Salivary glands ultrasound examination after radioiodine-131 treatment for differentiated thyroid cancer.

BACKGROUND: The most important side effect of radioiodine ((131)I) therapy is sialoadenitis and xerostomy. AIM: To evaluate by ultrasound (US) parotid and submandibular glands after (131)I therapy for differentiated thyroid cancer (DTC). PATIENTS: Seventy-six subjects thyroidectomized for DTC submitted to salivary glands US examination. Forty-three of them had been previously treated with (131)I: 22 with 1.11 GBq (30 mCi) for remnant ablation, and 21 with higher doses [up to 44.4 GBq (1200 mCi)] for metastases. Thirty-three subjects studied before (131)I therapy served as controls. Parotid and submandibular volume, homogeneity, and echogenicity were determined. (131)I-treated patients filled a questionnaire about sialoadenitis symptoms. RESULTS: Parotid gland volume was significantly higher in treated patients (28.3±16.2 ml) than in untreated patients (20.7±10.4 ml, p=0.0154) and related to the time from last (131)I therapy. Three had parotid volume <1.5 ml and complained severe xerostomy. Submandibular gland volume was similar in treated (11.2±7.6 ml) and untreated patients (8.6±4.2 ml, p=0.0602). Homogeneity and echogenicity were similar in treated and untreated patients. Sialoadenitis symptoms were reported in 26% and were related to the (131)I cumulative dose. Symptoms were not related to gland volume. Hypoechogenicity and inhomogeneity of the parotids were more frequent in patients with salivary stickiness. CONCLUSION: Parotid, but not submandibular, volume is increased after (131)I treatment depending on the received activity and the time from irradiation but not on sialoadenitis symptoms. Xerostomy is associated to gland atrophy at US.

The development of a simple questionnaire to screen patients with SLE for the presence of neuropsychiatric symptoms in routine clinical practice.

AIM: The creation of a physician-administered questionnaire to screen patients with Systemic Lupus Erythematosus (SLE) for the presence of symptoms suggestive of neuropsychiatric involvement (NPSLE). METHODS: The development of the questionnaire followed three phases. First, a list of manifestations was prepared based on the ACR case definitions for NPSLE. A first questionnaire was constructed including 119 items. To reduce their number, a Delphi analysis was carried out and a second questionnaire with 62 questions was developed. This questionnaire was administered to 139 patients with SLE (58 with NPSLE: 29 active, 29 inactive; and 81 without NPSLE: 39 active, 42 inactive). Questions relevant to the screening of patients were selected on the basis of the receiver operating characteristic (ROC) curve analysis. RESULTS: Twenty-seven questions concerning central nervous system and psychiatric manifestations were found to be relevant; the remaining could be eliminated without significantly affecting AUC. The area under the ROC curve (AUC) was 0.69 (95% CI 0.61-0.78). A score above 17 was considered as suggestive of the presence of NPSLE with a sensitivity of 92.9% (95% CI 85.1-97.3 %) and specificity of 25.4% (95% CI 14.7-39.00 %). CONCLUSIONS: This questionnaire could represent a 'core set' of questions that could help in clinical practice to identify patients with neuropsychiatric symptoms requiring further evaluation.

Mortality rate and outcome factors in mixed cryoglobulinaemia: the impact of hepatitis C virus.

OBJECTIVES: Mixed cryoglobulinaemia (MC) is a chronic small-vessel vasculitis. Shortly after the discovery of hepatitis C virus (HCV) in 1989, an association between HCV infection and MC was being increasingly reported, suggesting the potential pathogenetic implication of HCV in most of the cases that had been previously diagnosed as essential MC. A number of studies have pointed out prognostic factors linked to mortality in this disorder. None of them, however, have clarified the impact of HCV discovery on the natural history of the disease. The aim of the present study was to evaluate mortality in MC after the discovery of HCV infection. METHODS: We retrospectively collected clinical and serological data in 70 unselected HCV-positive patients being followed up at our unit from 1990. Clinical and prognostic factors linked to poor outcome were evaluated. RESULTS: Chronic hepatitis, renal involvement, and intestinal vasculitis were the most frequent causes of death. CONCLUSION: Compared to other series, the outcome in our MC seemed to be better. Factors linked to a poor outcome were renal involvement, widespread vasculitis, male sex, and cryocrit.

