A. Della Rossa

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 Δ-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) Δ-cardiopulmonary (4.0), Δ-skin (3.0), Δ-vascular (2.0), and Δ-articular/muscular (1.0) for patients with dSSc; (b) Δ-skin (2.5), erythrocyte sedimentation rate (ESR) >30 mm/1st h (2.5), Δ-cardiopulmonary (1.5), Δ-vascular (1.0), arthritis (1.0), hypocomplementaemia (1.0), and scleredema (0.5) for lSSc; (c) Δ-cardiopulmonary (2.0), Δ-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), Δ-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.

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 (rs=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 (rs=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 ⩽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.

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 enrol 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.

Cryoglobulins and cryoglobulinemia. Diagnostic and therapeutic considerations.

ConclusionMixed cryoglobulinemia remains a major challenge to the clinician, both in terms of diagnosis and treatment. The discovery of its association with the hepatitis C virus has helped to shed light on the mechanisms of its pathogenesis and on how this complex disease might be managed. In this respect, interferon represents the first attempt to take an etiological approach to the treatment of a virus-related, immune-mediated human disease. Its uneven results, however, have on the one hand raised hopes that a final solution to the problem may be near, and at the same time underlined the fact that we probably have a long way to go before our goal is actually reached.

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.

Blunted increase of digital skin vasomotion following acetylcholine and sodium nitroprusside iontophoresis in systemic sclerosis patients

OBJECTIVES To test the hypothesis that finger skin vasomotion (FSV), a known factor influencing microvascular blood flow motion, is impaired in SSc patients. Possible relationships between FSV abnormalities and the severity and/or activity of SSc were also investigated. METHODS FSV was investigated by means of spectral Fourier analysis of finger skin laser Doppler flowmetry (LDF) tracing, recorded before and following acetylcholine (ACh) or sodium nitroprusside (SNP) iontophoresis in 26 SSc patients and in 20 age-matched healthy controls. The power spectral density (PSD) of the 0.01-0.02, 0.02-0.06 and 0.06-0.2 Hz LDF oscillations (related to endothelial-, sympathetic- and myogenic-dependent FSV, respectively) was measured in PU(2) (perfusion units)/Hz. RESULTS Compared with controls, SSc patients exhibited a significantly lower post-ACh and/or post-SNP percentage increase in PSD of 0.01-0.02 Hz (492 +/- 297% vs 283 +/- 167%; P < 0.005), of 0.02-0.06 Hz (336 +/- 205% vs 239 +/- 170%; P < 0.05) and of 0.06-0.2 Hz (223 +/- 91% vs 194 +/- 227%; P < 0.01) skin LDF oscillations. The post-SNP normalized PSD value of the 0.01-0.02 Hz and of the 0.02-0.06 Hz LDF oscillations was negatively related to SSc severity index (r = -0.407, P < 0.05 and r = -459, P < 0.05, respectively). CONCLUSIONS This study showed a selective abnormality of the endothelial, sympathetic and myogenic-dependent FSV in SSc patients, consistent with a parallel endothelial, sympathetic and myogenic macrovascular dysfunction. This study also suggests a possible role of endothelial and sympathetic dysfunction in the progression of SSc.

Polymyositis occurring during α-interferon treatment for malignant melanoma: a case report and review of the literature

Abstract Polymyositis is a systemic autoimmune disorder characterised by proximal muscle weakness which most frequently involves the limbs, neck and trunk. Alpha interferon is an antiviral molecule with well-known immunomodulatory and antiproliferative effects, but its use is often associated with a variety of side effects, in particular autoimmune phenomena. We report the occurrence of polymyositis during treatment with alpha-interferon in a patient affected by malignant melanoma. Indirect evidence suggests that in this case the patients myositis was not linked to her neoplasia, since the melanoma was confirmed to be in remission both at the time of the diagnosis of the muscle disease and again after more than one year of follow-up.

Behçet's disease with gastrointestinal involvement associated with myelodysplasia in a patient with congenital panhypopituitarism

Myelodysplastic syndromes (MDS) are hematologic disorders characterised by peripheral cytopenias and the hystologic features of hematologic dysplasia. Their association with autoimmune manifestations have been suggested by several authors: recently, the appearance of Behçets disease during MDS has been reported. We describe the occurrence of MDS in a patient affected by Behçets syndrome with gastrointestinal involvement and congenital panhypopituitarism.

Oral sildenafil in skin ulcers secondary to systemic sclerosis

Digital ulcers (DUs) are a major clinical problem in scleroderma patients, associated with reduced quality of life, pain, and disability, and resulting in loss of productivity and mutilation that c...

Long-term cyclic intravenous iloprost in systemic sclerosis: clinical experience from a single center

The aim of the present study was to retrospectively evaluate response to therapy in 73 patients affected by systemic sclerosis (SSc) who underwent long-term cyclic treatment with intravenous iloprost for peripheral vascular involvement (average duration of treatment 54.12±41.04 months). Seventy-three SSc patients were enrolled. Data were collected by reviewing clinical records and by phone or direct interview. Patients underwent a thorough physical examination at the end of follow up. The incidence of severe vascular manifestations was also assessed. Statistical analysis was performed by Wilcoxons signed rank test and descriptive statistics using Statview software. In this study cohort, 55 of 73 (75.2%) patients had a history of ischemic digital ulcers (DUs); 28 patients (38.4%) had active DUs at the beginning of treatment. Skin ulcers healed completely in 25 of 28 patients (89.3%) at the end of the first treatment. However, 40 of 55 patients (72.6%) relapsed after an average of 24 months. There was a significant correlation between relapse rate and/or number of ulcers and clinical factors (diffuse subset, changes in results of Allens test, NT-pro BNP levels). The annual incidence of pulmonary arterial hypertension (PAH) was 2.34 (95%CI: 0.94-4.83) per 100 person years, the rate of gangrene was 2.7%, and no cases of scleroderma renal crisis were recorded. The incidence of PAH and of digital gangrene was higher than that observed in unselected SSc case series. These data suggest that our patients treated with iloprost have a higher vascular involvement than large case series of unselected SSc patients. A number of clinical factors are correlated to the severity of vascular involvement and could have an impact on the response to therapy. The clinical significance of these findings requires clarification and further investigation is needed.