Faculty Bibliography

Introduction. Functionality and immune-phenotypes of the human CD4+ T-cell compartment in Behcet's disease (BD) are under-investigated, but several lines of evidence point to its relevance in the pathogenesis and progression of the disease. Aims. We aimed to apply an unbiased single cell approach to assess protein expression levels of phenotypic and functional markers within the human CD4⁺ T cell compartment in subjects with prototypical BD in order to identify cell populations of potential pathobiological relevance. Methods. We determined single cell expression levels of CD3, CD4, CD8, CD127, CD25, CD45RA, CCR7, FoxP3, HELIOS, Ki76, HLA-DR, CD38, CD39 in PBMC by flow cytometry and computed the representation of all mathematically possible cell populations within pre-defined starting populations (i.e., CD3⁺CD4⁺CD8-; CD3⁺CD4⁺CD8-CD127-CD25⁺). PBMC from BD patients (n=13), healthy donors (HD) (n=25) and diseased subjects with non-BD auto-immune uveitis (n=11, VKH, Sarcoidosis, and HLA-B27 associated uveitis) were used. BD subjects met ISG criteria and were Arab or Chinese. 62% had pan-uveitis, 23% major vascular disease, and 7% parenchymal CNS disease. 46% were HLA-B51 carriers. Results. Computation of all populations defined by 8 markers (CD127, CD25, CD45RA, CCR7, FoxP3, HELIOS, Ki67, HLA-DR) within the CD3⁺CD4⁺CD8-(=CD4⁺ T cell) compartment yielded a total of 6560 (3'8-1) cell populations per subject out of which 45 populations reached a significance level of p<=0.000001 in ANOVA testing to differentiate 3 groups (BD, non-BD uveitis, and HD). All of these populations comprised sub-types of the human regulatory T (Treg) cell compartment with strong predominance of non-proliferating, non-activated, FoxP3⁺Helios⁺ Treg carrying central-memory phenotypes (CD45RA-, CCR7⁺). 2-group testing of BD vs non-BD revealed 43 distinct cell populations at a significance level of p<=0.002 representing CD25⁺ non-Treg; comparison of BD vs HD uncovered 58 populations at significance level of p<=0.0001 representing FoxP3⁺Helios⁺ subpopulations, and non-BD vs HD identified 61 populations at p<=0.001, comprising CD25⁺CD127⁺/-FoxP3⁺/-, but consistently HELIOS-, presumably non-Treg populations. A separate analysis using 6 marker combinations (CD38, CD39, CD226, TIGIT, CD45RA, CCR7) within the CD3⁺CD4⁺CD8-CD127-CD25⁺ compartment which contains most human Treg, showed 48 populations (p<=0.0001) in 3-way comparison (BD, non-BD uveitis, and HD) pointing to high significance of TIGIT and CD226 staining Treg subpopulations, and 18 populations with differential expression of CD39⁺ between BD and non-BD diseases subjects. TIGIT and CD226 co-expressing Treg (CD127-CD25⁺) subpopulations also reached significance (p<=0.02) in a longitudinal analysis of 7 BD subjects in active vs inactive disease states, as did 56 out of 6560 populations within total CD4⁺CD3⁺ cells, mostly representing non-Treg cells in active disease. Conclusion. Differential expression of CD4⁺ Treg and non-Treg cells shapes the immune-phenotype of BD in comparison to healthy and non-BD autoimmune diseases that have phenotypic overlap with BD (uveitis). The populations with the highest significance for differentiating BD from healthy states seem to exist within the HELIOS+⁺FOXP3+⁺compartment of non-activated, non-proliferating Treg, suggesting relevance of a true Treg phenotype. Non-Treg CD25⁺ cell populations seem more indicative of BD vs non-BD uveitic disease as well as of clinically active BD while populations with high CD39 expression may indicate non-BD states

