Evangelia Zampeli

Histamine H3 and H4 receptors as novel drug targets.

The identification of histamine H3 (H3R) and H4 (H4R) receptors some years ago revived interest in histamine research and exposed attractive perspectives for the potential therapeutic exploitation of these new drug targets. While the H3R is mainly localised in the CNS, the H4R is primarily expressed in hematopoietic cells, indicating their function in neurotransmission and immunomodulation, respectively. Although structural similarities between H3R and H4R and species differences in their pharmacological profiles are causes of limitations in the evaluation of their biological profile, the development of selective ligands for these receptors facilitates the elucidation of their physiological and pathophysiological functions. The H3R is a recognised drug target for neuronal diseases, such as cognitive impairment, schizophrenia, sleep/wake disorders, epilepsy and neuropathic pain; a small number of selective H3R antagonists have already passed some clinical Phase II trials. The H4R is the newest identified member of the histamine receptor family. Preclinical data strongly suggest its potential therapeutic exploitation in allergy, inflammation, autoimmune disorders and possibly cancer. Considering the topicality of this area of research, this review focuses on the pharmacology of selected promising indications and the rationales for the application of H3R and H4R ligands.

Subclinical peripheral arterial disease in rheumatoid arthritis

OBJECTIVE Rheumatoid arthritis (RA) is associated with accelerated atherosclerosis in the carotid arteries, but little is known about the magnitude of this process in peripheral arteries. Assessing preclinical atherosclerosis in both arterial beds in RA might provide additional prognostic value during risk stratification for primary prevention. Therefore in the present structural study we examined femoral versus carotid subclinical atherosclerosis in RA and controls. METHODS Intima-media thickness (IMT) and atheromatous plaque presence and vulnerability in femoral versus carotid arteries were examined in 80 RA patients without overt cardiovascular disease or diabetes and 80 controls matched 1:1 for age, gender and traditional cardiovascular disease risk factors. RESULTS Femoral IMT and plaque prevalence were increased in RA than controls (p=0.001 and 0.008, respectively). These increases remained significant after adjustment for potentially confounding factors that differed between groups, such as C-reactive protein and HDL-cholesterol serum levels, and statin use. Femoral plaque vulnerability did not differ between RA and controls. The presence of RA was found to be an independent predictor of increased femoral IMT (p=0.004), after adjustment for traditional cardiovascular risk factors, C-reactive protein and treatment with angiotensin converting enzyme inhibitors and statins. Femoral plaques were less frequent than carotid plaques in RA patients (22.5% vs 45.0% respectively, p=0.003) and in contrast to carotid plaques were independent of age and glucose levels. CONCLUSIONS Subclinical peripheral atherosclerosis in RA is more advanced than in controls. Prospective studies are required to confirm that RA is an independent risk factor for peripheral arterial disease.

Impact of risk factors associated with cardiovascular outcomes in patients with rheumatoid arthritis

Objectives Patients with rheumatoid arthritis (RA) have an excess risk of cardiovascular disease (CVD). We aimed to assess the impact of CVD risk factors, including potential sex differences, and RA-specific variables on CVD outcome in a large, international cohort of patients with RA. Methods In 13 rheumatology centres, data on CVD risk factors and RA characteristics were collected at baseline. CVD outcomes (myocardial infarction, angina, revascularisation, stroke, peripheral vascular disease and CVD death) were collected using standardised definitions. Results 5638 patients with RA and no prior CVD were included (mean age: 55.3 (SD: 14.0) years, 76% women). During mean follow-up of 5.8 (SD: 4.4) years, 148 men and 241 women developed a CVD event (10-year cumulative incidence 20.9% and 11.1%, respectively). Men had a higher burden of CVD risk factors, including increased blood pressure, higher total cholesterol and smoking prevalence than women (all p<0.001). Among the traditional CVD risk factors, smoking and hypertension had the highest population attributable risk (PAR) overall and among both sexes, followed by total cholesterol. The PAR for Disease Activity Score and for seropositivity were comparable in magnitude to the PAR for lipids. A total of 70% of CVD events were attributable to all CVD risk factors and RA characteristics combined (separately 49% CVD risk factors and 30% RA characteristics). Conclusions In a large, international cohort of patients with RA, 30% of CVD events were attributable to RA characteristics. This finding indicates that RA characteristics play an important role in efforts to reduce CVD risk among patients with RA.

