Sabrina Paolino

Vitamin D in rheumatoid arthritis

The discovery of the vitamin D receptor (VDR) in the cells of the immune system and the fact that activated dendritic cells produce the vitamin D hormone suggested that vitamin D could have immunoregulatory properties. VDR, a member of the nuclear hormone receptor superfamily, was identified in mononuclear cells, dendritic cells, antigen-presenting cells, and activated T-B lymphocytes. In synthesis, the most evident effects of the D-hormone on the immune system seem to be in the downregulation of the Th1-driven autoimmunity. Low serum levels of vitamin D3 might be partially related, among other factors, to prolonged daily darkness (reduced activation of the pre vitamin D by the ultra violet B sunlight), different genetic background (i.e. vitamin D receptor polymorphism) and nutritional factors, and explain to the latitute-related prevalence of autoimmune diseases such as rheumatoid arthritis (RA), by considering the potential immunosuppressive roles of vitamin D. 25(OH)D3 plasma levels have been found inversely correlated at least with the RA disease activity showing a circannual rhythm (more severe in winter). Recently, greater intake of vitamin D was associated with a lower risk of RA, as well as a significant clinical improvement was strongly correlated with the immunomodulating potential in vitamin D-treated RA patients.

Bone Metabolism Changes During Anti-TNF-α Therapy in Patients with Active Rheumatoid Arthritis

Abstract:  Osteoporosis (OP) occurs more frequently in patients with rheumatoid arthritis (RA) than in healthy individuals. Specific treatments of RA may increase susceptibility to OP, but at the same time decrease inflammatory activity, which is associated with accelerated bone loss. Treatment with TNF‐α blockers might influence bone metabolism and prevent structural bone damage in RA, in particular at the periarticular level. Our aim was to assess the influence of anti‐TNF‐α therapy on bone metabolism in RA patients. To that end we evaluated a group of 30 RA patients [mean age 50.6 ± 6.8 years; median disease duration 82 ± 38 months; median disease activity score (DAS‐28) 5.8 ± 1.2: 70% of whom were positive for the rheumatoid factor IgM (>40 IU/mL)]. Patients were treated with stable therapy of prednisone (7.5 mg/day) and methotrexate (MTX = 10 mg/week). Eleven of these RA patients further received etanercept (25 mg, twice/weekly) and 10 infliximab (3 mg/kg on 0, 2, 6, and every 8 weeks thereafter). A control group included 10 RA patients with stable therapy (prednisone and MTX) and without anti‐TNF‐α therapy. All the patients fulfilled the ACR criteria for the diagnosis of adult RA and were treated for 6 months. Quantitative ultrasound (QUS) bone densitometry was performed at the metaphyses of the proximal phalanges of both hands with a DBM Sonic 1200 QUS device (IGEA, Carpi, Italy). Amplitude‐dependent speed of sound (AD‐SoS) was evaluated at base line and at 3 and 6 months. Bone mineral density (BMD) of the hip and lumbar spine (L1–L4) was determined by a densitometer (GE Lunar Prodigy, USA) at base line at after 6 months. Soluble bone turnover markers [osteocalcin (BGP) and deoxypyridinoline/creatinine (Dpd/Cr) ratio] were measured in all patients at the same times, using enzyme‐linked immunosorbent assay tests. All data were compared using Wilcoxon signed rank test. Results were as follows: AD‐SoS values were found increased by 1.3% after 6 months of treatment in the RA patients treated with anti‐TNF‐α therapy. On the contrary, the Ad‐SoS levels decreased by 4.6% during the same period in the untreated RA group. BMD increased by 0.2% at lumbar spine and 0.1% at the hip in TNF‐α‐blocker‐treated patients and decreased by 0.8% and 0.6% (at lumbar spine and at the hip, respectively) in RA patients without anti‐TNF‐α therapy. However, BMD variations were not significant. In RA patients treated with TNF‐α blockers, BGP levels were found significantly increased (14.8 ± 3.8 mg/mL vs. 22.4 ± 4.2 mg/mL; P < 0.01) and Dpd/Cr levels were found significantly decreased (8.2 ± 2.1 nM vs. 4.6 ± 1.8 nM; P < 0.01) at 6 months when compared to base line values. On the contrary, there were no significant differences in the untreated RA patients concerning these latter parameters (BGP = 12.2 ± 3.1 mg/mL vs. 10.8 ± 2.8 mg/mL and Dpd/Cr = 8.9 ± 2.4 nM vs. 10.2 ± 1.8 nM, respectively). In conclusion, during 6 months of treatment of RA patients with TNF blockers, bone formation seems increased while bone resorption seems decreased. The reduced rate of OP appears to be supported by the same mechanisms involved in the decreased bone joint resorption during anti‐TNF‐α therapy, that is, the marked decrease of the proinflammatory (i.e., TNF‐α) cytokine effects on bone metabolism.

