early RA and may be difficult to diagnose. Thus, anti-CCP–positive test results in these patients can be misleading. Early studies showed that anti-CCP antibodies in RA patients are specific for citrullinated peptide and do not react with unmodified peptide (1). However, the majority of clinical studies on anti-CCP are based on commercial anti-CCP ELISA kits and do not use an unmodified peptide as a negative control (2). In the present study, the specificity of anti-CCP–positive sera for CCP versus unmodified arginine-containing peptide (CAP) was examined in patients with TB and compared with that in patients with RA.

Autoantibodies have been used extensively as a useful biomarker in systemic lupus erythematosus and other autoimmune rheumatic diseases. Antinuclear antibodies by immunofluorescence are a standard clinical test to screen for evidence of systemic autoimmunity. Different specific autoantibodies are associated with particular diagnoses, symptoms, unique syndromes, subsets of the disease and clinical activity. They are produced prior to the onset of clinical manifestations and have predictive value. This review focuses on a critical re-evaluation of the clinical significance of autoantibodies. Disease subsets defined by autoantibodies, coexistence of disease marker antibodies, and problems in testing and interpreting results are examined. Clinical approaches in differential diagnosis of antinuclear antibodies and the significance of antinuclear antibodies in healthy individuals are also discussed.

Objective To investigate the clinical and immunologic significance of autoantibodies to RNA helicase A (RHA) in patients with systemic rheumatic diseases. Methods The study group comprised 1,119 individuals enrolled in the University of Florida Center for Autoimmune Diseases registry from 2000 to 2005. Diagnoses were based on standard criteria. Autoantibodies were analyzed by immunoprecipitation and Western blot assays. Results Anti-RHA was observed in 17 (6.2%) of 276 patients with systemic lupus erythematosus (SLE), 2 patients with antiphospholipid antibodies, and 3 other patients, but anti-RHA was not observed in any patient with polymyositis/dermatomyositis, systemic sclerosis, rheumatoid arthritis, or Sjogren's syndrome. Anti-RHA was present in only 2.9% of African American patients, compared with 6.0% of white patients and 12–25% of patients of other races; this was in striking contrast to the frequency of anti-Sm in African American patients (27.2%). Among patients with SLE, anti-RHA was common in young patients (26% of those whose initial visit was at an age younger than 20 years versus 3–4% of those who were initially seen at ages 20–49 years) and at an early stage of disease (23% of those whose first clinic visit was within 1 year of disease onset versus 2–8% of those whose first visit was at least 1 year after disease onset). In 9 of 11 patients, levels of anti-RHA decreased to

There has long been a need for biomarkers of disease activity in lupus nephritis (LN). Such markers ideally would be capable of detecting early sub-clinical disease and could be used to gauge response to therapy thus obviating the need for serial renal biopsies. Since urine can be readily obtained it lends itself as an obvious biological sample. Much of the focus has been on the measurement of urinary chemokines and cytokines in patients with LN. Elevations in urinary IL-6 and IL-10 had initially been reported to be associated with disease activity in LN but these markers have proven to be less reliable in larger studies. We and others have recently reported that MCP-1, a key chemokine involved in monocyte chemotaxis can be consistently found at high levels in the urine of patients with active LN. Moreover urinary MCP-1 levels decline with treatment of nephritis. In contrast urinary IL-8, a chemokine involved primarily in neutrophil chemotaxis is not a good predictor of disease activity in LN. Further longitudinal studies with larger numbers of patients are needed to determine the utility of urinary biomarkers such as MCP-1 which may act as surrogates of ongoing inflammation in LN.