In vitro treatment of monocytes with 8-methoxypsolaren and ultraviolet A light induces dendritic cells with a tolerogenic phenotype.

Extracorporeal photopheresis (ECP) has been considered an efficient dendritic cell (DC) therapy, used for treating both T cell malignancy, as well as T cell-mediated diseases. During the ECP procedure leucocytes are exposed to photoactivable agent 8-methoxypsolaren (8-MOP) and ultraviolet (UV) A radiation (PUVA) prior to reinfusion. Despite its clinical efficacy the mechanism of action remains elusive. As it has been reported that ECP might promote the differentiation of monocytes into immature DCs, we investigated the effects of UVA light (2 J/cm(2)) and 8-MOP (100 ng/ml) on in vitro monocyte-to-DC differentiation from normal donors. DCs were generated from human purified CD14(+) cells. Because monocytes are killed by PUVA and taking into account that only 5-10% of circulating mononuclear cells are exposed to PUVA during the ECP procedure, we developed an assay in which 10% of PUVA-treated monocytes were co-cultured with untreated monocytes. We first demonstrate that the presence of 10% apoptotic cells and monocyte activation were not enough to induce monocyte differentiation into DCs. Adding cytokines to our culture system, we obtained immature DCs characterized by significantly higher phagocytic activity and human leucocyte antigen D-related (HLA-DR) expression. These DCs preserved the capacity to be activated by lipopolysaccharide, but showed a reduced capacity to induce allogeneic T cell proliferation when first co-cultured with 10% of PUVA-treated cells. Our experimental design provides a novel insight into the real action of 8-MOP and UVA light on dendritic cell biology, suggesting an additional mechanism by which 8-MOP and UVA light exposure may influence immune responses.

The newly developed three-dimensional (3D) and two-dimensional (2D) thyroid ultrasound are strongly correlated, but 2D overestimates thyroid volume in the presence of nodules.

The newly developed three-dimensional (3D) and two-dimensional (2D) thyroid ultrasound (US) were compared in assessing thyroid volume (TV) in 104 patients: 53 had an isolated thyroid nodule, 32 toxic diffuse goiter, 17 non-toxic multinodular goiter, 1 toxic multinodular goiter and 1 a toxic adenoma. A real-time Technos apparatus (Esaote SpA, Italy) with a 7,5 MHz linear transducer was used. The volume of thyroid lobes by 2D was calculated according to the ellipsoid formula. In the same session, TV by 3D US was calculated using a probe tracking system (in vivo ScanNT Esaote 3.4 MedCom. Darmasdt) and software to reconstruct 3D images, directly giving the lobe volume. There was a very good agreement between 2D and 3D, but in 94/208 lobes with nodular lesions 2D showed a 10% systematic overestimation compared to 3D, the percentage error being higher in lobes with lower volumes. A possible explanation for this result is the inadequacy of the ellipsoid formula in forecasting the correct lobe profile in the presence of nodules. This intrinsic defect of 2D US should be taken into account when evaluating TV in patients with nodular goiter.

Serum PSA levels are not affected by the menstrual cycle or the menopause, but are increased in subjects with polycystic ovary syndrome.

BACKGROUND/AIMS: Prostatic specific antigen (PSA) is the most specific prostatic tumor marker in man. Recently, PSA has been detected in a variety of tissues and fluids in women, and its determination suggested as a marker of hyperandrogenism. However, precise information about the physiology of PSA in females is not available. The goal of this study was to assess serum concentrations of PSA in healthy pre-menopausal women (healthy pre-menopausal group), menopausal women (menopause group) and patients with polycystic ovary syndrome (PCOS group). METHODS: PSA, androgens, LH, FSH, 17-beta-estradiol (E2), progesterone (Pg) were assessed in 40 post-menopausal women, 35 fertile controls and 35 women with PCOS. RESULTS: No significant difference in PSA concentrations could be demonstrated in different phases of the menstrual cycle in healthy pre-menopausal group and between pre- and post-menopausal groups. No correlations could be demonstrated between serum PSA levels and the following parameters: age, body mass index (BMI), LH, FSH, E2, testosterone (T), DHEAS, and SHBG, both in pre- and post-menopausal women. Significantly higher PSA levels (median=14 pg/ml) were found in the PCOS group compared to both pre-menopausal (median=5 pg/ml) and menopausal (median= 5 pg/ml) groups (p< 0.05). CONCLUSIONS: only minor fluctuations of serum PSA concentrations are observed in healthy pre- and post-menopausal women, while serum level is higher in PCOS, and therefore PSA can be considered a suitable marker of female hyperandrogenism.