Effects of Anti‐TNF‐α Treatment on Lipid Profile in Patients with Active Rheumatoid Arthritis

Abstract:  Cardiovascular morbidity and mortality appear to be increased in rheumatoid arthritis (RA), which might be due to increased prevalence of risk factors for cardiovascular disease, such as an accelerated progression of atherosclerosis. Patients with active RA frequently show an atherogenic lipid profile, which has been linked with the inflammatory reaction. Tumor necrosis factor‐α (TNF‐α), a pivotal proinflammatory cytokine implicated in the pathogenesis of atherosclerosis in RA, may be involved in the development of the altered lipid profile observed in active RA. Our aim was to investigate the effects of anti‐TNF‐α treatment in combination with methotrexate (MTX) and corticosteroid therapy on lipid profile in patients with active RA. In this prospective study 34 consecutive RA patients were included (all women, mean age 51.6 ± 7.9 years, range 46–72 years) with active (defined as Disease Activity Index 28 joint score [DAS‐28], of at least 3.2) and refractory RA, in stable treatment with MTX (7.5–10 mg/week) and prednisone (7.5–10 mg/day) for 3 months. All patients received TNF‐α blockers (n= 16, etanercept 25 mg twice weekly; n= 14, infliximab 3 mg/kg on 0, 2, 6, and every 8 weeks thereafter; and finally, n= 4, adalimumab 40 mg every other week). Total cholesterol, high‐density lipoprotein cholesterol (HDL cholesterol), triglycerides (TG) and lipoprotein (a) [Lp(a)] levels and the atherogenic index (ratio cholesterol/HDL cholesterol) were measured at base line, and at 16 and 24 weeks. Results were as follows: The DAS‐28 was 6.9 ± 2.1 at base line and decreased to 4.6 ± 1.8 after 16 weeks, and further to 4.1 ± 1.3 after 24 weeks (both, P < 0.01). Following anti‐TNF‐α treatment, the mean levels of total cholesterol were 168 ± 24 mg/dL at base line and increased to 188 ± 28 mg/dL at 16 weeks (P < 0.01), and 197 ± 26 mg/dL at 24 weeks (P < 0.001). However, also the mean levels of HDL cholesterol were significantly higher than basal values after 16 and 24 weeks of treatment (34 ± 12 mg/dL versus 36 ± 18 mg/dL [P < 0.05] and 38 ± 14 mg/dL [P < 0.01], respectively). TG and Lp(a) levels, as well as the atherogenic index were not significantly changed. Interestingly, variations in disease activity were significantly and inversely correlated with HDL cholesterol levels. In conclusion: Short anti‐TNF‐α treatment was associated with a significant increase of both total cholesterol and HDL cholesterol levels, and correlated with decreased disease activity. The atherogenic index showed no changes during the study. Therefore, anti‐TNF‐α treatment might affect lipid profile in RA patients.

Use of glucocorticoids and risk of infections.

Glucocorticoids (GC) exert many complex quantitative and qualitative immunosuppressive effects that induce cellular immunodeficiency and consequently might increase host susceptibility to various viral, bacterial, fungal, and parasitic infections. In chronic immune/inflammatory conditions cortisol is secreted at inadequate levels and GC therapy today is devoted in substituting this hormone in adequate doses (low) to compensate just for this; therefore, the correct timing of GC administration, such as given during the turning-on phase of TNF secretion (night), can be of major importance. Consequently, the use of the lowest possible GC dose, at the night time and even for the shortest possible time, should decrease dramatically the risk of infections.

Vitamin D involvement in rheumatoid arthritis and systemic lupus erythaematosus.

We read with interest the paper by Costenbader et al on vitamin D intake and risks of systemic lupus erythaematosus (SLE) and rheumatoid arthritis (RA) in women.1 The authors conclude that their prospective study does not lend evidence that to the hypothesis that increasing vitamin D intake can protect against SLE or RA. In this case, using semiquantitative questionnaires regarding the intake of food and the frequency of supplements to assess vitamin D status may not necessarily be a reliable way to indicate the actual absorption and serum levels. This is due to the fact that several other factors, including altered metabolic pathways and others, regulate the real availability. Therefore, the most reliable way to assess vitamin D …

