Central nervous system involvement in HCV-related mixed cryoglobulinemia.

An involvement of the peripheral nervous system is frequent in patients with HCV-related mixed cryoglobulinemia (HCV-MC), whereas central nervous system (CNS) impairment has been rarely reported. To investigate the possible CNS involvement in MC, we evaluated 18 patients by neurophysiological, neuroradiological and neuropsychological methods. Three patients (16.7%) had clinically evident neurological central signs, ten (55.5%) complained of mild symptoms, possibly indicative of CNS impairment, and five (27.8%) did not have any CNS symptom. Evoked potentials (EPs) were abnormal in 83% of the cases (SSEPs in 72%, VEPs in 44%, MEPs in 39% and BAERs in 22%). Brain magnetic resonance imaging (MRI) showed abnormal findings in 83% (small T2-weighted hyperintense lesions in 72%, focal or diffuse atrophy in 50%). Cognitive impairment was detected in 22% of the patients. A mild or subclinical CNS involvement is frequent in MC patients. Neuropsychological, neurophysiological and neuroradiological examination are useful to detect CNS involvement also in asymptomatic subjects.

Takayasu's arteritis: A study of 104 Italian patients.

OBJECTIVE: Takayasu's arteritis (TA) is a rare vasculitis. The Italian Takayasu's Arteritis study group was established with the aim to describe a large cohort of patients. METHODS: Data were collected by means of an ad hoc form. Demographic information, clinical history, vascular findings, treatment, risk factors, and comorbidities were analyzed. RESULTS: Data of 104 patients were collected. The median delay in diagnosis was 15.5 months (range 0-325 months). Age at onset <15 years was associated with a higher probability, whereas elevated erythrocyte sedimentation rate with a lower probability, of a delay in diagnosis. The majority of patients experienced nonspecific signs and symptoms indicative of an inflammatory disease in the early phase. Among vascular involvement, stenosis was the most frequent lesion, being present in 93% of patients, followed by occlusion (57%), dilatation (16%), and aneurysm (7%). Glucocorticoids were the mainstay of treatment in our series; however, treatment with cytotoxic agents was required in about half of the patients. Fifty-two patients underwent at least 1 surgical procedure. The main indications for intervention were renal vascular hypertension, cerebral hypoperfusion, and limb claudication. CONCLUSION: As with many rare diseases, delay in diagnosis is an important issue for patients with TA. The increasing occurrence of vascular lesions along with the disease progression put to question the long-term effectiveness of contemporary treatment. These data may be helpful in increasing physicians' awareness to prevent diagnosis delay, update guidelines, and plan future research projects.

Clinical and serological associations of ribosomal P autoantibodies in systemic lupus erythematosus: prospective evaluation in a large cohort of Italian patients.

OBJECTIVE: To verify the association of ribosomal anti-P antibodies (anti-P), as detected by a sensitive ELISA, with serological findings and clinical manifestations, including neuropsychiatric involvement evaluated according to the American College of Rheumatology (ACR) nomenclature, in a large cohort of patients with systemic lupus erythematosus (SLE). METHODS: Anti-P were evaluated in the serum of 149 consecutive Italian SLE patients by an ELISA using a multiple antigen peptide carrying four copies of a common P0, P1 and P2 epitope. A complete laboratory evaluation and clinical examination were performed in each patient. In addition, all patients underwent an accurate neuropsychiatric and neuropsychological assessment performed by trained specialists according to the 1999 ACR suggestions. RESULTS: Serum anti-P were detected in 18/149 patients (12.1%). The anti-P prevalence was similar (11.7%) when the analysis was performed in a larger series of sera including 82 additional SLE patients, who were not included in the clinical study. The age of anti-P-positive patients at disease onset was less than 33 yr and, in comparison with the anti-P-negative patients, these patients showed more active disease activity and a higher prevalence of photosensitivity and malar and discoid rash. A strong association between IgG anticardiolipin antibodies and anti-P was also found. However, anti-P were associated with neither neuropsychiatric syndromes nor cognitive impairment. CONCLUSION: This study does not seem to confirm the described association of anti-P with SLE neuropsychiatric manifestations. However, it supports the anti-P association with different skin manifestations as well as the presence of anticardiolipin in a subset of patients with SLE characterized by early disease onset.

