Faculty Bibliography

Pemphigus vulgaris (PV) is an autoimmune skin disease, which has been characterized by IgG autoantibodies to desmoglein 3. Here we studied the antibody signatures of PV patients compared with healthy subjects and with patients with two other autoimmune diseases with skin manifestations (systemic lupus erythematosus and scleroderma), using an antigen microarray and informatics analysis. We now report a previously unobserved phenomenon--patients with PV, compared with the healthy subjects and the two other diseases, show a significant decrease in IgG autoantibodies to a specific set of self-antigens. This novel finding demonstrates that an autoimmune disease may be associated with a loss of specific, healthy IgG autoantibodies and not only with a gain of specific, pathogenic IgG autoantibodies.

The aim of this study is to determine the effect of comorbidity assessed by the Charlson comorbidity index (CCI) at the time of diagnosis on the outcome of antineutrophil cytoplasmatic antibody (ANCA) associated vasculitis (AAV).This is a longitudinal observational study of 30 consecutive patients with AAV who were diagnosed and followed from January 1996 to December 2011. The degree of comorbidity at diagnosis and last visit was scored according to the age-adjusted Charlson comorbidity index (CCI (a)). The post hoc analysis of increment in CCI during the study period and its predictive value for patient and renal survival were analyzed.Thirty patients with AAV were included in this study. A higher CCI (a) at diagnosis was positively correlated with higher activity score of AAV (P = 0.016), a CCI (a) >5, and with an increased risk for mortality (odds ratio 12; confidence interval 1.8-79.68, P = 0.014). The mean increment (Delta) of CCI (a) during the study period was 1.26 +/- 2.03 (6-5). Correlation was found between lower Delta CCI (a) and chronic kidney disease (P = 0.036) and mortality (P = 0.002).Comorbidity at the time of diagnosis of AAV is associated with reduced patient and renal survival. We suggest including the CCI score in the assessment of patients with AAV at diagnosis and at disease relapse.

OBJECTIVE: The activities of two mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), correlate with disease severity in SLE patients. Whether they are also associated with long-term organ damage is unknown. The aim of the present work was to determine whether impaired expression and activity of ERK and JNK correlate with long-term damage in SLE. METHODS: The expression of ERK and JNK and their phosphorylated active forms was determined by western blot analysis four times during the first year of follow-up in peripheral blood mononuclear cells from 36 SLE patients. A correlation analysis was performed between ERK and JNK expression and longterm organ damage estimated by the SLICC/ARC Damage Index (SDI) 4 years later. RESULTS: Mean levels of ERK and JNK activities during the first year correlated with long-term organ damage severity (r = 0.38 and r = 0.35, respectively; P = 0.05). Overall JNK expression increased with the severity of chronic damage (P = 0.01; P = 0.05 for SDI score 2 and 3, respectively). In contrast, overall ERK expression significantly decreased in patients with maximal organ damage (SDI score 3) compared with patients with an SDI score of 2 (P = 0.03). The ERK/JNK ratio decreased by approximately 40% and 30% in patients with an SDI score of 3 as compared with patients without organ damage and healthy controls, respectively. CONCLUSION: These results demonstrate that early activation of ERK and JNK along with decreased overall ERK expression and reduced ERK/JNK ratio may predict the severity of long-term organ damage in SLE patients.

The objective is to investigate the accrual rate and risk factors of chronic kidney disease (CKD) in an inception cohort of patients with systemic lupus erythematosus (SLE) followed at a single tertiary center. A prospectively collected database of 256 consecutive patients with SLE followed over a 25-year period was systematically interrogated for demographic, disease manifestations, co-morbidities, and outcome. Standardized SLE activity and damage scores were determined for the first and last study visits, and estimated glomerular filtration rate (eGFR; MDRD formula) was calculated at the time of diagnosis and at each year of the follow-up. CKD was defined as eGFR <60 ml/min/1.73 m(2). Results were analyzed with univariate and multivariate models and Kaplan-Meier curves, as appropriate. The cohort was predominantly female (90 %) and Jewish (91.1 %). Mean age at diagnosis was 38 +/- 15.5 years, mean SLE activity score 6.4 +/- 3.8, mean disease duration 8.8 +/- 6.6 years, and mean damage score 0.2 +/- 0.6. Seventy-five patients (30.8 %) were diagnosed with American College of Rheumatology (ACR)-defined lupus renal disease during the study period. There was a progressive decrease in eGFR over time. The prevalence of CKD was 46.7 % in patients with ACR-defined renal lupus disease and 16.4 % in those without. The hazards ratio for CKD was significantly higher in patients with lupus nephritis (LN) than without (p < 0.001). Earlier CKD was positively associated with hypertension (p = 0.01), older age at diagnosis (p = 0.01), and LN (p < 0.001), and negatively associated with hydroxychloroquine treatment (p < 0.001). The prevalence of CKD increases cumulatively in patients with SLE, also in those without overt lupus renal disease. Lupus renal disease poses a significant hazard for earlier development of CKD, and hypertension is a major risk factor for patients with and without nephritis. Antimalarial treatment is associated with renal preservation only in patients with lupus nephritis.