It has been shown previously that chronic treatment with relatively low doses of chlordecone accelerates the development of systemic lupus erythematosus (SLE) in ovariectomized female (NZBxNZW) F(1) mice. In this study, the effect of chronic chlordecone treatment on SLE was evaluated in ovary-intact female (NZBxNZW) F(1) mice, as well as in female mice from a strain that is not lupus-prone, BALB/c. Chlordecone was administered chronically via implanted sustained-release pellets, and mice were monitored over time for the appearance of elevated autoantibodies (anti-dsDNA and anti-chromatin) and for the development of renal impairment, both indicators of SLE. Chlordecone treatment in (NZBxNZW) F(1) mice shortened significantly the time to onset of elevated autoantibody titers and renal disease in a dose-related manner. The doses required to produce this effect were similar to those observed previously to accelerate SLE development in ovariectomized females. Treatment of female BALB/c mice with chlordecone for up to one year did not produce elevated autoantibody titers or renal disease, suggesting an inability of chlordecone to cause a break in tolerance in this strain. These observations confirm the ability of chronic chlordecone to influence SLE, but demonstrate the importance of genetic background for this effect.

Giant cell arteritis (GCA) and Takayasu's disease are inflammatory vasculitic syndromes (IVS) causing sudden blindness and widespread arterial obstruction and aneurysm formation. Glucocorticoids and aspirin are mainstays of treatment, predominantly targeting T cells. Serp-1, a Myxomavirus-derived serpin, blocks macrophage and T cells in a wide range of animal models. Serp-1 also reduced markers of myocardial injury in a Phase IIa clinical trial for unstable coronary disease. In recent work, we detected improved survival and decreased arterial inflammation in a mouse Herpesvirus model of IVS. Here we examine Serp-1 treatment of human temporal artery (TA) biopsies from patients with suspected TA GCA arteritis after implant (TAI) into the aorta of immunodeficient SCID (severe combined immunodeficiency) mice. TAI positive for arteritis (GCApos) had significantly increased inflammation and plaque when compared to negative TAI (GCAneg). Serp-1 significantly reduced intimal inflammation and CD11b+ cell infiltrates in TAI, with reduced splenocyte Th1, Th17, and Treg. Splenocytes from mice with GCApos grafts had increased gene expression for interleukin-1 beta (IL-1β), IL-17, and CD25 and decreased Factor II. Serp-1 decreased IL-1β expression. In conclusion, GCApos TAI xenografts in mice provide a viable disease model and have increased intimal inflammation as expected and Serp-1 significantly reduces vascular inflammatory lesions with reduced IL-1β.

The goal of this study is to capture the quantitative optical features of degenerative finger joints based on x-ray aided three-dimensional (3D) diffuse optical tomography (DOT). It is anticipated that the fused imaging technique can be applied to identifying the significant differences between osteoarthritis (OA) and psoriatic arthritis (PA). For a case study, total 6 subjects were selected to study the distal interphalangeal (DIP) finger joints. 2 OA patients, 2 PA patients and 2 healthy subjects were examined clinically first. Their DIP finger joints were then scanned by the multimodality imaging method. Our findings suggested that the developed multimodality imaging approach may aid to contradistinguish OA patients from PA patients with the healthy control, which is essential for a better diagnosis and treatment of inflammatory arthritis in humans.

Polyarteritis nodosa (PAN) is a systemic necrotising vasculitis that affects medium-sized and small-sized arteries. The spectrum of disease ranges from involving a single organ to polyvisceral failure. We report a case of a 75-year-old male presented with solely hypertension and mild renal function impairment as a consequence of diffuse renal necrotising vasculitis with occlusive but non-stenotic lesions associated with PAN. The overall prognosis of PAN has been improved in recent decades, primarily reflecting early diagnosis and more effective treatments. Therefore, early diagnosis is critical and it warrants full investigations even in those patients without obvious multiorgan manifestations. In those instances, with mild disease, steroid monotherapy has been shown to be effective with excellent response. Our patient responded well to steroid monotherapy and we were able to gauge his response by improvement in his blood pressure.

We present for the first time in vivo experimental evidence that quantitative photoacoustic tomography (qPAT) has the potential to detect osteoarthritis (OA) in the finger joints. In this pilot study, 2 OA patients and 4 healthy volunteers were enrolled, and their distal interphalangeal (DIP) joints were examined photoacoustically by a PAT scanner. Tissue absorption coefficient images of all the examined joints, which were unavailable from the conventional PAT, were recovered using our finite element based qPAT approach. The recovered quantitative photoacoustic images revealed significant differences in the tissue absorption coefficient of the joint cavity (cartilage and synovial fluid) between the OA and normal joints.

