Effects of type II collagen epitope carbamylation and citrullination in human leucocyte antigen (HLA)-DR4(+) monozygotic twins discordant for rheumatoid arthritis.

The aim of this study is to investigate the effect of the native, citrullinated or carbamylated type II human collagen T cell- and B cell-epitopes on the adaptive immune response in rheumatoid arthritis (RA). Peripheral blood T and B cells obtained from a human leucocyte D4-related (antigen DR4(-) HLA-DR4)(+) woman with early RA, her healthy monozygotic twin and an unrelated HLA-DR3(+) woman with early RA were analysed for activation (CD154/CD69), apoptosis (annexin/7-aminoactinomycin), cytokine production [interferon (IFN)γ/interleukin (IL)-17/IL-4/IL-10/IL-6] and functional phenotype (CD45Ra/CCR7) after stimulation with the collagen native T cell epitope (T261-273), the K264 carbamylated T cell epitope (carT261-273), the native B cell epitope (B359-369) or the R360 citrullinated B cell epitope (citB359-369), and the combinations of these. The T cell memory compartment was activated by T cell epitopes in both discordant DR4(+) twins, but not in the DR3(+) RA. The collagen-specific activation of CD4(+) T cells was induced with both the native and carbamylated T cell epitopes only in the RA twin. Both T cell epitopes also induced IL-17 production in the RA twin, but a greater IL-4 and IL-10 response in the healthy twin. The citrullinated B cell epitope, particularly when combined with the carbamylated T cell epitope, induced B cell activation and an increased IL-6/IL-10 ratio in the RA twin compared to a greater IL-10 production in the healthy twin. Our data suggest that circulating collagen-specific T and B cells are found in HLA-DR4(+) subjects, but only RA activated cells express co-stimulatory molecules and produce proinflammatory cytokines. Carbamylation and citrullination further modulate the activation and cytokine polarization of T and B cells.

Gamma-delta T lymphocytes and 25-hydroxy vitamin D levels as key factors in autoimmunity and inflammation: the case of zoledronic acid-induced acute phase reaction.

Zoledronic acid (ZA) infusion for osteoporosis is frequently associated with the onset of an acute phase reaction (APR) secondary to the activation of γδ T cell receptor (TCR) lymphocytes (γδ T cells) and to low vitamin D levels, similar to what is observed in chronic inflammation and autoimmunity. In this study we investigated whether the phenotype of γδ T cells is associated with APR and 25-OH vitamin D (25-OHvD) levels. For flow-cytometry analysis, peripheral blood samples were obtained from 52 osteoporotic women prior to 5 mg ZA intravenous infusion and from nine women (five with APR) one week later. Twenty-six/52 (50%) patients reported APR and APR+ cases had a higher percentage of central memory Th1-like γδ T cells. One week after ZA infusion, APR was associated with a decreased percentage of central memory Th1-like γδ T cells, an increase in the percentage and activation of effector memory Th1-like γδ T cells, and an increase in Th17-like γδ T cells. Lower 25-OHvD levels were significantly associated with APR, but no correlation was found between 25-OHvD level and γδ T cell percentage or subsets. In conclusion, patients experiencing APR related to ZA infusion have lower 25-OHvD levels and we suggest that the higher percentage of central memory Th1-like γδ T cells and the expansion of effector memory Th1-like and Th17-like γδ T cells are associated with the occurrence of APR.

Statins and cardiovascular risk in rheumatic diseases.

Chronic inflammatory rheumatic diseases are associated with an increased risk of cardiovascular (CV) atherosclerotic events. The inflammatory state, which is the hallmark of chronic rheumatic diseases, is the important driving force for accelerated atherogenesis. Since the control of traditional risk factors alone is insufficient in reducing the risk, much attention has been directed towards the potential use of statins. Statins, a family of drugs that suppress cholesterol biosynthesis by inhibiting the hydroxymethyl glutaryl coenzyme A reductase, have been shown to significantly reduce CV-related morbidity and mortality. In addition to lower lipid levels, several non-lipid lowering pleiotropic effects, including anti-inflammatory and immunomodulatory activities, make statins potential therapeutic agents in chronic rheumatic diseases. However, lipid metabolism in chronic rheumatic diseases is complex, since inflammatory states can induce alterations in lipid levels and function, so that cholesterol target levels from general guidelines may not be adequate in chronic inflammatory rheumatic diseases. Larger trials are needed to refine the precise benefits and health-utility associated with this therapy.

Baseline characteristics of the population enrolled in the Italian Observational Study on Severe Osteoporosis (ISSO).