Vitamin D, steroid hormones, and autoimmunity

The endogenous serum metabolite of vitamin D (calcitriol, 1,25(OH)2D3) is considered a true steroid hormone (D hormone), and like glucocorticoids (GCs) and gonadal hormones, may exert several immunomodulatory activities. Serum vitamin D deficiency (25(OH) D), and therefore reduced 1,25(OH)2D3 availability, is considered a risk factor for several chronic/inflammatory or autoimmune conditions, including infectious diseases, type 1 diabetes, multiple sclerosis, and especially autoimmune rheumatic diseases (ARD). In ARD in particular, 1,25(OH)2D3 regulates both innate and adaptive immunity, potentiating the innate response (antimicrobial activity) but reducing adaptive immunity (antigen presentation, T and B cell activities). Regarding a possible synergism between vitamin D and GCs, several studies show that 1,25(OH)2D3 has significant additive effects on dexamethasone‐mediated inhibition of human lymphocyte and monocyte proliferation. Conversely, vitamin D deficiency seems to play a role in increasing autoantibody production by B cells, and seasonal vitamin D declines may trigger flares in ARD, as recently shown. Finally, 1,25(OH)2D3 seems to reduce aromatase activity and limit the negative effects related to increased peripheral estrogen metabolism (cell proliferation, B cell overactivity).

Longterm treatment with endothelin receptor antagonist bosentan and iloprost improves fingertip blood perfusion in systemic sclerosis.

Objective. To evaluate the longterm effects of endothelin-1 (ET-1) antagonism on peripheral blood perfusion (PBP) in patients with systemic sclerosis (SSc). Methods. Twenty-six patients with SSc already receiving cyclic intravenous iloprost (ILO) for severe Raynaud phenomenon were enrolled. Thirteen patients continued the treatment for a further 3 years (ILO group) and 13 patients, because of the appearance of digital ulcers, received in addition bosentan (BOS; 125 mg twice/day) for 3 years (ILO + BOS group). Both PBP at fingertips and nailfold microangiopathy were evaluated yearly by laser Doppler flowmetry and nailfold videocapillaroscopy, respectively. Results. A progressive significant increase of PBP was observed in the ILO + BOS group during the 3 followup years (p = 0.0007, p = 0.0002, p = 0.01, respectively). In contrast, an insignificant progressive decrease of PBP was observed in the ILO group. Difference of perfusion between the PBP evaluations at basal temperature and at 36°C (to test capillary dilation capacity), was found progressively decreased during the 3-year followup only in the ILO group (p = 0.05, p = 0.26, p = 0.09, respectively). A progressive increase of nailfold capillary number was observed only in the ILO + BOS group after 2 and 3 years of followup (p = 0.05). Conclusion. Longterm treatment of SSc patients with ET-1 antagonism, in combination with ILO, seems to increase fingertip blood perfusion, as well as both capillary dilation capacity and number.

Effects of etanercept or infliximab treatment on lipid profile and insulin resistance in patients with refractory rheumatoid arthritis

