Athina Pyrpasopoulou

Inhibition of TNFα does not induce viral reactivation in patients with chronic hepatitis C infection: two cases

Chronic infections, such as hepatitis C, in the setting of rheumatic disorders pose a potential hindrance to optimal management because of possible complications linked to the institution of immune suppression, as well as the high incidence of hepatotoxicity associated with many of the disease-modifying antirheumatic drugs included in the conventional therapeutic regimens. In the setting of hepatitis C, however, the effect of TNFα blockade may be potentially beneficial because TNFα appears to be involved in the pathogenesis of liver fibrosis through the stimulation of apoptotic pathways. Data related to this subject are, unfortunately, still limited and without detailed information regarding the clinical progression of the rheumatic disorder. We report the cases of two patients, one with ankylosing spondylitis and one with psoriatic arthritis, who were efficiently treated long-term with anti-TNF agents for their rheumatic disease without any evidence of reactivation or flaring of their hepatitis C infection or deterioration of their liver function. Our results indicate that TNFα blockade is a highly efficient and uncompromising therapy in hepatitis C-affected individuals with connective tissue disorders. However, systematic, large-scale studies addressing the issue of safety of these new efficient drugs, i.e., monoclonal antibodies targeted against TNFα, in patients with chronic hepatitis C will be needed to properly assess the risks and benefits of this treatment in analogous cases.

Reactivation of chronic hepatitis B virus infection following rituximab administration for rheumatoid arthritis

In chronic hepatitis B virus infection, immune suppression has been linked with potential activation and, in a number of cases, acute liver failure and fatal outcome; patients with haematologic or other malignancies under chemotherapy were mostly aVected [1]. In the same cohort of patients the incidence of HBV reactivation rose signiWcantly in the past decade, after the introduction of rituximab, a monoclonal antibody targeted against the CD20(+) lymphocytes [2, 3]. In this setting, reactivation was recorded even in HBsAb(+) patients [4]. In patients with rheumatic diseases, analogous cases are still mainly anecdotal. Taking into account the increasing application of rituximab in the treatment of autoimmune diseases, and the global prevalence of chronic hepatitis B virus infection, cases of treatment-induced reactivation need to be recorded, in order to formulate prophylaxis and treatment guidelines, and to safely establish the safety proWle of these agents in analogous circumstances [5].

Parvovirus B19 infection and systemic lupus erythematosus: Activation of an aberrant pathway?

Parvovirus B19 infection has been associated with a variety of rheumatic manifestations/diseases, mainly rheumatoid arthritis, vasculitis and systemic lupus erythematosus (SLE). B19 infection may simulate both clinical and laboratory features of SLE, presenting either as a potential first time diagnosis of SLE or as an exacerbation of previously established disease. The similarities in both clinical and serological features of parvovirus infection and SLE at presentation may hinder the differential diagnosis between these two conditions. Hence, parvovirus B19 infection mimicking SLE usually fulfils <4 ACR criteria for SLE, rarely includes cardiac or renal involvement or presents with haemolytic anaemia, and is usually associated with short-lived, low titers of autoantibodies. Rarely, cases of multisystemic involvement solely attributed to a recent parvovirus B19 infection have been reported, rendering early accurate diagnosis of particular importance and justifying the screening for evidence of parvovirus B19 involvement in newly diagnosed cases of SLE, especially the ones with abrupt onset of symptoms along with cases of SLE flares. This review describes basic features of parvovirus B19 structure and pathogenicity and expands on the parvo-associated auto-immune manifestations particularly in relation to SLE-mimicking or SLE-triggering reported cases. The proposed mechanisms for viral-induced pathologic autoimmunity are discussed with emphasis on emerging data regarding the aberrant expression and localization of autoantigens and their potential implication in alternatively activated immunological cascades.

Tumor necrosis factor-a antagonist-induced psoriasis: yet another paradox in medicine.

The therapeutic use of tumor necrosis factor a (TNFa) antagonists has added a highly effective treatment in the field of inflammatory musculoskeletal, skin, and bowel diseases. Most of the side effects of these very potential agents, like infections or skin reactions, were predictable; the development of psoriatic lesions was not, as they are very successfully used to treat psoriasis and psoriatic arthritis, too. There is a number of cases of anti-TNFa-induced psoriatic lesions in the literature, some of them developing with the use of two agents in the same patient, clearly suggesting a class effect. We report an additional series of 12 cases from a total of 300 patients (>800 patient years) and hypothesize on several mechanisms for the explanation of this paradoxical phenomenon namely, local action of TNF, dysregulation of regulatory T cells, or, finally, imbalance between TNF and interferon-a locally. Further studies are needed to elucidate the exact pathogenesis of these manifestations, so that the use of these agents will not only have changed the course of diseases like rheumatoid arthritis or ankylosing spondylitis but may also aid our in depth understanding of the underlying process of disease.

