Ioannis Gkougkourelas

The influence of therapy on CD4+CD25highFOXP3+ regulatory T cells in systemic lupus erythematosus patients: a prospective study

Objectives: Regulatory T cells (Tregs) are inversely correlated to disease activity in systemic lupus erythematosus (SLE). However, little is known concerning the influence of immunosuppressive agents on Tregs, which was the objective of this study. Method: Thirty-five patients with SLE (29 females, six males, mean age 42.4 ± 12.8 years) were included. CD4CD25highFOXP3 Tregs were prospectively assessed by flow cytometry every month for intravenous (iv) and quarterly for oral regimens. Clinical assessment was made with the SLE Disease Activity Index (SLEDAI). Statistical analysis was performed with a Student’s t-test; p < 0.05 was considered significant. Results: In total, 44 cases of SLE relapse were treated with iv cyclophosphamide (CYP, n = 10), iv methylprednisolone (MP, n = 7), iv immunoglobulins (IVIGs, n = 5), oral MP (n = 8), oral MP  azathioprine (AZA, n = 8), and hydroxychloroquine (HCQ, n = 6). CYP, iv MP, and IVIGs resulted in a significant increase in Tregs (4.2 ± 1.6 vs. 10.1 ± 5.7, 2.9 ± 1.3 vs. 10.6 ± 4.8, and 5.6 ± 2.7 vs. 15.2 ± 6.3 cells/mm3, respectively, p < 0.05). Oral MP, alone or combined with AZA, led to a significant increase in Tregs (7.4 ± 2.5 vs. 11.8 ± 3.8 and 5.1 ± 2.4 vs. 9.4 ± 3.6 cells/mm3, respectively, p < 0.05), as did HCQ (8.2 ± 2.4 vs. 12.8 ± 2.7 cells/mm3, p < 0.05). Time to Tregs recovery was significantly shorter with iv MP and IVIGs compared to CYP (1.4 ± 0.5, 1.6 ± 0.9, and 4.0 ± 1.5 months, respectively, p < 0.05). Conclusions: Increase in Tregs during SLE remission is independent of the therapeutic regimen used and probably represents an epiphenomenon of disease remission. Time to Tregs restoration was significantly shorter in patients treated with iv MP and IVIGs compared to CYP pulse therapy.

Tocilizumab Treatment Leads to a Rapid and Sustained Increase in Treg Cell Levels in Rheumatoid Arthritis Patients: Comment on the Article by Thiolat et al

To the Editor: In their recent article in Arthritis & Rheumatology, Thiolat and colleagues reported a significant expansion in the number of Treg cells in 15 rheumatoid arthritis (RA) patients after 3 months of treatment with tocilizumab (TCZ) (1). We have observed that the increase in Treg cell frequency occurs even sooner after the initiation of TCZ treatment (shortly after the first infusion) and is sustained over at least 12 months of regular drug administration. We studied 22 patients with active RA who were administered TCZ monthly (5 patients received 12 infusions, 4 received 8, 3 received 6, 3 received 4, and 7 received 2) along with disease-modifying antirheumatic drugs (DMARDs) at stable doses. Corticosteroids were not used throughout the study. Levels of CD25FoxP3 CD4 Treg cells were assessed before every TCZ infusion. After the first infusion, Treg cell frequencies were significantly increased and the 28-joint Disease Activity Score (2) was decreased (Table 1); this increment was sustained over the subsequent months. Related studies have assessed Treg cell levels after 2 months (3) or 3 months (1,4) of TCZ administration. Our results show that a significant increase in Treg cell frequency occurs after only 1 infusion; furthermore, the increase remains stable over time. Whether TCZ or another drug(s) is the direct cause of the Treg cell expansion or whether this is the result of disease remission remains a matter of controversy. In this context, corticosteroids (used in moderate doses in previous studies) (4) are known to increase Treg cell levels in other systemic autoimmune diseases, e.g., systemic lupus erythematosus (5). In our patients (who did not receive corticosteroids during the study), DMARDs were administered at stable doses; therefore, it is quite unlikely that the Treg cell expansion could be attributed to these drugs. In conclusion, TCZ is expected to skew the Th17/Treg cell balance toward the protective Treg cell arm (6,7) The exact mechanism(s) behind this action, the duration of the increase in Treg cell frequency, and its clinical significance remain to be determined.

Increase of peripheral T regulatory cells during remission induction with cyclophosphamide in active systemic lupus erythematosus.

Cyclophosphamide efficacy in lupus nephritis (LN) and neuropsychiatric systemic lupus erythematosus (NPSLE) is probably mediated by a non‐specific ablation of reactive lymphocytes. However, little is known in regard to its effect on T regulatory cells (Tregs) in such patients, which was the aim of this study.