Ventilation-perfusion lung scan for the detection of pulmonary involvement in Takayasu's arteritis.

The aim of study was to analyse ventilation and perfusion (V/Q) lung scan findings in a series of Italian patients with Takayasu's arteritis. Eighteen consecutive patients underwent V/Q lung planar scintigraphy and single-photon emission tomography (SPET). Before perfusion scan acquisition was started, a first-pass study with (99m)Tc-macroaggregates of albumin was performed to assess the right ventricular ejection fraction (RVEF). All patients had normal chest X-rays and were symptom free at the time of the investigation. They also underwent echocardiography to evaluate pulmonary artery pressure and in 13 patients respiratory function tests were performed. In four patients, perfusion lung scan was repeated after 1 year. In 10/18 patients (55.5%), 43 unmatched lobar, segmental or subsegmental perfusion defects were found on planar images; ventilation scintigraphy was normal in all cases. On SPET images, 55 defects were found; no defects were found with SPET in the remaining patients who had normal planar images. All patients had normal RVEF and 5/13 patients had mild restrictive-obstructive lung disease. The pulmonary artery pressure was increased in two patients with perfusion defects. In the four patients who had repeat scintigraphy, all defects remained unchanged. The prevalence of lung perfusion abnormalities observed in Italian patients with Takayasu's arteritis is within the range of values reported in other countries, and V/Q planar scintigraphy is sufficient for the screening of patients.

Effects of long-term cyclic iloprost therapy in systemic sclerosis with Raynaud's phenomenon. A randomized, controlled study.

OBJECTIVE: Iloprost is a stable prostacyclin analogue which has been shown to be effective in the short-term symptomatic treatment of Raynaud's phenomenon (RP) secondary to systemic sclerosis (SSc). The aim of this study was to evaluate the effects of long-term cyclic therapy with iloprost in comparison with nifedipine on the skin score, pulmonary function and Raynaud's severity score in patients with SSc and RP. METHODS: We conducted a 12-month prospective, randomised, parallel-group, blind-observer trial to compare the effects of intravenously infused iloprost (2 ng/kg/min on 5 consecutive days over a period of 8 hours/day and subsequently for 8 hours on one day every 6 weeks) with those of conventional vasodilating therapy with nifedipine (40 mg/day for os) in 46 patients with SSc and RP. RESULTS: At 12 months, iloprost but not nifedipine reduced the skin score (iloprost: from 13.26 +/- 2.05 to 9.26 +/- 1.32, p = 0.002; nifedipine: from 10.83 +/- 2.09 to 12.17 +/- 3.02, p = n.s.; iloprost vs nifedipine: p = 0.016) and the RP severity score (iloprost: from 2.17 +/- 0.2 to 1.22 +/- 0.13, p = 0.02 vs baseline; nifedipine: from 2.08 +/- 0.34 to 1.33 +/- 0.22, p = n.s.). Carbon monoxide diffusing capacity (DLCO), expressed as % of the predicted normal value, worsened significantly in the nifedipine group (from 69.6 +/- 7.4% to 61.5 +/- 6.5%, p = 0.044) and remained stable in patients treated with iloprost (from 53.2 +/- 4.8 to 56.0 +/- 4.6%, iloprost vs nifedipine: p = 0.026). CONCLUSION: In SSc patients, cyclic intravenous iloprost infusion is able to control vasospastic disease. Our results suggest that it might also act as a disease-modifying agent, as it seems to improve the course of the disease. Further studies principally focused on organ involvement and the natural history of the disease are needed to confirm our results.

Takayasu's arteritis: a changing disease.

Takayasu's arteritis (TA) is a chronic, giant-cell vasculitis of unknown etiology, which primarily involves the aorta, its main branches and coronary and pulmonary arteries. This review focuses on the epidemiological, diagnostic, and clinical aspects of the disease, which have been changed since the first description made by Mikito Takayasu in 1908. The article also summarizes the data collected by the Italian Registry of TA in the period 1993-1998.

