Serum Biomarkers for the Diagnosis of Glaucoma.

Despite the importance of the early detection of glaucoma, most patients with progressive glaucoma show minimal symptoms. We aimed to evaluate biomarkers for glaucoma diagnosis in Korea. Forty-two volunteers with/without open-angle glaucoma were enrolled from January through October 2015-divided into a control or open-angle glaucoma group, which was further divided into normal-tension glaucoma (NTG) and high-tension glaucoma (HTG) groups-and underwent assessments for myelin basic protein (MBP), heat shock protein 60, anti-Sjögren's-syndrome-related antigen A (SSA) and antigen B (SSB), anti-α-fodrin, and anti-nucleic acid. The glaucoma group showed a higher serum MBP level and lower serum anti-α-fodrin antibody level than the control group (p < 0.05). The NTG group showed higher serum anti-SSA and anti-SSB levels and lower anti-α-fodrin IgG/IgA levels than the HTG group. In the receiver operating characteristic curve analysis, the area under the curve (AUC) for serum MBP level was 0.917 in discriminating between controls and patients with glaucoma. Between the NTG and HTG groups, anti-SSA, anti-SSB, and anti-α-fodrin IgG/IgA levels showed an AUC above 0.8. Thus, these biomarkers were useful for diagnosing glaucoma and discriminating between controls and patients with glaucoma, and patients with NTG and HTG.

Neutrophil and lymphocyte counts are associated with different immunopathological mechanisms in systemic lupus erythematosus.

OBJECTIVE: Neutrophils contribute to the SLE pathogenesis. Neutrophil to lymphocyte ratio (NLR) is reported to correlate with disease activity in SLE. The aim of the study was to evaluate whether NLR reflects underlying immunopathogenic activity in SLE, as well as to determine the contribution of each component of NLR, neutrophil and lymphocyte count. METHODS: Data were obtained from a cohort of patients with SLE (n=141) recruited at Lund University, Sweden. NLR levels were compared between patients with SLE and healthy controls (n=79). The relationship between NLR and clinical and immunological markers was examined using Mann-Whitney U test and logistic regression analysis. High NLR was defined as above the 90th percentile of healthy individuals. RESULTS: Patients with SLE had elevated neutrophil count (p=0.04) and reduced lymphocyte count (p<0.0001), resulting in elevated NLR as compared with healthy controls (p<0.0001). Patients with high NLR had more active disease, and were more frequently on prednisone use and immunosuppressive medicines. High NLR was associated with immune complex (IC)-driven disease with presence of antidouble-stranded DNA antibodies (p=0.006), circulating ICs (p=0.02) and type I interferon (IFN) activity (p=0.009). Further, high NLR was associated with neutrophil abnormalities, including enrichment for low-density granulocytes (LDGs) (p=0.001), and increased levels of the serum neutrophil activation marker, calprotectin (p=0.02). Assessing the individual components within NLR, that is, neutrophil and lymphocyte count, high neutrophil count was associated with neutrophil activation markers (p<0.0001), whereas low lymphocyte count was associated with type I IFN activity and elevated numbers of LDGs (p=0.006 and p=0.001, respectively). CONCLUSIONS: NLR is elevated in patients with SLE as compared with healthy individuals, and is associated with key immunopathological events, including type I IFN activity and neutrophil activation. Neutrophil and lymphocyte count reflected different aspects of the pathogenesis of SLE. Further studies are needed to determine the causality of the associations.

Association of Chondrocalcinosis in Knee Joints With Pain and Synovitis: Data From the Osteoarthritis Initiative.