European Scleroderma Study Group to define disease activity criteria for systemic sclerosis. III. Assessment of the construct validity of the preliminary activity criteria.

OBJECTIVE: To further assess the construct validity of the three European Scleroderma Study Group (EScSG) preliminary activity indices for systemic sclerosis (SSc): for SSc as a whole, for diffuse SSc (dcSSc), and for limited SSc (lcSSc). METHODS: 30/290 SSc clinical charts collected for the EScSG study used to develop activity criteria for SSc were selected and sent to four clinical experts in SSc. The experts ranked the charts from 1 to 30 (1=lowest activity, 30=highest activity). The relationships among the ranks given by each investigator and each of the three scores, and between any two of the ranks were investigated. RESULTS: A consistently significant correlation (r(s)=0.530-0.712) was found between the ranks given by each of the four investigators and the index for the entire patient group. A similar level of agreement was detected between each couple of the four experts (r(s)=0.428-0.720). Moreover, the ranks given in patients with an index >3 were significantly higher than those given for patients with an index < or =3. This cut off point had previously been shown to best discriminate patients with active disease. CONCLUSIONS: Of the originally developed activity indexes, the whole series index has been externally validated. The index comprises the first preliminary, but necessary, groundwork to improve the concept of disease activity in SSc, which is still ill defined. It can be used as a preliminary activity index in clinical investigational studies.

Assessment of disease severity and prognosis.

The Subcommittee members initially agreed on the concepts of disease activity, damage and severity, defining severity as the total effect of disease on organ function. It was decided to start with the assessment of severity using the Medsger's severity scale. A revised version of this scale was constructed. The rationale for the exclusion of other variables was provided.

Psoralen and UVA light: an in vitro investigation of multiple immunological mechanisms underlying the immunosuppression induction in allograft rejection.

Photopheresis (ECP) is a novel immunomodulatory therapy effectively used to treat several T-cell-mediated diseases and to reverse allograft rejection after organ transplantation. It consists of infusion of UVA-irradiated autologous leukocytes collected by apheresis and extracorporeally incubated with 8-methoxypsoralen (8-MOP). In this study we explored the potential immunological events for therapeutic efficacy of photopheresis in preventing allograft rejection by evaluating in vitro the combined effects of 8-MOP and UVA (PUVA) on multiple immunological parameters, such as induction of apoptosis, production of soluble mediators, and expression of cell antigens. Peripheral blood mononuclear cells (PBMCs) obtained from healthy subjects were treated with 8-MOP and UVA at the same doses as those clinically used in ECP. We demonstrate that PUVA treatment induced leukocyte hyporesponsiveness and a decrease in expression of co-stimulatory and adhesion molecules as well as of cytokine levels. Additionally, PUVA treatment induced apoptosis in both mononuclear cells (possibly through the Fas/FasL system and/or the CD38 pathway) and purified monocytes. In conclusion, our work focuses attention on the initial phase of immune response and identifies some new targets of therapy (e.g., costimulatory molecules) able to trigger final effects underlying therapeutic efficacy of photopheresis.

131I therapy for differentiated thyroid cancer leads to an earlier onset of menopause: results of a retrospective study.

