Foot tendinopathies in rheumatic diseases: etiopathogenesis, clinical manifestations and therapeutic options.

Damage to the mutual and delicate articular relationships of the foot may lead to functional failure. A painful foot can be the heralding sign of inflammatory, metabolic or degenerative rheumatic disease that may cause severe disability if left untreated. Healthy tendons are brilliant white in colour, are fibroelastic in texture and can withstand huge mechanical loads. Pathological tendons are characterised by changes in cellular function, rupture of collagen bundles, increased production of the proteoglycan-water matrix and neurovascular proliferation. According to the underlying disease, tendinopathies may present with pain of variable duration and intensity and with functional impairment, or they may be an asymptomatic finding on imaging techniques. Pain is the most common presenting symptom in the inflammatory rheumatic diseases of the ankle and the foot and usually precedes ultrasound or radiographic changes; pain results from inflammatory changes of the synovia and soft tissue structures including bursae, tendons, fascias and peripheral nerves. The management of tendinopathies in inflammatory and non-inflammatory rheumatic patients includes "articular economy," pharmacological treatment, foot orthotics, cryotherapy, instrumental physiotherapy, rehabilitation and physical. This review highlights the differences between tendinopathies occurring in non-inflammatory rheumatic disorders compared to those appearing in the course of inflammatory rheumatic disorders and defines a conservative management framework that non-rheumatologists (orthopaedic surgeons) and rheumatologists could adhere for the management of foot tendinopathies.

Lack of association between IgA deficiency and respiratory atopy in young male adults.

BACKGROUND: The issue of atopy and increased serum IgE in IgA deficiency is still a matter of debate. The aim of this study was to evaluate the prevalence of IgA deficiency and its relationship with respiratory atopy. MATERIALS AND METHODS: A retrospective study on 4700 consecutive young males (age range 18-23), who underwent a health screen for admission to the Italian Airforce Academy between 1993 and 1995 was conducted. Serum IgA was measured by immunoturbidimetry and total and specific IgE by fluorescent enzyme immunoassay (Phadiatop FEIA, Pharmacia Cap System). Airway responsiveness was assessed by methacholine challenge. RESULTS: IgA deficiency was detected in 0.34% (16/4700) subjects and atopy was detected in 8.6% (406/4700). The mean IgA was 243 mg/dl (95% CI 107, 442) in the 406 atopic subjects and 238 mg/dl (95% CI 100, 441) in 1544 controls. Only 6 (37.5%) of the IgA deficient subjects had subnormal IgE levels and 6 were positive in the fluorescent EIA. None of the IgA deficient patients presented with respiratory hyper-reactivity. CONCLUSION: Atopy is not more prevalent in young male adult IgA deficient subjects, who rather display a high frequency of recurrent sinusitis.

Recurrent abdominal thrombosis despite heparin thromboprophylaxis in a patient with transient eosinophilia.

A 21-year-old girl with an ischemic bowel developed portal and splenic vein thrombosis 3 weeks later, despite thromboprophylaxis low-molecular-weight heparin. An extensive thrombophilia screen was negative and the only possible reason for her vascular occlusion was transient but severe eosinophilia. The role of transient eosinophilia in thrombosis is discussed in the light of other similar rare cases.

High-density lipoprotein inversely relates to its specific autoantibody favoring oxidation in thrombotic primary antiphospholipid syndrome.

