Michele Colaci

Capillaroscopic skin ulcer risk index: a new prognostic tool for digital skin ulcer development in systemic sclerosis patients.

OBJECTIVE Digital ulcerations are one of the most frequent manifestations of microangiopathy in patients with systemic sclerosis (SSc; scleroderma). The early detection of SSc patients who are at high risk to develop digital ulcers could allow a preventive treatment of these complications with reduction of morbidity and social costs. The aim of our study was to develop a capillaroscopic skin ulcer risk index (CSURI) that can predict the onset of new digital ulcers by using nailfold videocapillaroscopy (NVC) in patients with SSc. METHODS We performed NVC in 120 consecutive unselected patients with SSc (13 men, 107 women, mean +/- SD age 56.1 +/- 13.4 years, mean +/- SD SSc duration 44.7 +/- 60.7 months) to assess the total number of capillaries in the distal row (N), maximum loop diameter (D), number of megacapillaries (M), and the M:N ratio. RESULTS Within 3 months since NVC examination, 35 of 120 patients experienced digital ulcers. A significant association between ischemic lesions and the M:N ratio, N, and D was observed; the combination of these parameters allowed us to develop the CSURI, which is characterized by the formula D x M:N(2). A receiver operating characteristic curve analysis showed an area under the curve of 0.926 for ulcer appearance, with specificity and sensitivity of 85.9% and 94.3%, respectively, at the cutoff value of 2.94. Interestingly, 33 of 35 patients with new skin ulcers had a CSURI >2.94, but only 2 of 35 had a CSURI < or =2.94. CONCLUSION The proposed CSURI may represent a novel tool with the ability to predict the development of digital ulcers in patients with scleroderma.

Endocrine manifestations of hepatitis C virus infection

Chronic infection with hepatitis C virus (HCV) can result in both hepatic and extrahepatic disease and endocrine dysfunction represents an important class of HCV-related extrahepatic disease. The most frequently occurring—and clinically important—of these endocrine disorders are thyroid disease and type 2 diabetes mellitus. In this Review, we evaluate the evidence in support of a link between HCV infection and endocrine-system dysfunction, and discuss potential pathophysiological mechanisms. A meta-analysis of the literature has revealed significant associations between chronic HCV infection, thyroid autoimmunity and hypothyroidism. Furthermore, a high prevalence of thyroid cancer has been reported in HCV-positive patients. Several clinicoepidemiological studies have demonstrated that chronic HCV infection could lead to the development of type 2 diabetes mellitus, possibly as a result of HCV-induced metabolic disturbances. Some researchers have postulated that a type 1 T-helper -cell mediated immune response underpins the association of chronic HCV infection with endocrine disease. Indeed, the available data suggest that a common immunological, type 1 T-helper cell pattern of cytokine expression and activation (via interferon-γ) could provide the pathophysiological basis for this association. Nonetheless, additional studies will be necessary to elucidate fully all the mechanisms involved in HCV-related endocrine dysfunction.

Heart involvement and systemic sclerosis

Scleroderma heart involvement (SHI) is often manifest, and virtually always present when accurately searched and holds a significant prognostic value. Myocardial involvement by patchy fibrosis (secondary to both repeated ischaemia and immunoinflammatory damage) leads to ventricular diastolic dysfunction, whereas right ventricle overload and failure may complicate pulmonary hypertension. Left ventricular systolic dysfunction is present in a minority of patients, namely those presenting atherosclerotic coronary artery disease and/or arterial hypertension, sometimes triggered by sclerodermic renal involvement. Dysrhythmias and conduction disturbances are considered an hallmark of SHI, facilitated by autonomic dysfunction. SHI is frequently linked to parenchimal and/or vascular lung disease; they determine symptom occurrence, particularly dyspnoea, fatigue, palpitations and chest pain when pericardium is affected. Accurate cardiologic baseline screening and subsequent follow-up are mandatory in all patients, initially consisting in some noninvasive diagnostic procedures: visit, electrocardiogram (EKG), chest X-ray, Doppler-echocardiography. When needed, these examinations should be integrated by EKG Holter-monitoring, cardiopulmonary stress tests, cardiac magnetic resonance imaging, nuclear studies of myocardial function and perfusion, cardiac catheterization to better estimate pulmonary hypertension, and cardiac natriuretic hormone evaluation. Several vasodilator approaches (prostacycline or NO/endothelin) may counteract the microvascular dysfunction at peripheral and cardiopulmonary level, and fight the sequelae of pulmonary hypertension.