This goal of this study was to clinically evaluate the potential of a novel hybrid imaging techniques, called x-ray guided multispectral diffuse optical tomography, for identifying physiological parameters of joint tissues that can be used to distinguish between osteoarthritic and healthy joints in the hand. Between 2006 and 2009, the distal interphalangeal (DIP) finger joints from 40 subjects including 22 osteoarthritis patients and 18 healthy controls were examined clinically and scanned by the hybrid imaging platform that integrated a C-arm based x-ray tomosynthetic system with a mutlispectral diffuse optical imaging system. Based on the reconstructed results from the 40 subjects, it was observed that oxygen saturation and water content were two statistically most significant physiological discriminators for differentiation of the healthy joints from the osteoarthritic ones.

Patients with systemic lupus erythematosus (SLE) often suffer from depression and fatigue in addition to the physical manifestations of the autoimmune disease. Elevated production of type-I interferons (IFN-I) has been found in lupus patients and IFN-I can precipitate a variety of neuropsychiatric side effects. This study was conducted to evaluate the relationship between dysregulated IFN-I production and the presence of depression or fatigue in lupus patients. Through cross-sectional and longitudinal analysis we found no significant correlation between abnormal IFN-I levels (as measured by peripheral blood expression of IFN-I-stimulated genes) and neuropsychiatric manifestations. Elevation of endogenous serum IFN-I levels is unlikely to account for the depression and fatigue associated with SLE.

This goal of this study was to employ x-ray guided diffuse optical tomography to investigate the typical and quantitative optical findings that can be used to distinguish between osteoarthritis (OA) and psoriatic arthritis (PA) patients as well as healthy volunteers. Enhanced x-ray guided reconstruction results show that the optical properties between OA, PA and healthy joints are clearly different, suggesting that these functional imaging parameters could be used to diagnose OA or PA and monitor its progression.

This pilot clinical study shows for the first time that x-ray guided diffuse optical tomography is a potential tool to image osteoarthritis in large joints such as the knee.

We present a phantom study to show the ability of diffuse optical tomography for imaging the optical properties of the ‘articular cartilage’ in large ‘joints’.

X-ray guided diffuse optical imaging is used to investigate the typical findings that can detect osteoarthritis in the finger joints. The reconstruction results showed these functional imaging parameters can diagnose OA and monitor its progression.

In this study, we present a simplified spherical approximated-radiative transport model-based reconstruction algorithm for three-dimensional diffuse optical tomography of finger joints. The reconstruction algorithm is tested and validated using a series of phantom experiments and in vivo data from healthy and osteoarthritic joints. In all the phantom and in vivo experiments, the absorption and scattering images are recovered using both the transport model and diffusion approximation based reconstruction algorithms. We observe that while both the diffusion and transport based algorithms can effectively image the finger joints, the transport model based can provide quantitatively improved reconstruction quality over the diffusion approximated based.

Thus far optical imaging of the finger joints is limited to only one joint at a time. We have developed a CCD-based system that can image a whole finger, covering multiple joints. We show that the two joints of a volunteer's index finger can be imaged clearly and concurrently. The comparison of the optical images with the x-ray image of the same finger indicates that the recovered size of the whole finger, the bones and the two joint spaces are consistent with the findings from the x-ray. This study demonstrates a practicable system for full finger imaging and indicates the possibility of full hand imaging if a fast laser source scanning subsystem is integrated with the system.

We describe a multimodality imaging approach that com- bines x-ray tomosynthesis with near-infrared diffuse optical tomogra- phy DOT for high-resolution imaging of osteoarthritis in the finger joints. In this approach, we take advantage of high resolution x-ray imaging particularly of the bones and incorporate the fine structural maps obtained from x ray as a priori information into DOT recon- structions. To realize this multi-modality approach, we constructed a hybrid imaging platform that integrated a C-arm-based x-ray tomo- synthetic system with a multichannel optic-fiber-based DOT system. We also implemented improved hybrid regularization-based recon- struction algorithms that have shown to be especially effective for high-resolution modality-guided DOT. Initial evaluation of our x-ray- guided DOT reconstruction approach in the finger joints shows that spatial resolution of DOT can be enhanced dramatically when the three-dimensional geometry of bones is known a priori. In particular, the improved quantitative capability of imaging absorption and scat- tering coefficients of the joint tissues allows for more accurate diag- nosis of osteoarthritis over x-ray radiography or DOT alone. © 2008