Severe polyneuropathy in a patient with Churg-Strauss syndrome.

We describe the clinicopathologic features of a 56-year-old woman affected with Churg-Strauss syndrome with major peripheral nerve involvement. The patient presented with a 1-month history of mainly distal upper-limb symmetrical paresthesias and hypostenia (bilateral "wrist drop"), palpable purpura and eosinophilia. Multiple pulmonary infiltrates and asthma had been present since the age of 52. Skin biopsy demonstrated an eosinophilic necrotizing vasculitis. During the hospitalization she was submitted to cardiac, bronchopulmonary, renal, and gastrointestinal evaluation and EMG. Peripheral nerve and skeletal muscle biopsies were performed. Sural nerve biopsy showed a marked degree of demyelination. A perivascular cellular infiltrate within the epineurium was immunoreactive for T lymphocytes and macrophages. Strong HLA-DR immunostaining was present in the endoneurium. IgM, IgE and fibrinogen deposition was found in some epi- and endoneurial vessels. Muscle biopsy showed neurogenic changes and 1 thrombosed vessel surrounded by mononuclear cells. Membrane attack complex (MAC) deposition was present in a few capillaries and major histocompatibility complex products I (MHCP I) was expressed at the subsarcolemmal level in a few isolated perivascular muscle fibers. After immunosuppressive therapy, the patient showed progressive improvement of both clinical symptoms and neurophysiological parameters.

Five-year follow-up of 165 Italian patients with undifferentiated connective tissue diseases.

OBJECTIVE: To study those conditions with a proven or hypothesised immunologic pathogenesis and denominated under a working definition of undifferentiated connective tissue diseases (UCTD). METHODS: A multicentre prospective study was organised involving 10 tertiary referral centers of internal medicine in Italy, with the aim of describing the natural history of UCTD and the prevalence of its different clinical and immunological manifestations. RESULTS: After a five-year follow-up period, data on 165 patients were available for analysis. UCTDs occur mainly in females in their fourth decade of life. Articular and mucocutaneous features and Raynaud's phenomenon represent the most common findings. Nevertheless, we also detected a relatively high incidence of permanent major organ damage. Regarding the immunologic parameters, we documented some conflicting results in the correlation between serologic abnormalities and clinical features. In 10 patients UCTD evolved to a major disease, generally systemic lupus erythematosus or Sjögren's syndrome. CONCLUSION: A low rate of evolution to a defined autoimmune disease, the limited use of steroid or immunosuppressive therapy, and a favourable course in the majority of cases are the main characteristics of patients with UCTDs.

Non-invasive assessment of pulmonary artery involvement in Takayasu's arteritis.

OBJECTIVE: To evaluate pulmonary involvement in Italian patients with Takayasu's arteritis (TA). METHODS: A prospective analysis of 15 Italian patients with TA was carried out, including evaluation by perfusion and ventilation lung scintigraphy (planar and tomographic), standard chest X-ray, spirography and color-doppler echocardiography. All the patients were free of respiratory symptoms when examined. RESULTS: In all patients standard chest X-rays and ventilation scintigraphies were normal. 9/15 patients showed unmatched segmental perfusion defects (41 by planar evaluation vs. 48 by SPET). The number of defects was greater in the right lung than in the left (26 vs 18), with a higher frequency of moderate or large defects. Thirteen patients underwent spirography, which proved to be abnormal in 5 cases. Two of these patients were also positive on scintigraphy. No patient showed alterations attributable to TA on color-doppler echocardiography, except for 3 patients with mild to moderate aortic valve regurgitation. CONCLUSIONS: Our results show that vascular pulmonary involvement is frequent in TA (60% of cases) even in the absence of clinical signs. The planar image, simpler than the SPET to acquire, was sufficient to make an accurate diagnosis. Italian patients seem to show a pattern of extrapulmonary and pulmonary vascular involvement very similar to that reported in Japanese subjects, and different from that observed in other ethnic groups.