OBJECTIVES: Baseline characteristics of the population enrolled in the ISSO study, designed to evaluate the incidence of vertebral and non-vertebral fractures in Italian patients with severe osteoporosis treated according to clinical practice over 24 months observation. METHODS: Prospective observational study in 783 post-menopausal women and men entering 18-month treatment with teriparatide in a community setting at 57 centres in Italy. Characterisation included demographics, fracture risk factors, bone mineral density, fracture status, Health-Related Quality of Life (HRQoL) measured by the European Quality of Life Questionnaire, EQ-5D, and back pain assessed by VAS. RESULTS: Most patients were elderly women (90.5%), mean age±SD was 72.9±8.8 years. Nearly all (91.3%) had experienced ≥ 1 vertebral fracture (mean±SD, 3.6±2.2 per patient), 37.5% had ≥ 1 non-vertebral fracture (mean±SD, 1.4±0.7 per patient). Nearly all patients were suffering from back pain (94.9%), which had significantly restricted their daily activities (51.7%) and had likely or very likely been caused by vertebral fractures (29.2% and 55.8%, respectively). Mean EuroQoL EQ-5D index value was 0.58±0.25 and VAS score 49.2±23.6. Non-vertebral fractures, back pain and multiple vertebral fractures were associated with lower HRQoL (EuroQoL-5D Index both p<0.001, EQ-5D VAS score p=0.025 and p<0.016, respectively). Many patients were physically inactive (81.1%). One third (34.7%) of population had co-morbidities and 60.5% were on chronic concomitant treatments. Few subjects reported a maternal history of osteoporosis (15.5%), regular consumption of alcohol (13.3%) or were current smokers (11.5%). Nearly two-thirds (71.5%) had already been treated for osteoporosis, mainly with bisphosphonates. Calcium and vitamin D supplements were taken by 13% and 15.5% of the total population, respectively. CONCLUSIONS: At enrollment, the population of ISSO study mostly consisted in aging women, who had osteoporosis with high fracture risk, poor HRQoL and suffered from significant back pain. Most of them had already been treated by bisphosphonates but without calcium and vitamin D supplements. Back pain, as well as non-vertebral and multiple vertebral fractures, were associated with lower HRQoL.

Systemic sclerosis and cancer.

To review recent advances and current controversies on the association between systemic sclerosis (SSc) and cancer, PUBMED was searched from 1966 to the present using the terms: systemic sclerosis, cancer, morphoea, sclerotic diseases. Malignancies, mainly in lung and breast, coexist with idiopathic SSc or with SSc-like disorders, but not with localized forms of scleroderma (morphoea), with the exception of squamous cell carcinoma in patients with pansclerotic morphoea and skin ulcers. The mechanisms connecting SSc and malignancies are unknown. The occurrence of different cancer types with SSc or SSc-like disorders suggest different underlying mechanisms, including altered immune response, common genetic and environmental links, disease-dependent factors, tumor-derived biologic substances and therapies. The process of sclerosis itself may favour cancer in certain sites, and a reaction between T cells and neoantigens formed during irradiation has been suggested to explain the frequent development of morphoea after breast irradiation. Radiotherapy, especially when used for breast cancer, may trigger idiopathic SSc or morphoea and influence the severity of preexisting SSc, with the consequence that SSc is considered a relative contraindication to breast radiotherapy. In conclusion, cancer and SSc may be associated, but it is still controversial as to whether there is a causal relationship. Continuing interest in these associations, in particular in the different modalities of associations, may help to understand the underlying biological mechanisms and to identify patients at risk.

The safety of anti-TNF agents in the elderly.

Rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis are commonly thought of as inflammatory diseases that affect younger individuals. Although the initial presentation of these diseases is common in a patients twenties or thirties, they usually persist for the duration of the patients life. In addition, up to one-third of patients with RA have disease onset after 60 years of age. Anti-TNF-a therapies now have well-recognized safety profiles that have been demonstrated in the usual clinical trial populations for these diseases, but such populations under-represent patients > or =65 years of age. This retrospective study aims to determine the safety profiles for etanercept, infliximab and adalimumab in patients of 65 years or more, undergoing anti-TNF treatment for an active inflammatory disease such as rheumatoid arthritis, ankylosing spondylitis or psoriatic arthritis, or skin disease like psoriasis. Our data show that admitting elderly patients into anti-TNF therapeutic regimens is a safe option and that it grants these patients access to the best current therapeutic option, possibly leading to better disease outcome. Quality of life in elderly patients affected by arthritis or psoriasis, often reduced by comorbidities, is as important as quality of life in younger patients. Applying the recommended screening before using biological treatment helps to reduce adverse events related to the therapy, and the application of the same screening in elderly patients seems to lead to comparable results.

Successful treatment with etanercept of a patient with psoriatic arthritis after adalimumab-related hepatotoxicity.