Objective The premature atherosclerosis seen in patients with systemic lupus erythematosus (SLE) is not explained by traditional risk factors. SLE disease activity, such as renal involvement and presence of autoantibodies, is associated with elevated serum levels of type I interferon (IFN-I), a family of cytokines with potent antiviral and antiproliferative effects. This study was undertaken to test the hypothesis that elevated IFN-I levels could lead to endothelial dysfunction, a surrogate for cardiovascular disease, by causing a reduction in the number of endothelial progenitor cells (EPCs), bone marrow–derived cells that participate in endothelial repair. Methods EPCs were enumerated in the peripheral blood of SLE patients (n = 70) and healthy controls (n = 31), using a colony-forming assay. Serum IFN-I levels were quantified by real-time polymerase chain reaction measurement of the expression of the IFN-I–inducible gene MX1. Endothelial function was determined by peripheral arterial plethysmography. Results SLE patients had markedly reduced levels of EPC colony-forming units compared with controls (median 5.7/ml peripheral blood [interquartile range 1.9–12.8] versus 28.5/ml peripheral blood [14.7–47.3]; P < 0.0001), and the depletion of EPCs was more dramatic in patients with elevated levels of IFN-I. Stepwise multiple regression analysis showed that MX1 expression and serum levels of C-reactive protein were independently associated with the reduction of EPCs. Importantly, high IFN-I levels were associated with impaired endothelial function in patients with SLE. Conclusion These data support the novel hypothesis that depletion of EPCs caused by excessive IFN-I may be linked to endothelial dysfunction and increased cardiovascular risk in SLE.

This work presents a pilot study to show the potential of an emerging imaging modality, near-infrared diffuse optical tomography (DOT), for the diagnosis of osteoarthritis (OA). We report quantitative absorption and scattering images of joint tissue that allow for differentiation between diseased and healthy joints. An automatic, multichannel optical imaging system is used to image finger joints from two OA patients and three healthy volunteers. 3-D optical images of the joint tissue are recovered using a finite-element-based reconstruction algorithm. The reconstructed images demonstrate differences in optical properties at the joint region (cartilage/synovial fluid) between the OA and healthy joints. Quantitative analysis from the patients and healthy volunteers also indicate that the recovered joint sizes are consistent with those from x-ray findings. The results of this pilot study show potential for quantitative imaging and diagnosis of early OA by DOT.

Measurement of high sensitivity C-reactive protein (hs-CRP), has been used in the assessment of disease activity in numerous rheumatic conditions including systemic lupus erythematosus (SLE). However, the utility of hs-CRP measurement in patients with lupus is uncertain. This study examined if hs-CRP can be used to assess disease activity, severity and cardiovascular risk in SLE. Serum samples from 601 visits of 213 SLE patients and 134 controls were analysed for hs-CRP by nephelometry. Detailed demographic data were obtained from all subjects and medication history and key laboratory parameters were collected. Disease activity was assessed using the SLEDAI. High sensitivity CRP was not associated with disease activity (SLEDAI), number of ACR SLE criteria or presence of any particular organ involvement. hs-CRP levels were significantly correlated with standard cardiovascular risk factors including body weight ( P = 0.0002), hypertension ( P = 0.001), and apolipoprotein A-I ( P < 0.0001). Interestingly an inverse correlation was seen between hs-CRP levels and antimalarial use ( P = 0.0018). Our results suggest that measurement of hs-CRP, though not valuable as marker of disease activity in SLE may be of some use in the assessment of cardiovascular risk. We speculate that antimalarials may help to reduce cardiovascular risk in patients with SLE.