Central nervous system involvement in systemic lupus erythematosus patients without overt neuropsychiatric manifestations.

OBJECTIVE: To verify whether features of CNS involvement can be detected in SLE patients without overt neuropsychiatric manifestations. METHODS: 114 SLE patients who had never received a diagnosis of neuropsychiatric lupus (never-NPSLE) were studied and compared to 65 SLE patients with known neuropsychiatric involvement (NPSLE). The study relied on evaluation of neurocognitive functions by means of a battery of neuropsychological tests, on psychiatric and neuropsychological assessments and on neuroimaging studies (computed tomography, magnetic resonance, single photon emission computed tomography (SPECT)). RESULTS: Clinical features, including disease duration/activity and pharmacological therapy, of never-NPSLE and NPSLE patients were similar. Short-term and long-term memory, visuo-spatial and verbal information processing were similarly compromised in never-NPSLE and in NPSLE patients; only attention was significantly more compromised in NPSLE patients. Psychiatric morbidity was higher than expected in never-NPSLE patients, although less than in the control neuropsychiatric group. Ischemic lesions, multiple small high intensity lesions and cortical atrophy, detected by CT and MR scans, as well as abnormal SPECT were also frequently detected in never-NPSLE patients. Interestingly, left parietal and occipital area hypoperfusion by SPECT was significantly more frequent in the patients with impaired visuo-spatial intelligence and short-term memory. CONCLUSIONS: Most abnormalities detected by available diagnostic tools and characteristics of neuropsychiatric SLE are also present in non-symptomatic patients. They may derive from an unexpected widespread involvement of the CNS and are not per se sufficient, in the absence of clinical manifestations, for a diagnosis of neuropsychiatric SLE.

Hepatitis C virus genotypes and clinical features in hepatitis C virus-related mixed cryoglobulinemia.

Mixed cryoglobulinemia is a systemic disease, almost always associated with hepatitis C virus infection and characterized by purpura and cutaneous vasculitis, asthenia, arthralgias, and often renal and neurological involvement. No significant differences have been described to date in mixed cryoglobulinemia patients with type 1, 2, or 3 hepatitis C virus infection with respect to symptoms, while a higher prevalence of genotype 2a has been reported in patients without clinical and biochemical signs of liver disease or with serum autoantibodies. We examined 33 hepatitis C virus-positive patients with mixed cryoglobulinemia to assess if any clinical or serological feature is related to infection with different genotypes. All subjects underwent viral genotype determination by means of a single-step polymerase chain reaction. Thirteen patients (39%) were infected with hepatitis C virus type 1b, 17 (52%) with type 2a or 2a/c, and 3 (9%) with type 3. There was a significant difference in the frequency of peripheral nervous system involvement: paresthesias or other symptoms of peripheral neuropathy were less frequent in patients with 2a or 2a/c infection (29%) than in patients with type 1b or type 3 infection (88%, P = 0.003). Only patients with hepatitis C virus type 2 had urticaria or cutaneous ulcers. These patients also had a lower frequency of arthralgias, lower cryocrit values (P = 0.02), and lower serum levels of alanine-aminotransferase and gamma-glutamyl-transpeptidase (P < 0.04) than patients with type 1 and type 3 infection. The prevalence of antinuclear antibody positivity was similar in the three groups.

Central nervous system involvement in patients with HCV-related cryoglobulinemia.

Central nervous system involvement was rarely described in patients with mixed cryoglobulinemia (MC). Most cases were reported before 1991, so these patients were not tested for hepatitis C virus (HCV) infection. However, two cases of cerebral ischemia in patients with HCV-related MC were recently reported. We describe three patients with chronic HCV and cryoglobulinemia, who complained of mild neurologic symptoms (dizziness, equilibrium impairment, monolateral hyposthenia, and defective sensitivity) which can be ascribed to central nervous system involvement. In all of these patients, brain magnetic resonance imaging showed multiple small hyperintensities compatible with ischemic lesions.