Predictive role of capillaroscopic skin ulcer risk index in systemic sclerosis: a multicentre validation study

Introduction The early detection of systemic sclerosis (SSc) patients at high risk of developing digital ulcers could allow preventive treatment, with a reduction of morbidity and social costs. In 2009, a quantitative score, the capillaroscopic skin ulcer risk index (CSURI), calculated according to the formula ‘D×M/N2’, was proposed, which was highly predictive of the appearance of scleroderma digital ulcers within 3 months of capillaroscopic evaluation. Objectives This multicentre study aims to validate the predictive value and reproducibility of CSURI in a large population of SSc patients. Methods CSURI was analysed in 229 unselected SSc patients by nailfold videocapillaroscopy (NVC). All patients were re-evaluated 3 months later with regard to the persistence and/or appearance of new digital ulcers. Results 57 of 229 patients presented with digital ulcers after 3 months. The receiver operating characteristic curve analysis showed an area under the curve of 0.884 (95% CI 0.835 to 0.922), with specificity and sensitivity of 81.4% (95% CI 74.8 to 86.89) and 92.98% (95% CI 83.0 to 98.0), respectively, at the cut-off value of 2.96. The reproducibility of CSURI was validated on a random sample of 81 patients, with a κ-statistic measure of interrater agreement of 0.8514. Conclusions The role of CSURI was confirmed in detecting scleroderma patients with a significantly high risk of developing digital ulcers within the first 3 months from NVC evaluation. CSURI is the only method validated to predict the appearance of digital ulcers and its introduction into routine clinical practice might help optimise the therapeutic strategy of these harmful SSc complications.

Immunopathogenesis of HCV-related endocrine manifestations in chronic hepatitis and mixed cryoglobulinemia

Hepatitis C Virus (HCV) is known to be responsible for both hepatic and extrahepatic diseases (HCV-related extrahepatic diseases = HCV-EHDs). The most important systemic HCV-EHDs are mixed cryoglobulinemia and lymphoproliferative disorders, while the most frequent and clinically important endocrine HCV-EHDs are thyroid disorders and type 2 diabetes mellitus (T2D). From a meta-analysis of the literature a significant association between HCV infection and thyroid autoimmunity and hypothyroidism has been reported. A high prevalence of thyroid cancer has been reported, too. Furthermore, several clinical epidemiologic studies have reported that HCV infection is associated to T2D. Many studies have linked Th1 immune response with HCV infection, thyroid autoimmunity, or diabetes. These findings suggest that a possible common immunological Th1 pattern could be the pathophysiological base of the association of HCV-EHDs, with thyroid autoimmunity and T2D. In fact, HCV infection of thyrocytes or beta-cells may act by upregulating CXCL10 secretion in these cells that is responsible for Th1 lymphocyte recruitment. Th1 response leads to increased IFNgamma and TNFalpha production that in turn stimulates CXCL10 secretion by the target cells, thus perpetuating the immune cascade. This process may lead to the appearance of thyroid autoimmune disorders or T2D in genetically predisposed subjects.

RET TKI: Potential Role in Thyroid Cancers

The increasing incidence of thyroid cancer is associated with a higher number of advanced disease characterized by the loss of cancer differentiation and metastatic spread. The knowledge of the molecular pathways involved in the pathogenesis of thyroid cancer has made possible the development of new therapeutic drugs able to blockade the oncogenic kinases (RET/PTC) or signaling kinases (vascular endothelial growth factor receptor [VEGFR]) involved in cellular growth and proliferation. Some clinical trials have been conducted showing the ability of targeted therapies able to inhibit RET (sorafenib, imatinib, vandetanib) in stabilizing the course of the disease. The aim of the introduction of these targeted therapies is to extend life duration assuring a good quality of life; however, further studies are needed to reach these goals.