Abnormalities of the lipid profile partly explain the atherogenic tendency of systemic lupus erythematosus but the picture is unclear in thrombotic primary antiphospholipid syndrome (PAPS). Herein we compare the lipid profile, high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (CHO), apolipoprotein A (ApoA-I), apolipoprotein B (ApoB), triglycerides (TRY)), anti-lipoprotein antibodies, beta-2-glycoprotein I complexed to oxidized low-density lipoprotein (oxLDL-ss(2)GPI) and C-reactive protein (CRP) from thrombotic PAPS (n = 34), thrombotic patients with inherited thrombophilia (IT; n = 36), subjects persistently positive for antiphospholipid antibodies (aPL, n = 18) with no underlying autoimmune or non-autoimmune disorders and healthy controls (n = 28) and determined the reciprocal effects of anti-lipoprotein antibodies, the lipid profile, oxLDL-ss(2)GPI and CRP. Average concentrations of HDL (p < 0.0001), LDL (p < 0.0001), CHO (p = 0.0002), ApoA-I (p = 0.002) were lower in PAPS whereas average TRY was higher (p = 0.01) than other groups. Moreover, the aPL and PAPS group showed higher levels of IgG anti-HDL (p = 0.01) and IgG anti-ApoA-I (p < 0.0001) whereas the PAPS group showed greater average oxLDL-ss(2)GPI (p = 0.001) and CRP (p = 0.003). Within the PAPS group, IgG anti-HDL correlated negatively to HDL (p = 0.004) and was an independent predictor of oxLDL-ss2GPI (p = 0.009). HDL and ApoA-I correlated negatively with CRP (p = 0.001 and p = 0.007, respectively). IgG anti-HDL may hamper the antioxidant and anti-inflammatory effect of HDL favoring low-grade inflammation and enhanced oxidation in thrombotic PAPS.

Atherosclerosis in thrombotic primary antiphospholipid syndrome.

BACKGROUND: Primary antiphospholipid syndrome (PAPS) is characterized by arterial and venous thrombosis, pregnancy loss, often recurrent, in the presence and persistence on antiphospholipid antibodies (aPL). The issue of early atherosclerosis, as evaluated by measuring carotid intima media thickness (IMT), associated with aPL, has been limitedly explored in PAPS. METHODS: In an age- and sex-matched case-double-control study, intima media thickeness of carotid arteries was measured using high-resolution B-mode ultrasound in 49 thrombotic PAPS patients (18 M, 31 F, mean age 37+/-11), in 49 patients who suffered thrombosis for inherited thrombophilia and 49 healthy subjects. RESULTS: Average carotid IMT was always greater in PAPS than control patients (common carotid P=0.004, bifurcation P=0.013, internal carotid P=0.001). By dividing participants into age tertiles most of the difference was explained by greater IMT of PAPS patients in the second (common carotid P=0.003, bifurcation P=0.023, internal carotid P=0.003) and third tertiles (common carotid P=0.03, bifurcation P=0.004, internal carotid P=0.007). CONCLUSIONS: Premature atherosclerosis is a clinical feature of our thrombotic PAPS patients.

Anti-atherogenic and anti-inflammatory properties of high-density lipoprotein are affected by specific antibodies in systemic lupus erythematosus.

OBJECTIVE: To determine whether antibodies against high-density lipoprotein (aHDL) and apolipoprotein A-I (aApo A-I) interfere with the anti-atherogenic functions of high-density lipoprotein (HDL) and relate to disease activity and damage in SLE. METHODS: Seventy-seven SLE patients were compared with an age- and sex-frequency matched control group. Immunoglobulin G (IgG) aHDL, IgG aApoA-I, soluble vascular cell and intracellular cell adhesion molecules (VCAM-1 and ICAM-1, respectively) were measured by ELISA, paraoxonase (PON) activity by spectrophotometry, nitric oxide (NOx) metabolites by the Griess reaction, and total anti-oxidant capacity (TAC) by chemiluminescence. RESULTS: Compared with controls, SLE patients showed higher titres of IgG aHDL (P < 0.0001) and IgG aApo A-I (P < 0.0001), lower PON activity (P < 0.0001), increased NOx (P < 0.0001), VCAM-1 (P < 0.0001) and ICAM-1 (P = 0.0008) and lower TAC (P = 0.0006). Titres of IgG aHDL positively correlated with IgG aApo A-I (r = 0.64, P < 0.0001), NOx (r = 0.32, P = 0.007), inversely correlated with PON activity (r = -0.34, P = 0.002) and TAC (r = -0.43, P = 0.0004) and were independently associated with ICAM-1 (t = 3.509, P = 0.001). IgG aApo A-I titres correlated positively with NO (r = 0.37, P = 0.007), inversely with PON activity (r = -0.31, P = 0.006), TAC (r = -0.47, P < 0.0001) and were independently associated with HDL (t = -2.747, P = 0.008) and VCAM-1 (t = 3.311, P = 0.002), the latter alongside NOx (T = 2.271, P = 0.02). Elevated titres of IgG aHDL and IgG aApo A-I and reduced PON activity related to increased disease score (BILAG) and damage index (SLICC/ACR DI). CONCLUSION: In SLE, IgG aHDL and aApo A-I associate with disease activity and damage and interfere with the anti-oxidant and anti-inflammatory functions of HDL favouring atherogenesis.