Objective Lupus nephritis (LN) is a major contributor to morbidity and mortality in patients with systemic lupus erythematosus (SLE). There is evidence that polymorphisms in the genes of inflammatory mediators may predispose to the development of LN in patients with SLE. In this study, we examined the role of a functional monocyte chemoattractant protein 1 (MCP-1) polymorphism in SLE and LN. Methods DNA and paired urine and serum samples were obtained from 134 SLE patients (≥4 American College of Rheumatology criteria for SLE; 49 with and 85 without LN) and 118 controls. MCP-1 genomic variants were detected by polymerase chain reaction followed by restriction enzyme–fragment analysis. Urinary and serum MCP-1 levels and MCP-1 production by peripheral blood macrophages were measured by enzyme-linked immunosorbent assay. Results The A/A genotype was more common in controls than in SLE patients (P = 0.0002), whereas both the A/G (P = 0.009) and G/G (P = 0.0212) genotypes were more frequent in SLE patients. The A/A genotype was observed in only 23% of the patients with LN compared with 58% of those without LN (P < 0.0001). MCP-1 production by peripheral blood mononuclear cells from patients with the A/G and G/G phenotypes was markedly higher than the production by cells from patients with the A/A genotype. Urinary levels of MCP-1 were significantly higher in patients with LN. Conclusion These results suggest that an A/G or G/G genotype may predispose to the development of SLE and further indicate that SLE patients with these genotypes may be at higher risk of developing LN. Moreover, measurement of urinary levels of MCP-1 may be a useful tool for the detection and management of LN.

We present quantitative imaging of hemoglobin concentration and oxygen saturation in in vivo finger joints and evaluate the feasibility of detecting osteoarthritis (OA) in the hand using three-dimensional (3D) multispectral quantitative photoacoustic tomography (3D qPAT). The results show that both the anatomical structures and quantitative chromophore concentrations (oxy-hemoglobin and deoxy-hemoglobin) of different joint tissues (hard phalanges and soft cartilage/synovial fluid between phalanges) can be imaged in vivo with the multispectral 3D qPAT. Enhanced hemoglobin concentrations and dropped oxygen saturations in osteoarthritic phalanges and soft joint tissues in joint cavities have been observed. This study indicates that the multispectral 3D qPAT is a promising approach to detect the angiogenesis and hypoxia associated with OA disease and a potential clinical tool for early OA detection in the finger joints.

B cell abnormalities play a central role in the systemic autoimmune syndromes of lpr and gld mice. In the lpr model, autoantibody production requires the intrinsic expression of the lpr gene in B cells, while in the gld mouse the genetic defect is extrinsic, yet probably results in a similar failure of B cell tolerance. Despite their abnormality, lpr B cells require lpr (abnormal) T cells in order to produce autoantibodies.

In this study, a simplified spherical harmonics approximated higher order diffusion model is employed for 3-D diffuse optical tomography of osteoarthritis in the finger joints. We find that the use of a higher-order diffusion model in a stand-alone framework provides significant improvement in reconstruction accuracy over the diffusion approximation model. However, we also find that this is not the case in the image-guided setting when spatial prior knowledge from x-rays is incorporated. The results show that the reconstruction error between these two models is about 15 and 4%, respectively, for stand-alone and image-guided frameworks.

Background: Most individuals with autoimmune and otherimmunedisordersundergoinitialevaluationinthe community setting. Since misdiagnosis of systemic autoimmune diseases can have serious consequences, we evaluated community physicians’ accuracy in diagnosing autoimmune diseases and the consequences of misdiagnosis. Methods: We studied the patients referred to our Autoimmune Disease Center for 13 months (n=476). We estimated the degree of agreement with the final diagnosis ( statistic) and the accuracy indexes (sensitivity, specificity, and predictive values) of the referring physicians’ diagnoses. Results: We found a 49% agreement between the referring and final diagnoses (=0.36). Of 263 patients referredwithapresumptivediagnosisofsystemiclupuserythematosus (SLE), 125 received a diagnosis of other conditions(=0.34).OfthosereferredwithSLE,76(29%) were seropositive for antinuclear antibodies but did not have autoimmune disease. The degree of agreement for referring rheumatologists (=0.55) was better than that for nonrheumatologists (=0.32). Stepwise logistic regressionindicatedthatrheumatologistswere4timesmore likely to make an accurate diagnosis of SLE than were nonrheumatologists(P.003).Thirty-ninepatientswho were seropositive for antinuclear antibodies but had no autoimmune disease had been treated with corticosteroids at dosages as high as 60 mg/d. Conclusions: Many patients with a positive antinuclear antibody test are incorrectly given a diagnosis of SLE and sometimes treated with toxic medications. The data support the importance of continuing medical education for community physicians in screening for autoimmune diseases and identifying patients who may benefit from early referral to a specialist. Arch Intern Med. 2004;164:2435-2441