OBJECTIVE: To evaluate the relationship between chondrocalcinosis and pain or synovitis in knee joints by examining data from the Osteoarthritis Initiative (OAI). METHODS: Data were obtained from the OAI public-use data sets. The relationship between chondrocalcinosis on baseline knee radiograph and pain at baseline and at 4 years was examined. Analyses were adjusted for age, sex, body mass index, and Kellgren-Lawrence (K/L) grade and the correlation between 2 knees in a subject was controlled using generalized estimating equations. The relationship between chondrocalcinosis and synovitis on magnetic resonance imaging (MRI) was examined by comparing knees with chondrocalcinosis at baseline and age, sex, and K/L grade-matched knees with no chondrocalcinosis. We read MRIs of a subset of knees for synovitis using the MRI Osteoarthritis Knee Score (MOAKS) on baseline and 4-year MRI. RESULTS: Knees with chondrocalcinosis (n = 162) more often had pain compared to knees without chondrocalcinosis (n = 2,030) at baseline and had higher Western Ontario and McMaster Universities Osteoarthritis Index pain scores, both at baseline (mean 2.4 [95% confidence interval (95% CI) 1.9, 2.9]) versus mean 1.8 [95% CI 1.7, 1.9]) and at 4 years (mean 2.5 [95% CI 1.9, 3.1] versus mean 1.6 [95% CI 1.5, 1.8]), as well as higher Intermittent and Constant Osteoarthritis Pain intermittent pain scores at 4 years. There was no difference in MOAKS synovitis scores at baseline and at 4 years between the chondrocalcinosis group (n = 102) and the control group (n = 99). CONCLUSION: Knees with chondrocalcinosis had increased pain and did not have higher synovitis scores on MRI compared to knees without chondrocalcinosis. The mechanisms by which chondrocalcinosis is associated with increased pain remain to be determined.

Baseline CXCL10 and CXCL13 levels are predictive biomarkers for tumor necrosis factor inhibitor therapy in patients with moderate to severe rheumatoid arthritis: a pilot, prospective study.

BACKGROUND: TNF inhibitors have been used as a treatment for moderate to severe RA patients. However, reliable biomarkers that predict therapeutic response to TNF inhibitors are lacking. In this study, we investigated whether chemokines may represent useful biomarkers to predict the response to TNF inhibitor therapy in RA. METHODS: RA patients (n = 29) who were initiating adalimumab or etanercept were recruited from the rheumatology clinics at Cooper University Hospital. RA patients were evaluated at baseline and 14 weeks after TNF inhibitor therapy, and serum levels of CXCL10, CXCL13, and CCL20 were measured by ELISA. Responders (n = 16) were defined as patients who had good or moderate response at week 14 by EULAR response criteria, and nonresponders (n = 13) were defined as having no response. RESULTS: Responders had higher levels of baseline CXCL10 and CXCL13 compared to nonresponders (p = 0.03 and 0.002 respectively). There was no difference in CCL20 levels. CXCL10 and CXCL13 were highly correlated with each other, and were higher in seropositive RA patients. CXCL10 and CXCL13 levels were decreased after TNF inhibitor therapy in responders. Baseline additive levels of CXCL10 + 13 were correlated with changes in DAS score at 14 weeks after TNF inhibitor therapy (r = 0.42, p = 0.03), and ROC curve analyses for predictive ability of CXCL10 + 13 showed an AUC of 0.83. CONCLUSIONS: Elevated baseline levels of CXCL10 and CXCL13 were associated with favorable response to TNF inhibitor therapy in RA. Subjects with high CXCL10 and high CXCL13 may represent a subset of RA patients whose inflammatory reactions are primarily driven by TNF.

Clinical and Immunologic Profiles in Incomplete Lupus Erythematosus and Improvement with Hydroxychloroquine Treatment.

Objective. The study goals were to evaluate performance of SLE classification criteria, to define patients with incomplete lupus erythematosus (ILE), and to probe for features in these patients that might be useful as indicators of disease status and hydroxychloroquine response. Methods. Patients with ILE (N = 70) and SLE (N = 32) defined by the 1997 American College of Rheumatology criteria were reclassified using the 2012 Systemic Lupus International Collaborating Clinics criteria. Disease activity, patient reported outcomes, and levels of Type I interferon- (IFN-) inducible genes, autoantibodies, and cytokines were measured. Subgroups treated with hydroxychloroquine (HCQ) were compared to patients not on this drug. Results. The classification sets were correlated (R2 = 0.87). ILE patients were older (P = 0.0043) with lower disease activity scores (P < 0.001) and greater dissatisfaction with health status (P = 0.034) than SLE patients. ILE was associated with lower levels of macrophage-derived cytokines and levels of expressed Type I IFN-inducible genes. Treatment of ILE with HCQ was associated with better self-reported health status scores and lower expression levels of Type I IFN-inducible genes than ILE patients not on HCQ. Conclusion. The 2012 SLICC SLE classification criteria will be useful to define ILE in trials. Patients with ILE have better health status and immune profiles when treated with HCQ.

The CD27-CD70 pathway and pathogenesis of autoimmune disease.