Systemic Sclerosis and Silicone Breast Implant: A Case Report and Review of the Literature

Environmentally induced systemic sclerosis is a well-recognized condition, which is correlated with exposure to various chemical compounds or drugs. However, development of scleroderma-like disease after exposure to silicone has always been a controversial issue and, over time, it has triggered spirited debate whether there is a certain association or not. Herein, we report the case of a 35-year-old female who developed Raynauds phenomenon and, finally, systemic sclerosis shortly after silicone breast implantation surgery.

FRI0280 Cd4+cd25highfoxp3+ t regulatory cells as a biomarker of disease activity in systemic lupus erythematosus: a prospective study

Background Low numbers of T regulatory cells (Tregs) in active systemic lupus erythematosus (SLE) are believed to reflect the breakdown of immune tolerance in disease pathogenesis. However, it is not clear if these cells may be utilized as a biomarker in assessing disease activity. Objectives of the present study was the prospective evaluation of Tregs as possible biomarkers in assessing SLE activity. Methods Tregs (phenotype CD4+CD25highFOXP3+) were assessed by flow cytometry in 285 separate blood samples from 100 white Caucasian SLE patients and 20 healthy controls. Patients were divided, according to disease activity (as measured by Systemic Lupus Erythematosus Disease Activity Index, SLEDAI) into groups A (n=39, samples=94, SLEDAI=0), B (n=33, samples=92, SLEDAI=1-5), C (n=10, samples=53, SLEDAI=6-10) and D (n=18, samples=46, SLEDAI>10). Longitudinal measurements were performed in 131 cases (37 relapses, 44 remissions and 50 cases without alteration in disease activity). Statistics were performed by Student’s t-test or one-way ANOVA, post hoc analysis with Bonferroni multiple comparisons test and correlations with Pearson co-efficient; while p<0.05 was considered significant. Results Tregs were found significantly lower in severely active disease (group D), compared to healthy controls, inactive disease, mild and moderate disease activity (0.57±0.16% vs. 1.49±0.19%, 1.19±0.34% and 1.05±0.36%, 0.72±0.21%, p<0.05, respectively). There was a strongly inverse correlation between Tregs and SLEDAI (r=-0.644, p<0.001). Alterations in disease activity were characterized by inverse alterations in Tregs: relapse (from 1.23±0.44% to 0.64±0.19%, p<0.001, mean change 0.59±0.41%), remission (from 0.65±0.27% to 1.17±0.30%, p<0.001, mean change 0.52±0.35%). In cases with unaltered disease activity, Tregs numbers remained stable (from 0.98±0.35% to 1.03±0.34%, p=0.245). Tregs were practically halved during relapse (mean reduction 42.6±22.2%), and doubled during remission (mean increment 113±120.9%). Mean change of Tregs in cases with unaltered activity was significantly lower (7.3±20.6%, p<0.001). A clinically significant change in SLEDAI (sum of cases with relapse and remission, n=81) was followed by a significant (>20%) inverse change in Tregs in 71/81 cases (sensitivity 87.7%). In the 50 cases of unchanged SLEDAI, Tregs were significantly changed (>20%) in 13 cases (specificity 74%). Positive predictive value (PPV) was 84.5% and negative predictive value (NPV) was 78.7%. Conclusions CD4+CD25highFOXP3+ T regulatory cells displayed a strongly inverse correlation to disease activity, while their alterations reflected the changes in SLEDAI with high sensitivity. These cells may be a promising biomarker for the assessment of disease activity in SLE by longitudinal measurements. Disclosure of Interest: None Declared

Celiac trunk aneurysm in a patient with Adamantiades-Behçet disease

Major artery involvement in Adamantiades-Behcet disease (ABD) ranges from 5% to 18% and mainly manifests as arterial stenosis and/or aneurysm formation.1 Celiac artery involvement is considered rare; celiac aneurysms have been reported in isolated cases.2,3 We present computed tomography (CT) angiography of a 70-year-old male, suffering from ABD for 40 years (initial symptoms included recurrent oral and genital ulcerations and bilateral anterior uveitis). Treatment, over time, included methylprednisolone, cyclosporine and azathioprine. He was admitted for severe upper abdominal pain, accompanied by nausea and abdominal distension. Laboratory investigation showed elevated erythrocyte sedimentation rate and C-reactive protein. Abdominal CT angiography revealed a celiac artery aneurysm starting 2 mm from the aorta measuring 32 mm in length and with a maximum diameter of 16.7 mm (Panel A) with thrombus attached in the arterial wall. Additionally, the common hepatic artery was totally occluded; hepatic perfusion was sustained via the superior mesenteric and pancreatoduodenal arteries (Panel B). Intravenous methylprednisolone pulses (1000 mg/day for 5 consecutive days) were administered with satisfactory response. Maintenance treatment included methylprednisolone and mycophenolate mofetil, along with antiplatelet therapy (aspirin plus clopidogrel). After 12 months, repeated abdominal CT angiography revealed stabilization of the celiac artery aneurysm (maximum diameter 16.3 mm). During this period, the patient remained asymptomatic. Celiac artery aneurysm in ABD represents a rare entity and may require combined medical and surgical intervention. Urgent surgery, either by open or endovascular repair, is mandatory in case of enlarging or ruptured aneurysms or due to organ-threatening ischemia.3,4 Equally significant is the implementation of postoperative immunosuppressive therapy, to prevent relapse and common complications after arterial bypass surgery, such as graft occlusion and new aneurysm formation at the site of anastomoses. Remission induction with immunosuppressive drugs represents the first goal in uncomplicated cases of ABD, while Images in Vascular Medicine