Early systemic treatment of nonobese diabetic mice with high doses of recombinant adeno-associated virus (rAAV) vector expressing murine IL-10 prevents type 1 diabetes. To determine the therapeutic parameters and immunological mechanisms underlying this observation, female nonobese diabetic mice at 4, 8, and 12 wk of age were given a single i.m. injection of rAAV-murine IL-10 (104, 106, 108, and 109 infectious units (IU)), rAAV-vector expressing truncated murine IL-10 fragment (109 IU), or saline. Transduction with rAAV-IL-10 at 109 IU completely prevented diabetes in all animals injected at all time points, including, surprisingly, 12-wk-old animals. Treatment with 108 IU provided no protection in the 12-wk-old injected mice, partial prevention in 8-wk-old mice, and full protection in all animals injected at 4 wk of age. All other treatment groups developed diabetes at a similar rate. The rAAV-IL-10 therapy attenuated pancreatic insulitis, decreased MHC II expression on CD11b+ cells, increased the population of CD11b+ cells, and modulated insulin autoantibody production. Interestingly, rAAV-IL-10 therapy dramatically increased the percentage of CD4+CD25+ regulatory T cells. Adoptive transfer studies suggest that rAAV-IL-10 treatment alters the capacity of splenocytes to impart type 1 diabetes in recipient animals. This study indicates the potential for immunomodulatory gene therapy to prevent autoimmune diseases, including type 1 diabetes, and implicates IL-10 as a molecule capable of increasing the percentages of regulatory cells in vivo.

Introduction The present study examines the levels of recently reported biomarkers, adenosine deaminase acting on RNA (ADAR), C-C motif chemokine ligand 2 (CCL2), C-X-C motif chemokine 10 (CXCL10), signal transducers and activators of transcription 1 (STAT1), and miR-146a in systemic lupus erythematosus (SLE) patients over multiple visits. Methods Peripheral blood leukocytes were collected from 65 healthy donors and 103 SLE patients, 60 of whom had samples from 2 or more visits. Total RNA was isolated and analyzed for the expression of mRNA and microRNA using Taqman real time PCR assays. Relative expression of I-IFN signature genes, chemokines, and miR-146a were determined by the ΔΔCT method. Results were correlated with clinical data and analyzed by Wilcoxon/Kruskal-Wallis test and Fisher’s exact test. Results Levels of ADAR, CCL2, CXCL10, and STAT1 in SLE were significantly elevated compared with the healthy controls (P

Introduction: Our recent data showed that signal transducers and activators of transcription 1 (STAT1), adenosine deaminase acting on RNA (ADAR), C-C motif chemokine ligand 2 (CCL2), and C-X-C motif chemokine 10 (CXCL10) were significantly elevated in a systemic lupus erythematosus (SLE) cohort compared to healthy donors. High and low STAT1 subsets were identified in SLE patient visits. The present study analyzed the correlation of common treatments used in SLE with the levels of these biomarkers. Methods: Peripheral blood leukocytes were collected from 65 healthy donors and 103 SLE patients, of whom 60 had samples from two or more visits. Total RNA was isolated and analyzed for the expression of mRNA and microRNA using Taqman real-time polymerase chain reaction (PCR) assays. Relative expression of interferon signature genes, CCL2, and CXCL10 were determined by the ΔΔ CT method. Results were correlated with therapy using prednisone, mycophenolate mofetil, and hydroxychloroquine and analyzed by Wilcoxon/Kruskal-Wallis test and Fisher’s exact test. Results: CCL2 and CXCL10 were significantly higher in untreated patients compared to treated patients, however, in high STAT1 patient visits there is no significant difference between treated and untreated patients’ visits. When comparing linear regression fits of interferon (IFN) score with CCL2 and CXCL10, untreated patients and high STAT1 patients displayed significantly higher slopes compared to treated patients. There was no significant difference between the slopes of high STAT1 and untreated patients indicating that CCL2 and CXCL10 were correlated with type-I IFN in high STAT1 patients similar to that in untreated patients. CCL2 and CXCL10 levels in the high STAT1 subset remained high in treated patient visits compared to those of the low STAT1 subset. Conclusions: Among the biomarkers analyzed, only CCL2 and CXCL10 showed significantly reduced levels in treated compared to untreated SLE patients. STAT1, CCL2, and CXCL10 are potentially useful indicators of therapeutic action in SLE patients. Further work is needed to determine whether high STAT1 levels convey resistance to therapies commonly used to treat SLE and whether STAT1 inhibitors may have therapeutic implication for these patients.