Systemic sclerosis and cryoglobulinemia: Our experience with overlapping syndrome of scleroderma and severe cryoglobulinemic vasculitis and review of the literature.

OBJECTIVE Systemic sclerosis (SSc) is an immune-mediated disorder characterized by multiple organ fibrotic alterations and diffuse microangiopathy. The SSc can be associated with other connective tissue diseases and less frequently with systemic vasculitides, including cryoglobulinemic vasculitis (CV). The aim of the present study was to investigate the prevalence of CV in a large series of SSc patients. METHODS The presence of serum cryoglobulins was detected in 246 SSc patients (24 M and 222 F, age 61±13.5 SD years, disease duration 9.3±6.7 SD years); the observed clinico-serological findings, in particular the presence of SSc-CV overlapping syndrome, were carefully analyzed and compared with previous data reported in the literature. RESULTS The presence of circulating cryoglobulins was found in 7/246 (2.8%) of SSc patients; namely, 2 subjects only trace amounts of cryoglobulins, while 5 (2%) showed mixed cryoglobulinemia (type II, IgG-IgMk), low C4, rheumatoid factor seropositivity, and hepatitis C virus infection. Among SSc patients with serum mixed cryoglobulins, 4 (1.6%) developed a clinically overt CV, while the other one was totally asymptomatic with regard to typical vasculitic manifestations. Patients with SSc-CV overlapping syndrome had limited cutaneous SSc with serum anticentromere antibodies, pulmonary hypertension, clinico-serological features of HCV-related CV, and non-healing skin ulcers of the lower limbs. In all cases, the diagnosis of SSc preceded the clinical onset of CV, from 3 to 17years. The treatment with rituximab was useful on skin ulcers of lower limb in 2/3 patients; however, the overall clinical outcome of the four SSc-CV patients was unusually severe: one with very severe skin ulcers complicated by gangrene required bilateral through-the knee amputation, the other three subjects died because of severe heart failure, and in two cases because of untreatable pulmonary hypertension. In the literature, the prevalence of mixed cryoglobulinemia in scleroderma patients is quite rare (range 0.3-2%); while, the association of SSc with clinically overt CV is only anecdotally described, always in the absence of HCV infection. CONCLUSION The SSc-CV overlapping syndrome described here is characterized by markedly severe vascular manifestations responsible for very poor prognosis; these peculiar clinical manifestations suggest a synergic activity of typical scleroderma microangiopathy and cryoglobulinemic vasculitis.

Antiendothelial cell antibodies induce apoptosis of bone marrow endothelial progenitors in systemic sclerosis.

Objective. Patients with systemic sclerosis (SSc) have significantly fewer and functionally impaired endothelial progenitor cells (EPC) in peripheral blood and bone marrow; further, endothelial apoptosis seems to play a primary role in the pathogenesis of vascular damage. We investigated whether the failure of bone marrow EPC is related to their apoptotic phenotype and analyzed the possible mechanisms inducing apoptosis. Methods. The presence of apoptotic cells was investigated in bone marrow aspirates taken from patients with SSc; microvessel density (MVD) and the immunohistochemical expression of vascular endothelial growth factor (VEGF) were also measured in bone marrow biopsies. A correlation between EPC apoptosis and the presence of antiendothelial cell antibodies (AECA) was also investigated. Results. We confirmed the presence of bone marrow EPC dysfunction in SSc, while hematopoiesis was not impaired. Bone marrow studies showed a high percentage of apoptotic progenitors, no signs of fibrosis or an altered MVD, and an increased VEGF index. The patients’ bone marrow plasma showed significant titers of AECA, and their presence correlated with that of apoptotic progenitors. These findings were further confirmed by an in vitro assay in which the apoptosis of normal progenitors was induced by the addition of AECA+ purified IgG. Conclusion. Our results showed that apoptosis in patients with SSc involves the source compartment of endothelial progenitors and correlates with AECA activity. These findings support the hypothesis that AECA may play a pathogenetic role by affecting the bone marrow EPC machinery that should repair the peripheral vascular lesions.

