Andreina Manfredi

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.

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.

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.

Prediction risk chart for scleroderma digital ulcers: A composite predictive model based on capillaroscopic, demographic and clinico-serological parameters

BACKGROUND Digital ulcers (DU) affect 50% of systemic sclerosis (SSc) patients, representing a challenging clinical problem. Despite a high negative predictive value, capillaroscopic scores proposed to select patients at risk for DU show an inadequate positive predictive value, especially in patients without previous DU. AIM OF THIS STUDY To increase the predictive value for DU development of capillaroscopy, through a predictive risk chart taking into account capillaroscopic, demographic, and clinico-serological parameters. PATIENTS AND METHODS Two hundred and nineteen unselected SSc patients from 8 Italian Rheumatology Centers were consecutively enrolled during a 6-month period. Demographic, clinical, serological and instrumental data and capillaroscopy skin ulcers risk index (CSURI) were collected. RESULTS A multivariate logistic regression analysis showed a significant positive association between DU appearance and male gender, DU history, altered CSURI, and ESR. A prediction risk chart of the development of DU within 6 months were built on the basis of the above parameters. According to the risk level, four risk classes were identified: low (≤19.3%); medium (>19.3%, ≤58.6%); high (>58.6%, ≤89.2%), and very high risk (>89.2%). CONCLUSIONS The systematic evaluation of the above parameters can be helpful to identify patients at risk to develop DU optimizing preventive vasoactive therapy.

Interstitial pneumonia with autoimmune features and undifferentiated connective tissue disease: Our interdisciplinary rheumatology-pneumology experience, and review of the literature.

BACKGROUND Interstitial lung diseases (ILDs) are a heterogeneous group of disorders characterized by inflammation and/or fibrosis of the lungs, varying from idiopathic interstitial pneumonias to secondary variants, including the ILDs associated to connective tissue diseases (CTDs). In addition, a number of patients are recognized as unclassifiable ILD (U-ILD), because of the inability to reach a definite diagnosis; some of them show autoimmune manifestations not fulfilling the classification criteria of a given CTD. The term interstitial pneumonia with autoimmune features (IPAF) has been recently proposed for this particular ILD subset. METHODS Here, we report our experience resulting from the integrated - pneumology/rheumatology - approach to patients with suspected ILDs or CTDs referred to our university-based Center for the Rare Pulmonary Diseases and Rheumatology Unit, from January 2009 to June 2015, with particular attention to the above-mentioned U-ILD, IPAF, and undifferentiated connective tissue disease (UCTD). The comparative analysis of these clinical variants was carried out; moreover, the observed findings were compared with the results of the updated review of the literature. RESULTS After the first clinical assessment, the U-ILD were identified in 50 patients; afterwards, on the basis of clinico-serological and radiological findings U-ILD group was subdivided into 2 subgroups, namely U-ILD without any clinical extra-thoracic manifestations and/or immunological alterations (15 pts) and IPAF according to the above-mentioned classification criteria (35 pts). Patients with either IPAF or U-ILD were compared with a series of 52 stable UCTD (disease duration ≥3 years), followed at our Rheumatology Unit. Some important differences were evidenced among the 3 series of U-ILD, IPAF, and UCTD: firstly, female gender was more frequent in patients with UCTD (86%) or IPAF (69%) compared with U-ILD (60%) or idiopathic pulmonary fibrosis (24%; p=0.001). In addition, UCTD patients were younger and showed longer disease duration. More interestingly, both UCTD and IPAF series show a comparable prevalence of various clinical manifestations, with the exception of the interstitial lung involvement detectable in a very small percentage of UCTD patients. Concordantly, the review of the literature evidenced two main subsets of U-ILD, one is characterized by isolated unclassifiable interstitial pneumonia and another one composed by subjects with clinically prevalent lung involvement in the setting of not definite CTD, the recently proposed IPAF. CONCLUSION We hypothesize that IPAF and UCTD might represent two clinical variants of the same systemic autoimmune disorders. The marked difference regarding the prevalence of ILD, which is the clinical hallmark of IPAF but very rare in UCTD, may at least in part reflect a selection bias of patients generally referred to different specialist centers, i.e. pneumology or rheumatology, according to the presence/absence of clinically dominant ILD, respectively. Well-integrated, interdisciplinary teams are recommended for the assessment and management of these patients in the clinical practice. Finally, the cooperation between multidisciplinary groups with different experiences may be advisable for a validation study of the proposed nomenclature and classification criteria of these indefinable ILD/CTD variants.

Scleroderma digital ulcers complicated by infection with fecal pathogens

Digital ulcers represent one of the most frequent complications of systemic sclerosis (SSc; scleroderma); they are very painful, scarcely responsive to treatment, and often responsible for marked limitations on daily activities, including patient self‐care. Infectious complications may severely compromise the outcome of skin lesions in a significant percentage of patients. Numerous pathogens of different origin may be involved, including bacteria from patient endogenous flora. Here we evaluated the possible involvement of fecal pathogens in scleroderma digital ulcers.

Neurologic Complications Associated with Sjögren’s Disease: Case Reports and Modern Pathogenic Dilemma

Objectives. Sjögrens syndrome (SS) may be complicated by some neurological manifestations, generally sensory polyneuropathy. Furthermore, involvement of cranial nerves was described as rare complications of SS. Methods. We reported 2 cases: the first one was a 40-year-old woman who developed neuritis of the left optic nerve as presenting symptom few years before the diagnosis of SS; the second was a 54-year-old woman who presented a paralysis of the right phrenic nerve 7 years after the SS onset. An exhaustive review of the literature on patients with cranial or phrenic nerve involvements was also carried out. Results. To the best of our knowledge, our second case represents the first observation of SS-associated phrenic nerve mononeuritis, while optic neuritis represents the most frequent cranial nerve involvement detectable in this connective tissue disease. Trigeminal neuropathy is also frequently reported, whereas neuritis involving the other cranial nerves is quite rare. Conclusions. Cranial nerve injury is a harmful complication of SS, even if less commonly recorded compared to peripheral neuropathy. Neurological manifestations may precede the clinical onset of SS; therefore, in patients with apparently isolated cranial nerve involvement, a correct diagnosis of the underlying SS is often delayed or overlooked entirely; in these instances, standard clinicoserological assessment is recommendable.

D-penicillamine in the treatment of eosinophilic fasciitis: case reports and review of the literature.

Eosinophilic fasciitis (EF) is a rare disease characterized by symmetrical thickness and hardening of the skin, especially localized to forearms and thorax, with eosinophilia. Corticosteroids represent the first-line therapy, even if some patients are scarcely responsive and/or may develop important side effects due to long-term treatment. Here, we describe three cases of EF, two of them refractory to previous steroid therapy, successfully treated with D-penicillamine. The present clinical observations together with the updated review of the literature suggest usefulness of D-penicillamine in EF patients, as well as its potential steroid-sparing value.