OBJECTIVE: To critically examine current evidence regarding the role of the CD27-CD70 pathway in the pathophysiology of autoimmune disease with a focus on understanding the contributions of this pathway as a potential new therapeutic target for systemic lupus erythematosus and rheumatoid arthritis. METHODS: A PubMed search for articles was conducted using the following key words: ("CD27" OR "CD70") AND ("autoimmune disease" OR "systemic lupus erythematosus" OR "rheumatoid arthritis"). The search was limited to publications in English and included human and animal studies. The reference lists of identified articles were searched for further relevant citations. Publications on the list that was developed by this approach were assessed and those with relevance to CD27-CD70 pathway mediated pathophysiology in autoimmune disease were chosen for the detailed review. RESULTS: Data from human diseases and animal models document a major role for the CD27-CD70 receptor-ligand pair in providing signals that regulate T and B lymphocyte activation. The membrane receptor CD27 and its soluble form (sCD27) transmit co-stimulatory signals and induce activation and proliferation of T and B lymphocytes. CD70-expressing CD4 T lymphocytes are increased in autoimmune disease including systemic lupus erythematosus and rheumatoid arthritis and have been shown to produce pro-inflammatory cytokines. At the same time, preclinical evidence suggests that the outcome of CD27-CD70 signals may vary qualitatively between cell subsets and differentiation stages, especially for B lymphocytes. Blockade of the CD27-CD70 pathway has been shown to ameliorate disease manifestations in animal models including murine collagen-induced arthritis and experimental colitis. CONCLUSION: Current evidence from animal models and human diseases suggests that CD27-CD70 pathway contributes to the pathophysiology of autoimmunity. Although a number of basic questions still remain open, the available findings suggest that targeting the components of this pathway could provide useful and novel therapeutic interventions.

CD70-expressing CD4 T cells produce IFN-γ and IL-17 in rheumatoid arthritis.

OBJECTIVE: CD70-expressing CD4 T cells are enriched in RA and promote autoimmunity via co-stimulatory CD70-CD27 interaction. This study aimed to explore the phenotype and cytokine production of CD70(+) CD4 T cells in RA. METHODS: Peripheral blood mononuclear cells from 32 RA patients were isolated and frequencies of CD70(+) cells within different CD4 T subsets were analysed using flow cytometry. IFN-γ and IL-17 production were compared between the CD70(+) and CD70(-) cells. Expression of master transcription factors T-bet, GATA3 and retinoic acid-related orphan receptor gamma t (RORγt) were examined by real-time PCR. Results are presented as mean (s.e.m.). RESULTS: CD4 T cells of healthy controls rarely expressed CD70 as compared with CD4 T cells of RA patients [mean 0.9% (s.e.m. 0.3%) vs 7.6 (0.6), P < 0.001]. In RA, CD70(+) cells were present within all CD4 T cell subsets, i.e. CD45RA(+)CCR7(+) naive, CD45RA(-)CCR7(+) central memory, CD45RA(-)CCR7(-) effector memory and CD45RA(+)CCR7(-) terminally differentiated effector memory T cells with a mean frequency of 3.9% (s.e.m. 1.1%), 4.0 (0.5), 4.2 (0.7) and 9.4 (4.3), respectively. As compared to CD70(-) CD4 T cells, CD70(+) CD4 T cells produced significantly more IFN-γ and IL-17 after short activation. CD70(+) CD4 T cells preferentially expressed transcription factor RORγt. CONCLUSION: CD70(+) CD4 T cells are enriched in RA and may directly contribute to RA pathogenesis by producing IFN-γ and IL-17. Targeting CD70(+) CD4 T cells might offer new therapeutic opportunities in RA.

Criteria for the diagnosis of fibromyalgia: validation of the modified 2010 preliminary American College of Rheumatology criteria and the development of alternative criteria.