BACKGROUND: A 75 year old patient presenting with mucocutaneous bleeding was diagnosed with acquired thrombasthenia. The diagnosis was based on lack of platelet aggregation with adenosine diphosphate (ADP), arachidonic acid and collagen, and normal aggregation induced by ristocetin. OBJECTIVE: To study the mechanism of platelet function inhibition in a patient with acquired thrombasthenia. METHODS: Aggregation assays of platelets from the patient and healthy controls were performed. In addition, anti-glycoprotein (GP) IIbIIIa antibodies bindingto normal in the presence or absence of the patient's serum was by flow cytometry. RESULTS: Aggregation of normal platelets in the presence of patient's plasma was inhibited four- and 2.5-fold in the presence of ADP and arachidonic acid respectively, while collagen-induced aggregation was completely abolished. Ristocetin-induced aggregation was normal. The patient's serum inhibited binding of commercial anti-glycoprotein IIbIIIa antibodies to normal platelets twofold by flow cytometry. Treatment with anti-CD20 monoclonal antibody (rituximab) normalized the patient's platelet aggregation. CONCLUSIONS: These results suggest that the patient developed inhibitory anti-GPIIbIIIa autoantibodies that caused acquired thrombasthenia.

Systemic lupus erythematosus (SLE) is an autoimmune disease that can attack many different body organs; the triggering event is unknown. SLE has been associated with more than 100 different autoantibody reactivities - anti-dsDNA is prominent. Nevertheless, autoantibodies to dsDNA occur in only two-thirds of SLE patients. We previously reported the use of an antigen microarray to characterize SLE serology. We now report the results of an expanded study of serology in SLE patients and scleroderma (SSc) patients compared with healthy controls. The analysis validated and extended previous findings: two-thirds of SLE patients reacted to a large spectrum of self-molecules that overlapped with their reactivity to dsDNA; moreover, some SLE patients manifested a deficiency of natural IgM autoantibodies. Most significant was the finding that many SLE patients who were negative for autoantibodies to dsDNA manifested abnormal antibody responses to Epstein-Barr virus (EBV): these subjects made IgG antibodies to EBV antigens to which healthy subjects did not respond or they failed to make antibodies to EBV antigens to which healthy subjects did respond. This observation suggests that SLE may be associated with a defective immune response to EBV. The SSc patients shared many of these serological abnormalities with SLE patients, but differed from them in increased IgG autoantibodies to topoisomerase and centromere B; 84% of SLE patients and 58% of SSc patients could be detected by their abnormal antibodies to EBV. Hence an aberrant immune response to a ubiquitous viral infection such as EBV might set the stage for an autoimmune disease.

Connective tissue disorders are systemic, autoimmune, multiorgan diseases in which the central and peripheral nervous systems are frequently involved. The objective of this chapter is to describe the neurological manifestations of three of the most common systemic autoimmune disorders: systemic lupus erythematosus (SLE), scleroderma, and Sjogren's syndrome (SS). In SLE the neuropsychiatric manifestations involve mainly the central nervous system (CNS), including cognitive dysfunction, headache, psychosis and mood changes, seizures, cerebrovascular disease, and myelopathy. Peripheral nervous system (PNS) manifestations are less common and include polyneuropathies as well as mononeuropathies and acute inflammatory demyelinating polyneuropathy. Antiphospholipid syndrome (APLS) is relatively common and should be searched for whenever focal neurological symptoms occur. In scleroderma the PNS is more commonly involved; symptoms include polyneuropathies, entrapment neuropathies, and mononeuropathies (mostly cranial neuropathies or mononeuritis multiplex). Additionally autonomic involvement occurs and myopathies are relatively common. In SS the PNS is similarly involved with several types of polyneuropathies, mononeuropathies, and autonomic dysfunction. Also common are myelopathies and aseptic meningitides. These and other, less common manifestations, as well as the diagnostic procedures and the therapeutic approaches, will be dealt with in this chapter.