Headaches are a common, but under-recognized and understudied symptom in the context of the rheumatic diseases. They can result from intracranial pathology, such as parenchymal and meningeal inflammation, thrombosis, space-occupying lesions, and more. Inflammation, irritation, or degeneration of anatomically related structures such as the eyes, neck, and sinuses can equally cause headaches. In addition, patients with rheumatologic disorders have the same tendencies as the general population to develop primary headaches. While the latter are benign in nature, and generally require only symptomatic relief, the former type of headaches may signal disease manifestation, progression, or complication. Thus, familiarity with common and uncommon headache syndromes related to rheumatologic disorders as well as with their possible underlying disease processes and mechanisms is important. This will help to successfully develop an effective approach toward the evaluation of patients presenting with headaches in a rheumatologic context, and, ultimately, diagnose and treat potentially severe underlying disease.

A 40-year-old Chinese man was admitted for haemoptysis and progressive deep vein thrombosis involving the inferior vena cava (IVC) despite anticoagulation. An IVC filter had been placed earlier at an outside hospital. CT angiography revealed two pulmonary artery aneurysms. The patient was found to have a history of oral and genital ulcers, uveitis and erythema nodosum, thus meeting criteria for Behcet's disease. Other causes of the haemoptysis and thrombophilia were excluded. He underwent successful coil embolisation of the pulmonary artery aneurysms and responded well to immunosuppressive therapy with cyclophosphamide and steroids. Anticoagulation was cautiously continued to limit the long-term risk of secondary thrombosis from his IVC filter. The patient remains well 5 months after initiation of immunosuppressive therapy. Making a diagnosis of Behcet's disease in the setting of thrombosis is crucial, as treatment must include immunosuppression, and, thus, fundamentally differs from the management of most other thrombotic disorders.

OBJECTIVE: The aim of the study is to determine the frequency and functionality of blood conventional dendritic cells (cDCs) in relation to disease activity in systemic lupus erythematosus. METHODS: Blood cDCs were enumerated for 34 SLE patients, defined as "active" (SLEDAI>/=4) or "inactive" (SLEDAI<4), 26 RA subjects and 8 healthy subjects by FACS. cDC activation was measured by IL-12p40/70 staining following resiquimod stimulation. RESULTS: The frequency of blood cDCs was significantly lower in active compared to inactive patients, however, with comparable cDC functionality. CONCLUSION: cDC frequency in active SLE is decreased with no perturbation in cDC function, possibly due to enhanced turnover and/or tissue-specific migration.

OBJECTIVES: The best treatment for patients with Behcet's disease (BD) with major vessel thrombosis has not been fully determined. Our objective was to raise this therapeutic dilemma and to call for controlled studies to help establish guidelines to address this problem. METHODS: Three patients with BD and major vessel thrombosis whom we recently encountered are described. Their cases were presented to rheumatologists from Turkey, Israel and the USA. The physicians were asked about the kind of treatment they would give each patient at diagnosis of thrombosis and if they chose to give anticoagulation and for long. RESULTS: Fifty-five Turkish, 33 Israeli and 25 American rheumatologists responded to the questionnaire. More than 87% of the Israeli and American rheumatologists would give anticoagulation at the time of diagnosis for the cases of venous thrombosis compared with only 40-44% of the Turkish physicians. In these cases 56% of the American and 45% of the Israeli rheumatologists would give warfarin for life compared with only 5-18% of the Turkish physicians. Regarding a case with intra-cardiac thrombus, 96% of American, 94% of Israeli, and 60% of Turkish rheumatologists would start anticoagulation at diagnosis while 70%, 39% and 33%, respectively would give this treatment for life. CONCLUSIONS: The therapeutic approach towards thrombosis in Behcet's disease differs significantly among rheumatologists from different countries. The different prevalence of the disease in these countries may explain this difference. A randomised controlled prospective trial is needed in order to determine the exact role of anticoagulant treatment in BD.