Dear Editor, We have read with great interest the article by Tam et al. [1] concerning the impact of TNF inhibition on insulin resistance and lipid levels in patients with rheumatoid arthritis (RA). We are performing a similar study using two different anti-TNF-α blockers and we would like to describe our data and make some comments. Our aim was to assess whether etanercept or infliximab treatment may result in an reduction on insulin resistance and improvement of lipid profile in patients with refractory RA. In this prospective study, 32 patients, fulfilling the American College of Rheumatology 1987 criteria, were analyzed. All patients showed active disease as defined by the disease activity index (DAS), using a 28-joint score (DAS-28>3.2) at baseline. Patients received TNF-α blockers (n=18 etanercept, 25 mg twice weekly; n=14 infliximab, 3 mg/kg 0, 2, 6, and every 8 weeks thereafter), stable doses of nonsteroidal anti-inflammatory drugs, prednisolone (<7.5 mg/die) and methotrexate (MTX, 10 mg/week) during the study. A control group included 20 RA patients with stable therapy (prednisone at dose of <7.5 mg/die and MTX at dose of 10 mg/week). Fasting blood samples (between 8:00 and 10:00 AM) were collected in vacutainer tubes and frozen at −70°C until assay. The concentrations of total cholesterol, HDL cholesterol and triglyceride (TG) were determined by commercially available enzymatic reagents. LDL cholesterol value was calculated with the Friedewald formula, which provides reliable values up to a TG concentration of 8.0 mmol/l. Lipoprotein (a) [Lp(a)] concentrations were assayed by ELISA. Insulin resistance was estimated by the homeostasis model assessment for insulin resistance (HOMA) using the formula: fasting serum insulin (μU/ml)× fasting plasma glucose (mmol/l)/22.5; and the quantitative insulin sensitivity check index (QUICKI) using the formula: 1/log insulin (μU/ml)+log glucose (mg/dl) [2, 3]. Measurements of the evaluated parameters were made on blood samples collected before the administration of the TNF-α blockers and after12 and 24 weeks from the starting dosage. Body weight and body mass index (BMI) were assessed at each visit, when blood samples were collected. Concerning the results, the study showed that the BMI remained unchanged throughout the study period, whereas DAS-28 score decreased significantly from baseline to week 12 (5.8± 1.2 vs 3.1±1.3) and to week 24 (2.6±1.3) (p<0.01 for both), in treated patients with anti-TNF-α blockers. In RA patients total cholesterol and HDL cholesterol levels were 183±10 and 34.8±3.6 mg/dl at baseline, respectively. Total cholesterol and HDL cholesterol levels were significantly higher during treatment at 12 and 24 weeks than at baseline [total cholesterol 187±13 mg/dl (p<0.01) and 208±18 mg/dl (p<0.001), HDL cholesterol 37.1±2.6 mg/dl (p<0.05) and 38.9±2.8 mg/dl (p<0.01) at 12 and 24 weeks, respectively]. In contrast, TG and Lp(a) concentrations were not significantly changed during anti-TNF-α treatment at 12 and 24 weeks [TG 125±17 mg/dl (baseline) vs 123±17 mg/dl and 124±18 mg/dl (at 12 and 24 weeks, respectively); Lp(a) 31.1±4.1 mg/dl (baseline) vs 30.7±3.7 mg/dl and 30.1± 3.8 mg/dl (at 12 and 24 weeks, respectively]. The atherogenic index, however, showed no changes during the 24 weeks of anti-TNF-α treatment [3.9±0.3 (baseline) vs 3.9±0.2 (at 12 week) and 3.8±0.4 ( at 24 week)]. At Clin Rheumatol (2007) 26:1799–1800 DOI 10.1007/s10067-007-0702-2

Anti-TNF and sex hormones.

Abstract:  Whenever serum estrogen concentrations are normal in rheumatoid arthritis (RA) patients, lower androgen concentrations (i.e., testosterone, androstenedione, and dehydroepiandrosterone sulfate [DHEAS]) are detected in the serum as well as in the synovial fluid of male and female RA patients. The presence in the RA synovial fluid of a significant altered sex hormone balance resulting in lower immunosuppressive androgens and higher immuno‐enhancing estrogens, might determine a favorable condition for the development of the immunomediated RA synovitis. The inflammatory cytokines (i.e., TNF‐α), particularly increased in RA synovitis, are able to markedly stimulate the aromatase activity in peripheral tissues and, therefore, induce the peripheral metabolism from androgens to estrogens. The effects of TNF blockers (and generally of anticytokine agents) on peripheral sex hormone levels seem exerted in a faster way at the level of the RA synovial tissue (before any influence on serum levels) where they seem to block the conversion from androgens (anti‐inflammatory) to estrogens (proinflammatory) induced by aromatase. Therefore, the beneficial effects of restoring synovial androgens might be clinically more evident in male RA patients (as recently observed in ANTARES study) since they suffer more for the lack of androgens (anti‐inflammatory) on account of the action of TNF‐α on peripheral hormonal conversion. However, therapy (3 months) with anti‐TNF did not change serum levels of typical sex hormones in patients with RA, although baseline values were largely different from controls. In patients with at least long‐standing RA, this indicates that alterations of serum sex hormones and altered activity of respective converting enzymes are imprinted for a long‐lasting period over at least 12 weeks.

Effects of estrogens on extracellular matrix synthesis in cultures of human normal and scleroderma skin fibroblasts

To investigate the effects of 17beta‐estradiol (E2) on extracellular matrix (ECM) protein synthesis (collagen type I, fibronectin, and laminin) using cultures of normal and scleroderma (SSc) skin fibroblasts. Primary fibroblasts cultures, obtained from skin biopsies of six female voluntary subjects and three female SSc patients, were treated for 24 h with E2 (10−10M) alone or in combination with tamoxifene (TAM, 10−7M) as an estrogen receptor (ER) antagonist. ECM protein synthesis was analyzed by immunocytochemistry and Western blotting. E2 induced a significant increase of fibronectin, collagen type I, and laminin synthesis both in normal (P < 0.01, P < 0.05, P < 0.01, respectively) and SSc fibroblasts (P < 0.001, P < 0.05, P < 0.001, respectively) when compared to untreated fibroblasts. TAM induced a significant decrease of ECM protein synthesis when compared to E2‐treated TAM‐untreated fibroblasts. This study seems to support important modulatory effects of E2 in the fibrotic progression of the SSc process via ER interactions.