OBJECTIVE: This study aimed to determine the value of hypocomplementemia in predicting the renal and patient survival of patients with antineutrophil cytoplasmatic antibody-associated vasculitis (AAV). METHODS: A retrospective analysis of 30 consecutive patients who were diagnosed with AAV and followed at our hospital from 1996 to 2011 was performed. Renal outcome was determined by the Modification of Diet in Renal Disease equation. Disease outcome measures included patient survival and accrual of chronic kidney disease (CKD) defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2) from the date of diagnosis. Logistic regression analysis was used to identify predictors of survival. RESULTS: At presentation, 6 (20%) patients had a low C3 level, which was significantly associated with older age (p = 0.009), higher C-reactive protein (p = 0.02), a lower eGFR (p = 0.03), and anti-MPO antibody positivity (p = 0.03). A low C3 level at presentation was significantly associated with a reduced eGFR at the last study visit (p = 0.015, OR = 11; 95% CI 1.27-95.15). During a mean follow-up of 9.0 +/- 6.2 years, 8 (26.6%) patients had accrued CKD that was significantly associated with low C3 levels at presentation (p = 0.002, OR = 22; 95% CI 2.36-204.7). Mortality was significantly associated with low serum C3 levels at presentation (p = 0.02). CONCLUSION: We found that a low serum C3 level at the time of diagnosis was significantly associated with reduced renal and patient survival in patients with anti-MPO AAV. Our results suggest a role for complement activation in the pathogenesis of AAV.

We sought to determine serum triggering receptor expressed on myeloid cell-1 (sTREM-1) level in a cohort of patients with systemic lupus erythematosus (SLE). Serum sTREM-1 level of 98 patients with SLE and 49 healthy controls was assayed by ELISA. Serum sTREM-1 level was significantly elevated in a cohort of 78 unselected consecutively recruited patients with SLE (mean 1.1 +/- 2.8 rhog/ml, median 0.02 rhog/ml) compared to that of the controls (mean 0.11 +/- 0.3 rhog/ml, median 0 rhog/ml; p < 0.0001). We also determined serum sTREM-1 level of 20 SLE patients with a concurrent infection (mean 0.6 +/- 1.1 rhog/ml, median 0.12 rhog/ml) and found it not statistically significant compared with that of the patients without infection. Serum sTREM-1 level did not correlate with SLE disease activity. Our finding of elevated serum sTREM-1 level suggests an increased shedding of TREM-1 in SLE and a possible novel pathway of innate immune response in autoimmunity.

CpG-oligonucleotide (ODN)-induced TLR9 activation exerts anti-inflammatory effects. TREM-1 is a DAP12-associated receptor, which is up-regulated in response to LPS-mediated TLR4 activation, and plays an essential role in innate immune response by augmenting the production of pro-inflammatory chemokines and cytokines. TREM-1 up-regulation resulted in a grave outcome in animal models, and in patients with sepsis and rheumatoid arthritis, while its soluble form (sTREM-1) exerted anti-inflammatory effects. We hypothesized that CpG-ODN regulates membrane TREM-1 expression and sTREM-1 shedding. The effect of CpG-ODN-induced TLR9 activation on TREM-1 expression and shedding was studied in mouse peritoneal macrophages and the mouse macrophage cell line RAW 264.7. While TREM-1 expression was not altered by CpG-ODN alone, stimulation with both LPS and CpG-ODN significantly abrogated TREM-1 LPS-induced up-regulation. Moreover, CpG-ODN-induced TLR9 activation either alone or in combination with LPS resulted in a significant increase of supernatant sTREM-1. The release of sTREM-1 was correlated positively with MMP-9 activity and was inhibited by chloroquine. These results suggest (i) a novel CpG-ODN-induced TLR9 pathway for the regulation of macrophage TREM-1 expression and MMP-9-mediated TREM-1 shedding; and (ii) a novel mechanism for an anti-inflammatory effect of CpG-ODN through abrogation of LPS-induced membrane TREM-1 up-regulation and increased MMP-9-mediated TREM-1 shedding.