Immunopathophysiology of Large Vessel Involvement in Giant Cell Arteritis — Implications on Disease Phenotype and Response to Treatment

Giant cell arteritis (GCA) or temporal arteritis or Horton’s disease is classified amongst the primary large-vessel vasculitides, according to the 2012 revision of the Chapel-Hill classifica‐ tion criteria. The disease develops almost exclusively in patients older than 50 years (preva‐ lence of 1 in 500 individuals in this age spectrum) and represents the most common vasculitis in Western countries. [1] Incidence rates are progressively increased and estimated to range between 10-30 new cases per 100000 persons beyond the age of 50, while the highest frequency is reported in Scandinavian and North American populations. [2]

Fatal refractory thrombotic thrombocytopenic purpura complicating systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is characterized by a diverse clinical spectrum, ranging from mild skin and musculoskeletal involvement to life-threatening complications. Thrombotic thrombocytopenic purpura (TTP) is a rare comorbidity, affecting, mainly, active lupus patients. Even if, TTP recognition is based on clinical and simple laboratory grounds (thrombocytopenia, microangiopathic hemolytic anemia), recent studies have demonstrated that low levels of ADAMTS-13 (a disintegrin-like and metalloproteinase with thrombospondin type 1 motif 13) may further support diagnosis in complicated cases. ADAMTS-13 is a metalloprotease, which normally cleaves the large thrombogenic multimers of von Willebrand factor that are released from the Weibel-Palade bodies, under endothelial stress. These multimers serve as functional bridges between the endothelium and platelets, which allow intense platelet aggregation and subsequent thrombosis. ADAMTS-13 insufficiency is multifactorial, whereas the most common acquired cause is the immune-mediated inhibition of its normal function. Among autoimmune diseases, SLE is the most frequent cause of secondary TTP, as the lupus-related inflammatory, prothrombotic microenvironment may promote the disequilibrium between ADAMTS-13 and von Willebrand factor, leading to thrombotic microangiopathy and increased mortality. Furthermore, literature regarding the optimal therapeutic approach in these patients is inconclusive. Herein, a fatal case of SLErelated TTP, refractory to conventional therapeutic modalities, is presented.

Discrepancies in reference values of soluble Triggering Receptor Expressed on Myelocytes 1 (sTREM-1) question the reliability of related studies

Soluble Triggering Receptor Expressed on Myelocytes 1 (sTREM-1) is a promising innate immunity biomarker that may be able to differentiate infectious from aseptic (non-infectious) systemic inflammation. Ambiguous results on its discriminative value have been reported by different studies. In addition, controversy still exists regarding its reference values in normal individuals, further impeding solid conclusions. This article is protected by copyright. All rights reserved.

Assessing the Patient With Arthralgia, Fevers, and Rash

Both scenarios imply that the average GRS-BMI should be lower for study participants in earlier birth cohorts. However, we showed (Table 2 in the article and eTable 1 in the Supplement) that genetic risk remained stable across the birth cohorts, despite major changes in BMI. Furthermore, GRS-BMI did not predict mortality for white participants in HRS (P = .45). Additionally, we estimated a model testing whether the birth year by GRS-BMI interaction differed for white respondents above or below age 65 years and found no evidence of such effect modification by age (P = .24). With respect to Mr Liu and Dr Guo, upon reviewing their article,6 we agree that our results for white respondents substantially overlap with theirs. This type of overlap is always a risk with publicly available data sets such as the HRS, but missing their citation was a mistake on our part. Our manuscript was mostly finished prior to their publication (first full draft completed March 2014).Weattemptedtoupdateourliteraturereview,butwefailed to identify this important publication. We apologize for our error.Weconsideritanindicationoftheimportanceofthisresearch questionthatitwasundertakenbymultipleindependentresearch groups, and we are pleased that the findings are consistent.