Treatment with 131I for differentiated thyroid cancer may give a follicle-damaging radiation dose to the ovaries. This damage to the ovarian function could shorten the fertile life span and advance the natural menopause. To address this issue, we studied retrospectively the menopausal age of 130 women treated with 131I for differentiated thyroid cancer in our institution from 1974-1993. The menopausal age of women treated with 131I for differentiated thyroid cancer after total thyroidectomy and subjected to suppressive L-T4 therapy was compared with the menopausal age of a control group including 127 goitrous women who were treated with suppressive L-T4 for a comparable period of time. The cumulative therapeutic 131I dose to cancer patients ranged from 1,110-40,700 MBq (mean +/- SD, 5,308 +/- 5,483 MBq; median, 3700 MBq). All patients chosen for the study were younger than 45 yr when first treated (i.e. first administration of 131I and L-T4 for cancer patients, and institution of L-T4 therapy for goitrous patients), and older than 45 yr at the end of the study period. The menopausal status of both groups was assessed from the clinical records and compared using Kaplan-Meier survival analysis. The menopausal age of cancer women treated with 131I and suppressive L-T4 therapy was less than that of goitrous patients treated with suppressive L-T4 therapy (P < 0.001). We could not detect any relationship between menopausal age and the age at the first or last 131I dose or to the cumulative 131I dose received. These data indicate that 131I treatment is probably associated with an earlier ovarian failure in thyroid cancer patients. Conceivably, the ovarian irradiation by 131I might contribute to the process of the follicular atresia, thus inducing earlier menopause.

European multicentre study to define disease activity criteria for systemic sclerosis. I. Clinical and epidemiological features of 290 patients from 19 centres.

OBJECTIVE: To investigate the existence of differences among European referral centres for systemic sclerosis (SSc) in the pattern of attendance and referral and in the clinical and therapeutical approaches. METHODS: In 1995 the European Scleroderma Study Group initiated a multicentre prospective one year study whose aim was to define the disease activity criteria in SSc. During the study period each participating European centre was asked to enroll consecutive patients satisfying American College of Rheumatology criteria for SSc and to fill out for each of them a standardised clinical chart. Patients from various centres were compared and differences in epidemiological, clinical, and therapeutical aspects were analysed. RESULTS: Nineteen different medical research centres consecutively recruited 290 patients. The patients could be divided into two subgroups: 173 with the limited (lSSc) and 117 with the diffuse (dSSc) form of the disease. The clinical and serological findings for the series of 290 patients seemed to be similar to data previously reported. However, when the data were analysed to elicit any differences between the participating centres, a high degree of variability emerged, in both epidemiological and clinical features and in the diagnostic and therapeutic approaches to the disease. CONCLUSIONS: The clinical approach to SSc, not only in different countries but also in different centres within the same country, is not yet standardised. To overcome this problem, it will be necessary for the scientific community to draw up a standardised procedure for the management of patients with SSc. This would provide a common research tool for different centres engaged in research on this complex disease.

European multicentre study to define disease activity criteria for systemic sclerosis. II. Identification of disease activity variables and development of preliminary activity indexes.

OBJECTIVE: To develop criteria for disease activity in systemic sclerosis (SSc) that are valid, reliable, and easy to use. METHODS: Investigators from 19 European centres completed a standardised clinical chart for a consecutive number of patients with SSc. Three protocol management members blindly evaluated each chart and assigned a disease activity score on a semiquantitative scale of 0-10. Two of them, in addition, gave a blinded, qualitative evaluation of disease activity ("inactive to moderately active" or "active to very active" disease). Both these evaluations were found to be reliable. A final disease activity score and qualitative evaluation of disease activity were arrived at by consensus for each patient; the former represented the gold standard for subsequent analyses. The correlations between individual items in the chart and this gold standard were then analysed. RESULTS: A total of 290 patients with SSc (117 with diffuse SSc (dSSc) and 173 with limited SSc (lSSc)) were enrolled in the study. The items (including Delta-factors-that is, worsening according to the patient report) that were found to correlate with the gold standard on multiple regression were used to construct three separate 10-point indices of disease activity: (a) Delta-cardiopulmonary (4.0), Delta-skin (3.0), Delta-vascular (2.0), and Delta-articular/muscular (1.0) for patients with dSSc; (b) Delta-skin (2.5), erythrocyte sedimentation rate (ESR) >30 mm/1st h (2.5), Delta-cardiopulmonary (1.5), Delta-vascular (1.0), arthritis (1.0), hypocomplementaemia (1.0), and scleredema (0.5) for lSSc; (c) Delta-cardiopulmonary (2.0), Delta-skin (2.0), ESR >30 mm/1st h (1.5), total skin score >20 (1.0), hypocomplementaemia (1.0), scleredema (0.5), digital necrosis (0.5), Delta-vascular (0.5), arthritis (0.5), TLCO <80% (0.5) for all patients with SSc. The three indexes were validated by the jackknife technique. Finally, receiver operating characteristic curves were constructed in order to define the value of the index with the best discriminant capacity for "active to very active" patients. CONCLUSIONS: Three feasible, reliable, and valid preliminary indices to define disease activity in SSc were constructed.