Association between retinal vessel caliber and arterial stiffness in a population comprised of normotensive to early-stage hypertensive individuals.

BACKGROUND Although impairment of the micro- and macrocirculation is considered inherent to sustained hypertension, there is a substantial lack of studies investigating whether an association exists between micro- and macrovascular damage, especially in early-stage hypertension. METHODS We studied a meticulously selected population, free of diabetes and cardiovascular disease, of 223 individuals: 137 never-treated, newly diagnosed patients with recent onset of hypertension and 86 normotensive individuals. Nonmydriatic retinal photography was used to assess retinal microvascular diameters, including central retinal arteriolar (CRAE) and venular equivalent and arteriovenous ratio (AVR). Arterial stiffness was evaluated by measurement of pulse wave velocity (PWV) and aortic augmentation index (AIx). RESULTS Compared with normotensive subjects, hypertensive patients exhibited significantly increased PWV (8.1 vs. 7.1 m/sec; P < 0.001) and AIx (23.86% vs. 18.8%; P = 0.01) and decreased CRAE (86.47 vs. 91.44 μm; P = 0.001) and AVR (0.74 vs. 0.78; P = 0.007). A significant inverse association was demonstrated between PWV and CRAE (r = -0.205; P = 0.002), which remained significant after multivariable analysis. Likewise, CRAE (P = 0.04) and AVR (P = 0.02) were independent predictors of AIx. CONCLUSIONS This study shows for the first time an association between quantitatively assessed retinal abnormalities and increased arterial stiffness in a sample of early-stage hypertensive and normotensive individuals, suggesting that micro- and macrocirculation impairment in hypertension is a dynamic, mutual, interdependent process present from its very early stages. Given the predictive value of both retinal arteriolar narrowing and arterial stiffness in terms of cardiovascular mortality and morbidity, identification of combined micro- and macrovascular damage might be helpful in cardiovascular risk stratification of hypertensive patients.

Divergent Retinal Vascular Abnormalities in Normotensive Persons and Patients With Never-Treated, Masked, White Coat Hypertension

BACKGROUND Hypertensive patients with retinal arteriolar abnormalities are at increased risk for cardiovascular events. However, the extent of retinal microvascular changes in naïve, never-treated patients with hypertension of short duration has not been established. In addition to this, the lack of relevant data about other phenotypes of hypertension (masked and white-coat hypertension) determined by ambulatory blood-pressure measurement (ABPM) is notable, despite their relationship to increased cardiovascular risk mediated by underlying target-organ and vascular damage. METHODS We conducted a study in which nonmydriatic retinal photography was used to assess central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE) diameters and the retinal arteriovenus ratio (AVR) in a group of 103 individuals with never-treated hypertension of recent (< 1 year) appearance, 28 individuals with masked and 20 with white-coat hypertension, and 50 normotensive individuals, as appropriately classified by ABPM. RESULTS Patients with sustained and masked hypertension had narrower values of CRAE than did normotensive individuals (86.7±10.1 and 87.6±9.2 vs. 94.8±10.6, P < 0.001 and P = 0.02, respectively). The AVR was lower in patients with sustained hypertension (0.736±0.102), masked hypertension (0.716±0.123), and white-coat hypertension (0.739±0.127) than in normotensive subjects (0.820±0.095), P < 0.001, P < 0.001, and P = 0.03, respectively. Both AVR and CRAE were negatively associated with mean systolic and diastolic daytime, nighttime, and 24-hour blood pressures, even after adjustment for other factors. CONCLUSIONS Subtle retinal microvascular signs of pathology are observed in hypertensive patients at early stages of hypertension and in patients with both masked and white coat hypertension. These changes may be indicative or may mediate the differences in cardiovascular mortality in persons with masked and white-coat hypertension, and relevant information about this can be easily accessed with retinal photography.