Primary antiphospholipid syndrome: a low-grade auto-inflammatory disease?

OBJECTIVE: To test the inflammation and immune activation hypothesis in primary thrombotic APS (PAPS) and to identify clinical and laboratory factors related to inflammation and immune activation. METHODS: PAPS (n = 41) patients were compared with patients with inherited thrombophilia (IT, n = 44) and controls (CTR, n = 39). IgG aCL, IgG anti-beta2-glycoprotein I (beta(2)GPI), high-sensitivity CRP (hs-CRP), serum amyloid A (SAA), CRP bound to oxidized low-density lipoprotein-beta(2)GPI complex (CRP-oxLDL-beta(2)GPI) (as inflammatory markers) neopterin (NPT), soluble CD14 (sCD14) (as immune activation markers) were measured by ELISA. RESULTS: After correction for confounders, PAPS showed higher plasma levels of hs-CRP (P = 0.0004), SAA (P < 0.01), CRP-oxLDL-beta(2)GPI (P = 0.0004), NPT (P < 0.0001) and sCD14 (P = 0.007) than IT and CTR. Two regression models were applied to the PAPS group: in the first, IgG aCL and IgG beta(2)GPI were included amongst the independent variables and in the second they were excluded. In the first model, SAA (as the dependent variable) independently related to thrombosis number (P = 0.003); NPT (as the dependent variable) independently related to thrombosis type (arterial, P = 0.03) and number (P = 0.04); sCD14 (as the dependent variable) independently related to IgG beta(2)GPI (P = 0.0001), age (0.001) and arterial thrombosis (P = 0.01); CRP-oxLDL-beta(2)GPI (as the dependent variable) independently related to IgG beta(2)GPI (P = 0.0001). In the second model, sCD14 and NPT independently related to each other (P = 0.002) (this was noted also in the IT group, P < 0.0001) and CRP-oxLDL-beta(2)GPI independently predicted SAA (P = 0.002). CONCLUSION: Low-grade inflammation and immune activation occur in thrombotic PAPS and relate to clinical features and aPL levels.

Antibodies toward high-density lipoprotein components inhibit paraoxonase activity in patients with systemic lupus erythematosus.

Patients with systemic lupus erythematosus (SLE) have an increased incidence of vascular disease, and oxidative stress is recognized as an important feature in this condition, despite the underlying mechanisms not being fully understood. In these patients, an interaction between lipoproteins and the immune system has been suggested, but most studies have only looked at antibodies against oxidized low-density lipoproteins. This study was undertaken to determine the presence of antibodies directed against high-density lipoproteins (HDL) and to identify a possible association between these antibodies and paraoxonase (PON), an antioxidant enzyme present in HDL. Plasma from 55 patients with SLE was collected and IgG aHDL and antiapolipoprotein A-I (aApo A-I) antibodies were assessed by enzyme-linked immunosorbent assay. Standardization of the method was performed in a control population of 150 healthy subjects. Plasma levels above 5 standard deviations of the mean of the control population were considered positive. PON activity was assessed by quantification of p-nitrophenol formation (micromol/mL/min). Patients with SLE had higher titers of aHDL (P < 0.0001) and aApo A-I (P < 0.0001) antibodies, and lower PON activity (P < 0.0001) than healthy controls. There was also a direct correlation between the titers of aHDL and aApo A-I antibodies (r = 0.61; P < 0.0001). PON activity was inversely correlated with aApo A-I (P = 0.0129) antibody levels. Anti-HDL and aApo A-I antibodies from patients with high titers were isolated and subsequently incubated with human HDL. These antibodies reduced PON activity up to a maximum of 70.2% and 78.4%, respectively. This study showed the presence of aHDL and aApo A-I antibodies in patients with SLE. These antibodies were associated with reduced PON activity in plasma, and the in vitro inhibition assay confirmed a direct inhibition of the enzyme activity.