Therapy with pulse methylprednisolone and short course pulse cyclophosphamide for diffuse proliferative glomerulonephritis.

The incidence of renal flares and the long-term outcome in a group of 33 systemic lupus erythematosus (SLE) patients with diffuse proliferative glomerulonephritis (DPGN) treated with pulse steroids and a short course of pulse cyclophosphamide (CYC) are evaluated. Fifteen patients (45%) experienced a flare of renal disease at some time after the discontinuation of the immunosuppressive (IS) therapy; among these half (24%) were 'early' flares occurring shortly after the discontinuation of therapy, and the other half (21%) were 'late' flares occurring more than 2 y after the discontinuation of the treatment. Nine patients (27%) showed a poor renal outcome at the end of follow-up. On multiple regression analysis, a younger age and a high activity index (AI) on renal histology were found to be correlated with the occurrence of renal flares. Our results suggest that the combination of pulse steroids with a short course of pulse CYC (six to nine pulses) is effective in both controlling disease activity and in preventing the occurrence of renal flares in DPGN. However, short term IS therapy might not be sufficient to maintain disease control in younger patients with active lesions on renal histology. Such patients might be candidates to receive more prolonged IS treatment.

The validity of the ECLAM index for the retrospective evaluation of disease activity in systemic lupus erythematosus.

AIM: To determine whether the European Consensus Lupus Activity Measurement Index (ECLAM) can be used to evaluate disease activity in patients retrospectively from the data provided in their clinical charts. METHODS: The ECLAM score was calculated twice in a series of 64 consecutive SLE patients: first for each patient during the course of a standard clinical evaluation (direct-ECLAM), and then one to two weeks later solely on the basis of the data provided in the patient's clinical chart (chartECLAM). The scorings for each patient were performed by two different assessors. RESULTS: The direct-ECLAM and chart-ECLAM scores were highly correlated (Spearman's rank correlation coefficient = 0.86). The regression line was not significantly different from the identity line (t-test). The Pearson's coefficient was 0.88. The interobserver variability of the chart-ECLAM showed a low inter-rater variability. CONCLUSION: ECLAM could represent a valid and reliable instrument for the retrospective analysis of disease activity in SLE patients.

Hepatitis C virus infection: prevalence in psoriasis and psoriatic arthritis.

OBJECTIVE: To study the prevalence of hepatitis C virus (HCV) infection in 2 groups of patients, one group with psoriasis and the other with psoriatic arthritis (PsA). METHODS: We detected anti-HCV antibodies by ELISA and by a recombinant immunoblot assay (RIBA) in the sera of 50 patients with psoriasis and 50 with PsA. As controls we used a group of 76 patients with rheumatoid arthritis (RA), and referred to data on the prevalence of HCV in the general Italian population. RESULTS: By ELISA, anti-HCV antibodies were detected in 6/50 (12%) patients with PsA, in 5/50 (10%) patients with psoriasis, and in 4/76 (5.2%) patients with RA. All the reactive PsA and RA sera also tested positive on RIBA, while only 3 of the 5 positive results for sera of patients with psoriasis were confirmed by RIBA. The prevalence of HCV infection in patients with psoriasis was not significantly higher than in controls. In contrast, the rate of HCV infection observed in the 50 patients with PsA was higher than that in the other groups, the difference being statistically significant between patients with PsA and the general population. CONCLUSION: Our data do not support the hypothesis that HCV infection may play a role in the pathogenesis of psoriasis. On the other hand they show a statistically significant difference between the prevalence of HCV infection in patients with PsA and the general population.