Subclinical femoral atheromatosis in rheumatoid arthritis: comparable prevalence to diabetes mellitus in a case-control study

Objective Rheumatoid arthritis (RA) is associated with increased coronary artery disease (CAD) and subclinical carotid atheromatosis, reportedly to equal diabetes mellitus (DM). The presence of atheromatic plaques in femoral arteries of RA patients without DM was compared with with DM patients. Methods Femoral plaques were recorded in 30 (17 men, age 43.0±12 years, disease duration 9.9±7.1 years) and 60 older RA patients (27 men, age 63.0±7.1 years, disease duration 11.4±7.9 years) matched 1:1 for age, gender and disease duration with DM types 1 and 2 patients, respectively. All were asymptomatic and free of CAD. Results The number of femoral plaques per patient in either RA subgroup was comparable with DM (0.64±0.82 vs 0.77±0.89 in total respective populations, p=0.340); percentages of patients with femoral plaques were also comparable (RA vs DM type 1 20% and 13%, respectively; RA vs DM type 2 58% and 66%, respectively). Hypertension and dyslipidaemia were significantly more frequent in both DM groups than RA groups. Conclusions Subclinical femoral atheromatosis in RA is analogous to DM, further confirming the territorial unrestricted acceleration of the atheromatic process in these patients. Cardiovascular risk stratification based on both carotid and femoral plaque detection in RA should be addressed prospectively.

A comprehensive evaluation for the treatment of lupus nephritis

Systemic lupus is the prototypic human autoimmune disease. It is a kaleidoscope of autoreactivities, with clear indications of both a genetic and environmental basis. Indeed, it is a disease that can manifest in virtually every tissue and organ and can also be found spontaneously in a number of animal species, including dogs, cats and horses. Moreover, there are multiple murine models of lupus, the first of which, New Zealand Black (NZB) mice, were discovered in 1959. Despite an enormous effort from scientists in multiple disciplines, the etiology of lupus remains elusive and the introduction of new therapies has been disappointing. Fortunately, significant advances have occurred to help patients through the general principles of internal medicine, including antibiotics, dialysis, and of course use of steroids and immunosuppressive agents. However, the magic bullet has yet to be discovered. One of the major causes of morbidity in lupus remains lupus nephritis and there has been significant effort and encouragement in understanding the pathogenesis, renal histologic classification, and use of therapeutic protocols to induce and sustain remission of lupus nephritis. Indeed, the first use of evidence-based clinical trials in lupus was initiated by Dr. Alfred D. Steinberg at NIH in pioneering studies involving either oral or intravenous pulses of cyclophosphamide, azathioprine or corticosteroids alone and/or some combination. Cyclophosphamide intravenously proved to be superior and the use of cyclophosphamide in combination with methylprednisolone remained the standard protocol for the treatment of lupus nephritis for decades. Although alternative therapies have been introduced, including mycophenolate mofetil, the use of therapies first pioneered at NIH may still be considered standard of care in the appropriate indications. More targeted therapies are much desired. In this review we provide a comprehensive overview of lupus nephritis and the evolution of clinical treatments.

IgG4-related sialadenitis and Sjögren's syndrome

IgG4-related disease (IgG4-RD) has emerged as a new entity in the last decade. It comprises numerous conditions previously thought to be unrelated. Macroscopically, these diseases cause diffuse organ swelling and formation of pseudotumorous masses. Histopathologically, they are characterized by a lymphoplasmacytic infiltrate with increased IgG4+ plasma cells and storiform fibrosis. Despite rapid progress within the last years, our knowledge on these conditions is still fragmented. To date, more than forty organs have been reported to be included in IgG4-RD, and salivary gland involvement is amongst the most common organs affected [IgG4-related sialadenitis (IgG4-RS)]. Interestingly, IgG4-RS shares commonalities with Sjögrens syndrome (SS), like glandular enlargement, sicca symptoms, arthralgias, hypergammaglobulinemia, hypocomplementemia, and circulating antinuclear antibodies. Nonetheless, they differ in that the incidence of anti-Ro and anti-La reactivity is not frequently found in patients with IgG4-RS, their salivary glands are infiltrated by a large number of IgG4+ plasma cells and IgG4-RS symptoms respond promptly to steroids. The aim of this review was to describe the clinical, serological, histopathological and pathophysiological aspects of IgG4-RS in the context of IgG4-RD and highlight the differences between IgG4-RS and SS.