Second line chemotherapy with ifosfamide as outpatient treatment for advanced bladder cancer.

We have carried out a phase II study in advanced or metastatic transitional cell carcinoma of the bladder. Eligible patients had unresectable bladder cancer, previously treated with one line of systemic chemotherapy. Treatment consisted of ifosfamide 1000 mg/sm in a 2-hour infusion for 5 consecutive days from d.1 to d.5. Mesna was administered intravenously at a 20% of the ifosfamide dosage before ifosfamide and orally at 40% after 4 and 8 hours from the ifosfamide infusion. Twenty patients entered the study and received a total of 62 cycles: the treatment resulted feasible on an outpatient basis, with mild toxicity. Only one partial response was observed. With this dose and schedule, ifosfamide appeared less effective than in a previous report at higher doses. Toxicity was acceptable.

Intensified M-VEC chemotherapy with G-CSF support as outpatient treatment for advanced bladder cancer.

The M-VAC regimen (methotrexate, vinblastine, doxorubicin and cisplatin) is widely used in the treatment of advanced or metastatic bladder cancer. In the present trial, an alternate week regimen of M-VEC (with epidoxorubicin instead of doxorubicin) supported by G-CSF (filgrastim) was evaluated. Eligible patients had metastatic or surgically unresectable bladder cancer, not previously treated with systemic chemotherapy. Treatment consisted of methotrexate 30 mg/m2 day 1, vinblastine 3 mg/m2 day 2, epidoxorubicin 60 mg/m2 day 2 and cisplatin 35 mg/m2 days 2 and 3. G-CSF was administered s.c. at the dose of 300 mcg from day 4 to day 11: the treatment was repeated every 2 weeks for six cycles. Twenty-one patients entered the study, and 19 received more than 1 cycle: 78.9% were able to receive full doses of M-VEC as scheduled. The treatment resulted feasible on an outpatient basis, with mild toxicity. Three complete responses (15.8%) and 9 partial responses (47.4%), with an overall objective response rate of 63.2%, were observed.

Differential effects of cyclo-oxygenase pathway metabolites on cytokine production by T lymphocytes.

Cyclo-oxygenase pathway metabolites released in the microenvironment by activated platelets and endothelial cells are potential local modulators of the immune response. In the present study, we have investigated the modulatory role of PGE2, iloprost (prostacyclin analogue), U-46619 (thromboxane analogue) on the release of IL-2, IFN-gamma, TNF-alpha and IL-6 by T lymphocytes. Our results show that PGE2 and prostacyclin differ in the regulation of cytokine production. PGE2 inhibited the release of IL-2 and IFN-gamma, while iloprost did not affect their production. The addition of PGE2 or iloprost greatly decreased the amount of TNF-alpha measured in the supernatants, although the rates of inhibition differed according to the kind of stimulation. Unlike that of PGE2, inhibition by iloprost was stronger in alloactivated cultures than in PHA-stimulated ones. In vitro IL-6 production was stimulated by PGE2 in alloactivated cultures and by iloprost, whatever the stimulus. These results are probably due to other cellular subsets contaminating the T-lymphocyte preparations. After complete removal of monocytes from cell cultures, there were inhibitory effects of lloprost and PGE2 on IL-6 released in the supernatants. We did not observe any significant effect of thromboxane analogue on the production of either cytokine.

Common variable immunodeficiency following Epstein-Barr virus infection.

The authors present a case of a patient who developed recurrent bacterial upper respiratory and pulmonary infections and marked hypogammaglobulinemia with a gradual decrease of serum IgG, IgA and IgM some months after acute Epstein-Barr virus infection. Test for identification of lymphocyte subpopulation showed increased CD8+ T-cells with a surface phenotype (CD8+, CD57+, HLA-DR+) characteristic of virus-induced, activated cytotoxic cells. Viral investigations showed a positive anti-EBNA titer, an IgG titer anti-VCA of 1:40, a negative IgG titer anti-EA and human immunodeficiency virus negativity. The authors conclude that these clinical features are indicative of possible common variable immunodeficiency following Epstein-Barr virus infection.