Antibodies against beta2-glycoprotein I complexed with an oxidised lipoprotein relate to intima thickening of carotid arteries in primary antiphospholipid syndrome.

To explore whether antibodies against beta2-glycoprotein I (beta2GPI) complexed to 7-ketocholesteryl-9-carboxynonanoate (oxLig-1) and to oxidised low-density lipoproteins (oxLDL) relate to paraoxonase activity (PONa) and/or intima media thickness (IMT) of carotid arteries in primary antiphospholipid syndrome (PAPS). As many as 29 thrombotic patients with PAPS, 10 subjects with idiopathic antiphospholipid antibodies (aPL) without thrombosis, 17 thrombotic patients with inherited thrombophilia and 23 healthy controls were investigated. The following were measured in all participants: beta2GPI-oxLDL complexes, IgG anti-beta2GPI-oxLig-1, IgG anti-beta2GPI-oxLDL antibodies (ELISA), PONa, (para-nitrophenol method), IMT of common carotid (CC) artery, carotid bifurcation (B), internal carotid (IC) by high resolution sonography. Beta2GPI-oxLDL complex was highest in the control group (p < 0.01), whereas, IgG anti-beta2GPI-oxLig1 and IgG anti-beta2GPI-oxLDL were highest in PAPS (p < 0.0001). In healthy controls, beta2GPI-oxLDL complexes positively correlated to IMT of the IC (p = 0.007) and negatively to PONa after correction for age (p < 0.03). PONa inversely correlated with age (p = 0.008). In PAPS, IgG anti-beta2GPI-oxLig-1 independently predicted PONa (p = 0.02) and IMT of B (p = 0.003), CC, (p = 0.03) and of IC (p = 0.04). In PAPS, PONa inversely correlated to the IMT of B, CC and IC (p = 0.01, 0.02 and 0.003, respectively). IgG anti-beta2GPI-oxLig-1 may be involved in PAPS related atherogenesis via decreased PON activity.

Lymphocyte subpopulations and intima media thickness in primary antiphospholipd syndrome.

The aim of this study was to evaluate a possible association between lymphocyte subsets and intima media thickness (IMT) of carotid arteries in primary antiphospholipid syndrome (PAPS). We used a cross-sectional study on PAPS patients (n = 18) and healthy controls (n = 16). IgG anti-cardiolipin antibody (aCL), IgG anti-beta2glycoprotein-I (anti-beta2GPI), IgG anti-beta2glycoprotein-I complexed to oxidized low-density lipoprotein (oxLDL) and to a specific oxidized moiety of LDL (oxLig1), and beta2GPI-oxLDL were measured by ELISA. Lymphocyte immunophenotyping was performed using pairs of monoclonal antibodies directly labelled with fluorescein isothiocyanate, or phycoerythrin or phycoerythrin-Texas-red-X. Intima media thickness (IMT) of carotid arteries was determined by high-resolution sonography. Total peripheral blood lymphocytes did not differ between PAPS and controls. Memory CD4+/CD45RO + T cells were lower in PAPS than controls (P = 0.0007) as well as CD16+56+ natural killer cells (P = 0.02). In PAPS memory T CD45RO + cells positively correlated with IgG anti-beta2GPI-oxLigl (P = 0.002) and to IMT of carotid arteries (common carotid P = 0.02, bifurcation P = 0.007). Naive CD4+/CD45RA+ T cells inversely correlated with beta2GPI-oxLDL (P = 0.009). The relation between IgG anti-beta2GPI-oxLig1 and IMT of carotid arteries with memory CD45RO + T lymphocytes suggests a role for the latter in PAPS related atherogenesis.