The Additive Value of Femoral Ultrasound for Subclinical Atherosclerosis Assessment in a Single Center Cohort of 962 Adults, Including High Risk Patients with Rheumatoid Arthritis, Human Immunodeficiency Virus Infection and Type 2 Diabetes Mellitus

Background Presence of femoral atheromatic plaques, an emerging cardiovascular disease (CVD) biomarker additional to carotid plaques, is poorly investigated in conditions associating with accelerated atherosclerosis such as Rheumatoid Arthritis (RA), Human Immunodeficiency Virus (HIV) infection and Type 2 Diabetes Mellitus (T2DM). Objective/Methods To assess the frequency of femoral/carotid subclinical atheromatosis phenotypes in RA, HIV and T2DM and search for each disease-specific probability of either femoral and/or carotid subclinical atheromatosis, we examined by ultrasound a single-center cohort of CVD-free individuals comprised of consecutive non-diabetic patients with RA (n=226) and HIV (n=133), T2DM patients (n=109) and non-diabetic individuals with suspected/known hypertension (n=494) who served as reference group. Results Subclinical atheromatosis - defined as local plaque presence in at least on arterial bed - was diagnosed in 50% of the overall population. Among them, femoral plaques only were found in 25% of either RA or HIV patients, as well as in 16% of T2DM patients and 35% of reference subjects. After adjusting for all classical CVD risk factors, RA and HIV patients had comparable probability to reference group of having femoral plaques, but higher probability (1.75; 1.17 - 2.63 (odds ratio; 95% confidence intervals), 2.04; 1.14 - 3.64, respectively) of having carotid plaques, whereas T2DM patients had higher probability to have femoral and carotid plaques, albeit, due to their pronounced dyslipidemic profile. Conclusion RA and HIV accelerate predominantly carotid than femoral. A “two windows” carotid/femoral, rather than carotid alone ultrasound, screening improves substantially subclinical atheromatosis detection in patients at high CVD risk.

Histamine H3 and H4 receptor ligands modify vascular histamine levels in normal and arthritic large blood vessels in vivo.

Growing evidence associates histamine with arthritis, but its implication in shaping vascular function in chronic inflammation remains largely elusive. This study explored the involvement of vascular histamine in the extra-articular responses in peripheral large blood vessels using a rat model of adjuvant-induced arthritis. Histamine levels were increased in the abdominal aorta and the inferior vena cava of arthritic animals. Contrary to the H1 receptor antagonist dimetindene, histamine induction was observed following administration of the H3 and H4 receptor ligands GSK334429 and JNJ7777120, respectively. In arthritis, prophylactic treatment with GSK334429 partially attenuated the clinical signs and restored basal histamine levels only in the abdominal aorta. This study is the first to implicate the H3 and H4 receptors in a concerted constitutive regulation of basal vascular histamine in the rat large blood vessels and to identify the H3 receptor as a component that may influence arterial histamine during the onset of arthritis.