Inhibitors of tumor necrosis factor (TNF) alpha (infliximab, etanercept, adalimumab) are nowadays widely used for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS), not responding to conventional therapies. Anti-TNF alpha drugs have demonstrated great efficacy in slowing the disease, however, to date, concern still remains regarding acute and long-term toxicity related to TNF block. Increase in liver tests may be observed during treatment with anti-TNF agents, more often related to concomitant drugs (i.e. NSAIDS, methotrexate) or to reactivation of chronic HBV or HCV infections. However, liver damage directly induced by the drug has been described in patients treated with infliximab or adalimumab. To our knowledge, no cases of liver injury closely related to etanercept have been reported so far. We report the case of a patient with PsA who presented liver dysfunction during adalimumab, subsequently successfully treated with etanercept.

Myocardial involvement in systemic sclerosis.

OBJECTIVE: To identify clinical and/or laboratory characteristics that could be risk factors for myocardial microvascular involvement in patients with SSc. METHODS: Twenty-one SSc patients, clinically silent for cardiovascular disease, were consecutively evaluated for myocardial perfusion defects through 99m-Tc sestamibi gated myocardial perfusion SPECT with a stress-rest protocol. RESULTS: Eight patients (38%) had myocardial perfusion defects. Perfusion defects were related to skin scores (P < 0.0001), digital ulcers (P = 0.02) and oesophageal involvement (P = 0.046). A trend for anti-Scl 70 antibody positivity was observed in these patients (P = 0.09). Three SPECT-positive patients had re-establishment of normal myocardial perfusion after a course of prostanoid therapy. There were no significant associations between myocardial involvement and age, sex, diffuse/limited SSc, duration of RP or lung involvement. CONCLUSIONS: Myocardial perfusion defects in SSc patients are frequent, and the presence of severe skin thickness, digital ulcers and perhaps oesophageal involvement might warrant screening for myocardial involvement. Further studies are necessary to evaluate the effect of prostanoid therapy on myocardial perfusion.

Interstitial lung disease in systemic sclerosis.

Interstitial lung disease is an early and serious complication of systemic sclerosis (SSc). Because it may be asymptomatic for a long period, and only the early flogistic phase is at present susceptible to treatment, early diagnosis and identification of risk are critical to the outcome. However, identifying SSc patients at risk for developing interstitial lung disease is at present difficult; therefore, a strict monitoring of the disease, especially in the first years, is mandatory. Treatment strategy is aimed at suppressing inflammation. Unfortunately, optimal therapy has not yet been established. Combination of corticosteroids and cyclophosphamide is considered the best therapeutic approach available so far, but doses and duration of treatment need to be determined. Future research should focus on new anti-inflammatory or immunosuppressive agents.

[Pulmonary hypertension in autoimmune rheumatic diseases]. / L'ipertensione polmonare nelle malattie reumatiche autoimmuni.

OBJECTIVE: Pulmonary hypertension is a severe and rapidly progressive disease, particularly frequent in patients with rheumatic diseases. The aims of this study were the following: to determine the prevalence of pulmonary hypertension in Italian patients with autoimmune rheumatic diseases, and to evaluate if the presence of a rheumatic disease in general, or of a specific autoimmune rheumatic disease, is a risk factor for the development of pulmonary hypertension. PATIENTS AND METHODS: One hundred and thirteen Italian patients with connective tissue diseases (105 females, 8 males), aged 19 to 83 yrs, entered the study. Fifty-one had systemic sclerosis (SSc): 49 were females, 2 males, aged 34 to 83 yrs; 41 had limited cutaneous SSc, 8 diffuse cutaneous SSc, and 2 SSc sine scleroderma. Thirty-three patients had systemic lupus erythematosus (SLE): all but one were females, their age ranged from 19 to 82 yrs. Twenty-five had rheumatoid arthritis (RA): 21 females, 4 males, aged 26 to 45 yrs. Three females and one male, 51-77 yrs, had mixed connective tissue disease (MCTD). Systolic pulmonary arterial pressure (SPAP) was assessed by Doppler echocardiography. RESULTS: Twenty three patients had pulmonary hypertension, which was more frequent in MCTD than in SLE (75% vs 6.1%, p=0.0002) or in AR (20%, p=0.0313). Pulmonary hypertension was more frequent in SSc than in SLE (25.5% vs 6.1%, p=0.0028) and in limited than in diffuse SSc (21.6% vs 3.9%). SPAP was significantly related to age (r=0.35, p=0.0275), with patients with pulmonary hypertension older than patients with normal SPAP (66+/-13 vs 52+/-16 yrs, p=0.0003). CONCLUSIONS: These data show a significant association between pulmonary hypertension and autoimmune rheumatic diseases. Therefore, pulmonary hypertension assessment seems mandatory, at least in MCTD and SSc. However, more studies are needed to clarify the relationship between age and pulmonary hypertension and to verify whether the low prevalence of pulmonary hypertension we found in our SLE patients is related or not to their lower age.