Development of a clinical chart to compute different disease activity indices for systemic lupus erythematosus.

Between 1990 and 1995 a European Consensus Group carried out a multicenter study to reach agreement of the definition of disease activity in systemic lupus erythematosus (SLE). A new index, the European Consensus Lupus Activity Measurement (ECLAM) index, was developed. In a second phase of the study, a prospective survey aimed at validating ECLAM and 4 other scales as steady-state and transition indices for disease activity in SLE was completed. We present the results of this survey. A standardized clinical chart was developed, together with a computer program that could automatically calculate the ECLAM score, as well as the scores for some of the disease activity scales most widely used at present, i.e., the British Isles Lupus Assessment Group, Systemic Lupus Activity Measure, SLE Disease Activity Index, and the SLE Index Score (SIS). With the participation of 28 centers in 15 different European countries, data from 121 prospectively selected new lupus patients were collected. The validity of the 5 activity scales was assessed by comparing the computed scores for each patient to a gold standard, i.e., the physician's subjective judgment on disease activity measured using a semiquantitative scale. All the indices were found to be valid instruments for measuring disease activity in SLE in both the steady-state and transition phases. The results for the various indices closely correlated with one another. Thus, the computerized chart developed by the European Consensus Group offers a simple and reliable instrument to assess disease activity and could be used to monitor lupus patients both in clinical practice and in clinical trials.

Undifferentiated connective tissue diseases: the clinical and serological profiles of 91 patients followed for at least 1 year.

The objective of this work was to evaluate the clinical and serological profiles of patients with undifferentiated connective tissue diseases (UCTD) who had been followed for at least 1 year. The retrospective analysis (197495) was based on UCTD patients diagnosed on the basis of clinical manifestations suggestive of a connective tissue disease, and the presence of at least one non-organ-specific autoantibody. A total of 91 patients were evaluated. The condition of 79 remained stable during the follow up, while in 12 the UCTD evolved to systemic lupus erythematosus (SLE) within a mean period of 3 years (min. 1 year, max. 8 years, median 2 years) after the onset of the disease. At baseline none of the variables, considered alone, showed an association with the future development of SLE. Multiple regression analysis, however, suggested that the association of sicca symptoms, Raynaud's phenomenon and/or photosensitivity was inversely correlated with the development of SLE (P = 0.0012, Fisher's exact test). The most common clinical manifestations of UCTD included arthritis, arthralgias, Raynaud's phenomenon, xerostomia, xerophthalmia and leukopenia. The stable UCTD patients showed a simple autoantibody profile characterized by a single autoantibody specificity in 82% of the cases 30% with anti-Ro/SSA alone and 28% with anti-RNP alone. This profile remained stable during the follow up. Anti-RNP antibodies alone correlated with the presence of Raynaud's phenomenon and arthritis (P < 0.001 and P < 0.01, respectively), while anti-Ro/SSA antibodies alone correlated with xerostomia and xerophthalmia (P < 0.01). In conclusion, the UCTDs in most of our patients seem to represent distinct clinical entities with a limited autoimmune repertoire rather than the early phases of definite connective tissue diseases. They could therefore provide an ideal model for the study of the clinico-serological correlations in autoimmune diseases.

Predictors of renal outcome in diffuse proliferative glomerulonephritis in systemic lupus erythematosus.

The occurrence of nephritis is considered to be the most important factor influencing the prognosis in systemic lupus erythematosus (SLE). Despite the apparent histological similarity of the lesions, however, patients with diffuse proliferative glomerulonephritis (DPGN) may exhibit different outcomes. A retrospective study was carried out on 81 SLE patients with DPGN to evaluate the prognostic significance of different clinical, serological and histological variables; in particular, 95 renal biopsies were re-evaluated and the activity and chronicity indices for the patients were determined. A positive correlation was observed between the presence of chronic lesions on renal biopsy and a poor renal outcome (< 0.001). Moreover, in the repeat biopsies the patients with a poor outcome showed a higher degree of chronic lesions. Active lesions and other clinical and serological parameters did not correlate with the outcome.