Detection of Subclinical Synovial Inflammation by Microwave Radiometry

Objective Microwave Radiometry is a non-invasive method which determines within seconds the in vivo temperature of internal tissues at a depth of 3–7 cm with an accuracy of ±0.2°C. In this proof-of-concept study, we tested the hypothesis that, in absence of relevant clinical signs, increased local temperature detected by microwave radiometry reflects subclinical synovial inflammation, using ultrasound as reference method. Methods Knees of healthy controls, subjects with recent knee trauma and symptom-free patients with rheumatoid arthritis (RA) or osteoarthritis were examined by placing the microwave radiometry sensor, a) at the upper one third of the anterior surface of the thigh (control-point), and b) over the suprapatellar recess. Ultrasound was performed immediately after and the possible presence of fluid and/or synovitis was correlated with microwave radiometry findings. Results In 30 healthy and 10 injured knees the temperature was always lower than thigh (32.3±1.1 and 31.8±1.4 versus 34.1±0.9 and 33.6±1.2°C with a difference (ΔΤ) of −1.8±0.2 and −1.9±0.4°C respectively). Of 40 RA and 20 osteoarthritis knees examined, ultrasound findings indicative of subclinical inflammation (fluid effusion and/or Doppler signal) were found in 24 and 12, respectively, in which the temperature was higher than healthy knees and ΔΤ was lower (−0.9±0.7 in RA and −1.0±0.5 in osteoarthritis versus −1.8±0.2°C, p<0.001). The 5 RA knees with power Doppler findings indicative of grade 2 inflammation had a ΔΤ 3 times lower compared to healthy (−0.6±0.6, p = 0.007), whereas the 9 RA and the 7 osteoarthritis knees with additionally fluid effusion, had even lower ΔΤ (−0.4±0.7, p<0.001). Conclusion Using a safe, rapid and easy-to-perform method, such as microwave radiometry, thermal changes within the knee joint may reflect non-clinically apparent joint inflammation. Refinement of this method, including production of sensors for small joints, could result to the development of the ideal objective tool to detect subclinical synovitis in clinical practice.

Low-Dose Prednisone Inclusion in a Methotrexate-Based, Tight Control Strategy for Early Rheumatoid Arthritis

TO THE EDITOR: The article by Bakker and colleagues (1) presents impressive control of disease activity in patients with rheumatoid arthritis (RA), which ironically may have attenuated the apparent treatment effect of prednisone. Overall, 67% of patients who received no prednisone had no erosions—only 11% fewer than the 78% of patients treated with 10 mg/d of prednisone for 2 years, albeit a statistically significant difference. The strongest treatment effects that were maintained over 2 years involved patient functional status, which generally is more significant than laboratory and radiographic data to predict work disability and mortality in patients with RA (2). Although unequivocal advantages are documented for 10-mg/d prednisone treatment added to tight control with methotrexate (and adalimumab if indicated by Disease Activity Score 28), 10 mg of prednisone may not necessarily be “low-dose,” as noted in the report (1). No statistically significant differences in adverse events were seen over 2 years (1). However, over long periods, 10 mg/d of prednisone is associated with increased osteoporosis, atherosclerosis, infection, adrenal suppression, and mortality rates, even when discontinued after 2 years (2). Randomized trials reported after initiation of the CAMERA-II (Computer Assisted Management in Early Rheumatoid Arthritis-II) trial have documented clinical and radiographic efficacy of prednisone, 5 mg/d (3), and clinical efficacy of prednisone, 3 mg/d (2). Clinical effectiveness of long-term use of 3-mg/d prednisone was found in more than 90% of patients treated after 1990, when almost all patients received concomitant methotrexate treatment (2). Patients could titrate their dose and discontinue prednisone, but most chose to continue doses of 1 to 4 mg/d over long periods, despite bruising and skin-thinning in some patients. Hypertension, diabetes, and cataracts were not increased over expected numbers (2), consistent with the CAMERA-II trial and population-based evidence comparing moderate (7.5 mg/d) with high doses (4). Doses of prednisone less than 5 mg/d do not suppress the hypothalamic–adrenal– pituitary axis (2). These comments in no way detract from the excellently executed Utrecht study. Nonetheless, Annals readers should be aware that, although not documented as elegantly, initial and long-term use of prednisone, 3 to 5 mg/d, might also clinically and structurally enhance methotrexate therapy, with a considerably lower likelihood of adverse effects (2). Furthermore, although costs are higher, biological agents may be safer than 10 mg/d of prednisone over long periods, analogous to evidence that less than 5 mg/d of prednisone may be safer than nonsteroidal anti-inflammatory drugs. As noted a decade ago, “long-term very low doses of prednisone for patients with rheumatoid arthritis may be as helpful as high doses are harmful” (5), and 10 mg/d may not be “low-dose” or needed for most patients.