Antiphospholipid antibodies are associated with enhanced oxidative stress, decreased plasma nitric oxide and paraoxonase activity in an experimental mouse model.

OBJECTIVE: Oxidative stress contributes to atherosclerosis, and evidence of enhanced oxidative stress exists in antiphospholipid syndrome (APS). In a non-lupus murine model, we evaluated whether anticardiolipin (aCL) antibodies could affect the oxidant/antioxidant balance as an early biochemical step of APS. METHODS: Hybridomas producing human and murine aCL and anti-beta(2)-glycoprotein I (abeta2-GPI) monoclonal antibodies were injected into three groups of five female BALB/c severe combined immunodeficiency (SCID) mice. Corresponding hybridomas secreting non-antiphospholipid antibodies of the same isotype were employed as controls. Sera and organs were collected after 30 days. Paraoxonase (PON) activity, peroxynitrite, superoxide, nitric oxide (NO) and nitrotyrosine were measured in plasma. Expression of endothelial nitric oxide synthase and inducible nitric oxide synthase (iNOS) was assessed by western blot and immunohistochemistry. RESULTS: PON activity and NO (sum of nitrate and nitrite) levels were reduced in the human aCL IgG group (P<0.002 and P<0.04, respectively), whilst peroxynitrite and superoxide and expression of total antioxidant capacity of plasma were increased (P<0.01). PON and NO were decreased in the murine abeta2-GPI IgG and IgM aCL groups (P<0.03 and P<0.05, respectively). Nitrotyrosine was elevated in the human aCL IgG group (P<0.03). Western blotting showed reduced iNOS expression in the hearts of the IgG aCL group, confirmed by immunostaining. PON inversely correlated with IgG aCL titres (P<0.001), superoxide (P<0.008) and peroxynitrite levels (P<0.0009). Peroxynitrite and total IgG aCL were independent predictors of PON (P<0.0009 and P<0.02, respectively). Superoxide was the only independent predictor of NO (P<0.008) and of nitrotyrosine (P<0.002). CONCLUSION: aCL antibodies are associated with the decreased PON activity and reduced NO that may occur in the preclinical phase of APS.

Premature atherosclerosis in primary antiphospholipid syndrome: preliminary data.

OBJECTIVE: To investigate the atherosclerosis hypothesis in primary antiphospholipid syndrome (PAPS). METHODS: The intima media thickness (IMT) of carotid arteries and other cardiovascular risk factors was measured in 20 patients with PAPS (mean (SD) age 35 (12) years) and in 20 controls matched for age and sex (34 (12) years). RESULTS: The frequency of smoking, hypertension, and dyslipidaemia was similar in the two groups, but plasma homocysteine was higher in patients with PAPS (mean (SD) 11.9 (6.2) v 8.2 (3.4) micromol/l, p = 0.037). The IMT was slightly greater in patients with PAPS than in controls at the carotid bifurcation (mean (SD) 0.61 (0.24) v 0.48 (0.09) mm, p = 0.04) and internal carotid artery (0.52 (0.22) v 0.40 (0.08), p = 0.01). These differences were more evident in patients aged >40 years than in those aged <30 years at the carotid bifurcation (0.76 (0.25) v 0.55 (0.06), p = 0.0007) and internal carotid artery (0.63 (0.25) v 0.45 (0.09), p = 0.02); no differences were seen in the younger age group compared with controls. CONCLUSION: Atherosclerosis is a possibility in patients with PAPS in their fourth decade of life or older.