Scleroderma heart disease.

Heart disease is a frequent and often severe feature of systemic sclerosis (scleroderma). Cardiomyopathy, with ventricular diastolic dysfunction and arrhythmias, is the most important form, since it is associated with a very poor prognosis. The current challenge is to define its pattern and identify individuals at risk, but evaluation in vivo may be hard to perform. The aim of this review is to provide an update on the clinical aspects of scleroderma heart disease and the early pivotal role that coronary microcirculation dysfunction plays in its development. A discussion of the diagnostic tools now available for this frequently asymptomatic condition will be provided. Treatment options will be reviewed, even though no cure for systemic sclerosis exists, and the current therapy of diastolic dysfunction remains unsatisfactory.

Comparison between iloprost and alprostadil in the treatment of Raynaud's phenomenon.

OBJECTIVE: The prostanoids iloprost and alprostadil are widely used to treat ischaemic changes in patients with Raynaud's phenomenon (RP), but the optimal regimen is poorly defined. We evaluated whether there are differences between iloprost and alprostadil, in terms of either clinical efficacy or of laboratory data, with the aim of assisting in the treatment of connective tissue disease (CTD)-associated RP. METHODS: Twenty-one women with CTD-associated RP were given intravenous iloprost (11 patients) or alprostadil (10 patients) cyclically (5 consecutive days, followed by 1 day every 30 days). Clinical efficacy (RP symptoms, skin score, digital ulcers) and circulating levels of von Willebrand factor (VWf), tissue plasminogen activator (tPA), thrombomodulin (TM) and Type III procollagen N-terminal propeptide (PIIINP) were evaluated by enzyme-linked immunoassay at different intervals. RESULTS: The overall benefits of iloprost and alprostadil were similar. RP improved in 45% versus 90% of patients; ulcers in 60% versus 40% of patients (iloprost versus alprostadil). Skin score did not significantly change with either drug. Circulating VWf decreased with either drug (iloprost -6.2%, alprostadil -9.4%), while tPA, TM, and PIIINP remained unchanged. Side effects were only minor and less frequent with alprostadil. CONCLUSION: Iloprost and alprostadil were both of benefit in CTD-associated RP, without significant differences in either clinical efficacy or circulating markers. However, ease of handling and the lower price favours alprostadil.

Problems of drug surveillance--an international view.

The importance of Post Marketing Surveillance (PMS) is stressed, both to determine the therapeutic value of the drug and its adverse effects revealed in a large population of patients. A survey of such adverse effects of anti-epileptic drugs is provided: metabolic, dose-related and idiosyncratic. Problems of monotherapy and of drug interactions are discussed, as well as questions of central nervous system toxicity and of teratogenicity.

Effects of GM1 ganglioside in cerebrovascular diseases: a double-blind trial in 40 cases.

A randomized, double-blind trial on the effects of GM1 ganglioside in cerebrovascular diseases was done on 40 patients; the treatment (40 mg/day i.m. injection) began after the acute phase and lasted 6 weeks. 18 cases took the drug and 16 the placebo. The evaluation of the cases was made by graduating the severity of the clinical signs, and some neurophysiological and morphological parameters, i.e., EEGs, flash-evoked potentials and computer tomography scans. We found that the drug, in comparison with the placebo treatment, improved the clinical signs and also the neurophysiological parameters, whereas it was ineffective for the morphological damage. These data seem of some interest in relation to the action of GM1 ganglioside in the processes of neurotransmission and neuronal plasticity as described in the experimental animal.

[Physiopathology of neurotransmitter metabolites in the cerebrospinal fluid in brain tumors]. / Fisiopatologia dei metaboliti liquorali dei neurotrasmettitori nei tumori cerebrali.

The results in the group of III ventricle tumors, that is a decrease in the ventricular concentration of 5-HIAA in CSF, show that the hypothalamic metabolism of 5-HT is of importance for the concentration of 5-HIAA in the CSF. The results in posterior fossa tumors and in non communicating hydrocephalus (non tumor patients) for 5-HIAA and HVA confirm that the reabsorption of the metabolites from CSF occurs mainly in the caudal region of the ventricular system: the data in communicating hydrocephalus demonstrate that the intracranial hypertension can interfere by itself with the out transport mechanism of the metabolites from CSF. The results in normotensive idiopathic hydrocephalus sustain the hypothesis of a disturbance in 5-HT metabolism: it seems possible to separate this group from patients with secondary hydrocephalus in which the intracranial hypertension is only clinically compensated. The results in lumbar determinations demonstrate that in intracranial hypertension there is an impairment of the reabsorption of 5-HIAA also in the lumbar subarachnoid spaces. The concentration of 5-HIAA can depend mainly on the spinal cord metabolism, while lumbar HVA derives from the brain metabolism.