Capillary Rarefaction as an Index for the Microvascular Assessment of Hypertensive Patients

Arterial hypertension represents a leading cause of cardiovascular mortality and morbidity worldwide through its detrimental effects on target organs. Therefore, the early identification and appropriate management of high-risk patients emerges as extremely important. Given that the microvasculature is subject to a series of morphological and functional changes under the continuous effect of high blood pressure, research over the last years has gradually moved toward the identification of specific microcirculatory alterations that may serve as early prognostic markers of cardiovascular risk. Dermal capillaries represent an “open window” for the in vivo study of human microcirculation that has been long used mainly for the study of rheumatic diseases. However, capillaroscopy has been relatively understudied and only recently applied in the field of hypertension. Capillaroscopy represents a forthcoming promising estimate of the microvascular status in hypertensive patients, with capillary rarefaction representing the most typical finding. The present review aims at summarizing available evidence and the main findings, as well as the premises and promises, of capillary rarefaction as a tool for evaluating patients with hypertension.

Vascular Disease in Systemic Lupus Erythematosus

Vascular disease, either as a direct complication of the disease or developing as an accompanying comorbidity impairs significantly the quality of life of patients with SLE and represents the most frequent cause of death in established lupus. This paper aims to give an overview of the prevalence of the different forms of vasculopathy that can be encountered in a lupus patient, describe their pathogenesis, and address their impact on disease severity and outcome.

Upregulation of VEGF expression is associated with accumulation of HIF-1α in the skin of naïve scleroderma patients

Systemic sclerosis is a disease hallmarked by microangiopathy; the enlargement and leakage of skin capillaries in active stages develops into extensive avascular areas, clinically associated with severe tissue hypoxia and the formation of digital ulcers. Vascular endothelial growth factor (VEGF) is upregulated in all stages of the disease, with little effect on efficient neovascularization. The oxygen-regulated α-subunit of hypoxia-inducible transcription factor-1 (HIF-1α) represents a key mechanism involved in the transcriptional regulation of VEGF. The aim of this study is to investigate expression of the oxygen-regulated α-subunit of HIF-1 and VEGF in naïve scleroderma patients. For this purpose, skin biopsies (dorsal hand surface) from scleroderma patients were analyzed and compared with control skin biopsies. Immunoreactivity for VEGF was enhanced in scleroderma patients, in contrast to restricted positive immunostaining in suprabasal keratinocytes observed in normal skin. In a similar fashion, all skin biopsies from scleroderma patients were strongly HIF-1α reactive, compared with rare immunoreactivity observed in normal skin. The pattern was similar in all stages of scleroderma. These observations for the first time directly connect constitutive hypoxia with VEGF upregulation in scleroderma patients. The sequence of events needs to be precisely mapped, and the pro- and antiangiogenic switches which may interfere with efficient tissue neovascularization identified, in order to provide meaningful therapeutic strategies.

Response to Rituximab and Timeframe to Relapse in Rheumatoid Arthritis Patients

AbstractObjective: Rituximab is used to deplete B cells and control disease activity, mainly in patients with rheumatoid arthritis (RA) who have not responded to anti-tumor necrosis factor (TNF) therapy. Response rates and time to relapse vary significantly among treated individuals. The objective of this study was to monitor the response of seropositive and seronegative RA patients to rituximab and correlate relapse with B-cell markers in the two groups. Methods: Seventeen RA patients (eight seropositive for rheumatoid factor [RF+] and nine seronegative [RF-]) were treated with two cycles of rituximab. After treatment, all patients were re-evaluated at the outpatient clinic, and rituximab was readministered when disease relapse was confirmed by clinical-laboratory measures (Disease Activity Score [DAS]-28). CD20+ cells and CD20 receptor expression levels were estimated at initiation, relapse, and re-evaluation timepoints, and were compared between the two groups. Results: Seropositive patients responded favorably to treatment compared with the seronegative group. The mean time to relapse was 337.5±127.0 days for the RF+ patients versus 233.3 ± 59.6 days for the RF-patients (p = 0.043), despite more aggressive concomitant treatment in the seronegative group. The DAS28 decrease 3 months after treatment was 1.695 ± 1.076 in seropositive patients versus 0.94±1.62 in seronegative patients. At relapse, CD20 receptor expression (molecules/cell) was higher in RF+ patients than in their RF-counterparts, despite a significantly lower percentage of CD20+ cells. Conclusion: Rituximab treatment is efficient in both seropositive and seronegative RA. However, seropositive RA patients tend to respond favorably compared with seronegative patients. The differential CD20 receptor expression in the two groups at relapse potentially suggests a different pathogenetic mechanism of relapse and merits further investigation.