Introduction Myositis specific autoantibodies are associated with unique clinical subsets and are useful biomarkers in polymyositis/dermatomyositis (PM/DM). A 120 kD protein recognized by certain patients with DM was identified and clinical features of patients with this specificity were characterized. Methods The 120 kD protein recognized by a prototype serum was purified and identified by mass spectrometry and immunological methods. Autoantibody to this 120 kD protein was screened in sera from 2,356 patients with various diagnoses from four countries, including 254 PM/DM, by immunoprecipitation of 35S-methionine labeled K562 cell extracts. Clinical information of patients with this specificity was collected. Results The 120 kD protein, which exactly comigrated with PL-12, was identified as transcription intermediary factor TIF1β (TRIM28) by mass spectrometry and validated by immunoassays. By immunofluorescence, anti-TIF1β positivity showed a fine-speckled nuclear staining pattern. Four cases of anti-TIF1β were identified; all are women, one each in a Japanese, African American, Caucasian, and Mexican individual. Three had a diagnosis of DM and one case was classified as having an undifferentiated connective tissue disease with an elevated CPK but without significant muscle symptoms. This individual also had a history of colon cancer, cervical squamous metaplasia and fibroid tumors of the uterus. Myopathy was mild in all cases and resolved without treatment in one case. The anti-TIF1β specificity was not found in other conditions. Conclusions Anti-TIF1β is a new DM autoantibody associated with a mild form of myopathy. Whether it has an association with malignancy, as in the case of anti-TIF1γ, or other unique features will need to be evaluated in future studies.

Introduction: The presence of anti-topoisomerase I (topo I) antibodies is a classic scleroderma (SSc) marker presumably associated with a unique clinical subset. Here the clinical association of anti-topo I was reevaluated in unselected patients seen in a rheumatology clinic setting. Methods: Sera from the initial visit in a cohort of unselected rheumatology clinic patients (n = 1,966, including 434 systemic lupus erythematosus (SLE), 119 SSc, 85 polymyositis/dermatomyositis (PM/DM)) were screened by radioimmunoprecipitation. Anti-topo I-positive sera were also tested with immunofluorescence and RNA immunoprecipitation. Results: Twenty-five (15 Caucasian, eight African American, two Latin) anti-topo I positive patients were identified, and all except one met the ACR SSc criteria. Coexistence of other SSc autoantibodies was not observed, except for anti-U1RNP in six cases. When anti-topo I alone versus anti-topo I + U1RNP groups were compared, African American (21% vs. 67%), overlap with SLE (0 vs. 50%; P = 0.009) or PM/DM (0 vs. 33%; P = 0.05) or elevated creatine phosphokinase (CPK) (P = 0.07) were more common in the latter group. In comparison of anti-topo Ipositive Caucasians versus African Americans, the latter more frequently had anti-U1RNP (13% vs. 50%), mild/no skin changes (14% vs. 63%; P = 0.03) and overlap with SLE (0 vs. 38%; P = 0.03) and PM/DM (0 vs. 25%; P = 0.05). Conclusions: Anti-topo I detected by immunoprecipitation in unselected rheumatology patients is highly specific for SSc. Anti-topo I coexisting with anti-U1RNP in African American patients is associated with a subset of SLE overlapping with SSc and PM/DM but without apparent sclerodermatous changes.