OBJECTIVE: To validate the 2011 modification of the 2010 American College of Rheumatology (ACR) preliminary criteria for the diagnosis of fibromyalgia (2011ModCr) and develop alternative criteria in a sample of patients with diverse pain disorders that are commonly seen in everyday practice by pain specialists, rheumatologists, and psychologists. METHODS: Eight clinicians from geographically varied locations in the US evaluated patients with chronic pain and psychiatric disorders using a standard set of questions that included the 2011ModCr questions, the Symptom Impact Questionnaire (SIQR), a 28-area pain location inventory (PLI), and the Short Form 36. Alternative diagnostic criteria were developed from the same data set using logistic regression and receiver operating curve analysis. RESULTS: Complete data on 321 patients were evaluated; there were 135 patients with fibromyalgia (according to the 1990 ACR criteria) and 186 patients with 16 other common chronic pain problems. Comparing the 2011ModCr with the 1990 ACR criteria provided a sensitivity of 83%, a specificity of 67%, and a correct classification of 74%. Alternative criteria were derived from the 10-item symptom score from the SIQR symptoms and the 28-area PLI. Maximal diagnostic accuracy was obtained with ≥17 pain sites (range 0-28) and an SIQR symptom score of ≥21 (range 0-50). These alternative criteria had a diagnostic sensitivity of 81%, a specificity of 80%, and a correct classification of 80%. CONCLUSION: The 2011ModCr had robust operating characteristics. Alternative criteria based on symptom items from the SIQR and pain locations from the PLI had comparable operating characteristics, with somewhat better specificity and ease of use.

SLE peripheral blood B cell, T cell and myeloid cell transcriptomes display unique profiles and each subset contributes to the interferon signature.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by defective immune tolerance combined with immune cell hyperactivity resulting in the production of pathogenic autoantibodies. Previous gene expression studies employing whole blood or peripheral blood mononuclear cells (PBMC) have demonstrated that a majority of patients with active disease have increased expression of type I interferon (IFN) inducible transcripts known as the IFN signature. The goal of the current study was to assess the gene expression profiles of isolated leukocyte subsets obtained from SLE patients. Subsets including CD19(+) B lymphocytes, CD3(+)CD4(+) T lymphocytes and CD33(+) myeloid cells were simultaneously sorted from PBMC. The SLE transcriptomes were assessed for differentially expressed genes as compared to healthy controls. SLE CD33(+) myeloid cells exhibited the greatest number of differentially expressed genes at 208 transcripts, SLE B cells expressed 174 transcripts and SLE CD3(+)CD4(+) T cells expressed 92 transcripts. Only 4.4% (21) of the 474 total transcripts, many associated with the IFN signature, were shared by all three subsets. Transcriptional profiles translated into increased protein expression for CD38, CD63, CD107a and CD169. Moreover, these studies demonstrated that both SLE lymphoid and myeloid subsets expressed elevated transcripts for cytosolic RNA and DNA sensors and downstream effectors mediating IFN and cytokine production. Prolonged upregulation of nucleic acid sensing pathways could modulate immune effector functions and initiate or contribute to the systemic inflammation observed in SLE.

Are ocular complications of a high-dose glucocorticoid treatment appropriately monitored in patients with rheumatic diseases?

Glucocorticoid is frequently used in treating various rheumatic conditions. However it is known to cause multiple toxicities including cataract or glaucoma. In this study, we examined whether patients with rheumatic diseases had appropriate ocular monitoring for glucocorticoid toxicities. From rheumatology clinics in South New Jersey of the USA, we retrospectively identified patients with ages between 18 and 60 years old who received a high accumulative dose of glucocorticoid, which was defined as glucocorticoid dose greater than prednisone 7.5mg/day × 6 months = 1,350 mg. We observed rheumatologists recommended eye examinations only in 14/37 (37.8 %) of patients. Family history was present for cataract in 13/37 (35.1 %) patients and for glaucoma in 6/37 (16.2 %) patients. Rheumatologists recommended eye examinations in 4/13 (30.7 %) and 0/6 (0 %) patients in each group. This study suggested that rheumatologists did not appropriately monitor ocular complications of a high dose glucocorticoid, even in patients with a positive family history.

Polyarteritis nodosa complicated by catastrophic antiphospholipid syndrome.

Polyarteritis nodosa (PAN) is a vasculitis of small- and medium-sized vessels, characterized by vascular aneurysms that can lead to ischemia and infarction. We present the case of a patient with classic polyarteritis nodosa in abdominal organs who additionally demonstrated antitreponemal and antiphospholipid antibodies, resulting in a severe cerebral thrombosis. This case highlights: 1. The potential for false-positive syphilis serology in PAN patients, and 2. The rare coexistence of polyarteritis nodosa and the catastrophic antiphospholipid syndrome.