Current treatment of hepatitis C-associated rheumatic diseases

The hepatitis C virus (HCV) is both hepatotropic and lymphotropic, responsible for a great number of hepatic and extrahepatic immune-system disorders that comprise the so-called HCV syndrome. HCV-associated rheumatic diseases are characterized by frequent clinico-serological overlap; therefore, correct classification of individual patients is necessary before therapeutic decisions are made. This is particularly difficult to do, however, because of the coexistence of viral infection and complex autoimmune alterations. In this context, mixed cryoglobulinemia syndrome (MCs) represents the prototype of virus-related autoimmune-lymphoproliferative diseases. MCs can be treated at different levels by means of etiological treatment with antivirals (peg-interferon-alpha plus ribavirin) aimed at HCV eradication and/or pathogenetic/symptomatic treatments directed to both immune-system alterations and the vasculitic process (rituximab, cyclophosphamide, steroids, plasmapheresis, and so on). In clinical practice, the therapeutic strategy should be modulated according to severity/activity of the MCs and possibly tailored to each individual patients conditions. Cryoglobulinemic skin ulcers may represent a therapeutic challenge, which should be managed by means of both local and systemic treatments. HCV-associated arthritis should be differentiated from the simple comorbidity of HCV infection and classical rheumatoid arthritis. It may be treated with low doses of steroids and/or hydroxychloroquine; the use of biologics (rituximab) may be considered in more severe cases. Primary Sjögrens syndrome is rarely associated with HCV infection, while sicca syndrome and myalgia are frequently detectable in hepatitis C patients, with or without cryoglobulinemic vasculitis. Other autoimmune rheumatic disorders (poly/dermatomyositis, polyarteritis nodosa, osteosclerosis, fibromyalgia, and so on) have been reported as potentially associated with HCV infection in patient populations from different countries, suggesting the role of genetic and/or environmental co-factors. The therapeutic approach to these disorders should be decided according to each individual patients evaluation, including hepatic, virological, and immunological findings.

Breast cancer in systemic sclerosis: Results of a cross-linkage of an Italian Rheumatologic Center and a population-based Cancer Registry and review of the literature

OBJECTIVE Increased frequency of few types of cancer in systemic sclerosis (SSc) has been reported in the literature; in particular, breast carcinoma has been proposed as one of the most frequent malignancy in SSc patients, even though data are not univocal. The aim of the present study was to retrospectively evaluate the prevalence of breast cancer in our SSc series, compared with sex-/age-matched general population of the same geographical area, and the possible correlations with SSc features, including X-ray exposure for clinical investigations. A review of the world literature about this topic was also done. METHODS Clinical records of 318 consecutive SSc patients, 31 M and 287 F, age 51.5±14.5 SD years, disease duration 10±6.5 SD years, referred to our Rheumatology Unit between January 2002 and December 2012 were evaluated. RESULTS Twelve (3.8%) cases of breast cancer were recorded, including 11/287 females (3.8%) and 1/31 (3.2%) male patients. Considering the subgroup of 202 SSc patients resident in the Province of Modena compared with data of the local Tumor Registry, the incidence of breast cancer observed in our SSc series is significantly higher than expected (SIR 2.1; 95% interval of confidence: 1.13-3.90; p<0.01). On the whole, the comparison between SSc patients with cancer and those without did not show any significant differences with regard to SSc clinical features, including the X-ray exposure. Of note is the relatively shorter disease duration at the time of breast cancer detection (median 2.5years, range 1-21; disease duration of mean 10±6.5 SD years in the entire cohort). The review of the literature revealed that the observed incidence of breast cancer in our case series is comparable to the few studies reporting the highest percentages of this malignancy. CONCLUSIONS A significant increase of breast cancer incidence compared to sex-age-matched general population from the same geographic area was observed. Moreover, a close temporal relationship between SSc and breast cancer onset was found, independently from clinical, serological, and instrumental features of SSc. The possible pathogenetic link between this systemic autoimmune disease and complicating breast cancer, as well as the results of previous studies, are discussed.