Silvia Bellando Randone

To be or not to be, ten years after: evidence for mixed connective tissue disease as a distinct entity.

OBJECTIVES To determine if mixed connective tissue disease (MCTD) can be considered an independent clinical entity, to compare 3 different classification criteria for MCTD (Kasukawa, Alarcón-Segovia, and Sharp), and to define predictors (clinical features and autoantibodies) of potential evolution toward other connective tissue diseases (CTDs). METHODS One hundred sixty-one MCTD patients were evaluated retrospectively at the diagnosis and in 2008. They were classified, at the diagnosis, according to the 3 classification criteria of MCTD (Sharp, Alarcón-Segovia, and Kasukawa) and reclassified in 2008 according to their evolution. Statistical analyses were performed to find out predictors (clinical features and autoantibodies) of evolution into other CTDs. RESULTS After a mean of 7.9 years of disease, 57.9% of patients still satisfied MCTD classification criteria of Kasukawa; 17.3% evolved into systemic sclerosis, 9.1% into systemic lupus erythematosus, 2.5% into rheumatoid arthritis, 11.5% was reclassified as affected by undifferentiated connective tissue disease, and 1.7% as suffering from overlap syndrome. Kasukawas criteria were more sensitive (75%) in comparison to those of Alarcón-Segovia (73%) and Sharp (42%). The presence of anti-DNA antibodies (P = 0.012) was associated with evolution into systemic lupus erythematosus; hypomotility or dilation of esophagus (P < 0.001); and sclerodactyly (P = 0.034) with evolution into systemic sclerosis. CONCLUSIONS MCTD is a distinct clinical entity but it is evident that a subgroup of patients may evolve into another CTD during disease progression. Initial clinical features and autoantibodies can be useful to predict disease evolution.

Systemic sclerosis and infections

Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular obliteration, excessive extracellular matrix deposition and fibrosis of the connective tissues of the skin, lungs, gastrointestinal tract, heart, and kidneys. Numerous infectious agents (bacterial and viral) have been proposed as possible triggering factors (Parvovirus B19, Cytomegalovirus, Epstein-Barr virus, Retroviruses). Homology between viruses and autoantibody targets suggests that molecular mimicry may have a role in initiating antibody response in different disorders characterized by diffuse vascular disease, including SSc. Endothelial cell may be infected bacteria or viruses that play a particular role in inducing vasculitis. The pathogenic hypothesis include: a mechanism of molecular mimicry, the role played by endothelial cell damage, the presence of superantigens and the role of microchimeric cells. Although several studies provide important information linking infectious agents to SSc, a direct casual association between infections and SSc is still missing. In SSc viral products could synergize with other factors in the microenvironment predisposing to SSc development.

Lung ultrasound for the screening of interstitial lung disease in very early systemic sclerosis

Background A high percentage of patients with systemic sclerosis (SSc) develop interstitial lung disease (ILD) during the course of the disease. Promising data have recently shown that lung ultrasound (LUS) is able to detect ILD by the evaluation of B-lines (previously called ultrasound lung comets), the sonographic marker of pulmonary interstitial syndrome. Objective To evaluate whether LUS is reliable in the screening of ILD in patients with SSc. Methods Fifty-eight consecutive patients with SSc (54 women, mean age 51±14 years) who underwent a high resolution CT (HRCT) scan of the chest were also evaluated by LUS for detection of B-lines. Of these, 32 patients (29 women, mean age 51±15 years) fulfilled the criteria for a diagnosis of very early SSc. Results At HRCT, ILD was detected in 88% of the SSc population and in 41% of the very early SSc population. A significant difference in the number of B-lines was found in patients with and without ILD on HRCT (57±53 vs 9±9; p<0.0001), with a concordance rate of 83%. All discordant cases were false positive at LUS, providing a sensitivity and negative predictive value of 100% in both SSc and very early SSc. Conclusions ILD may be detected in patients with very early SSc. The presence of B-lines at LUS examination correlates with ILD at HRCT. LUS is very sensitive for detecting ILD even in patients with a diagnosis of very early SSc. The use of LUS as a screening tool for ILD may be feasible to guide further investigation with HRCT.

Interstitial lung disease in systemic sclerosis: where do we stand?

Interstitial lung disease (ILD) is common in systemic sclerosis (SSc) patients and despite recent advances in the treatment is, at present, the major cause of death. Today, an early diagnosis of ILD is possible, and is mandatory to improve the prognosis of the disease. Pulmonary function tests and high-resolution computed tomography remain the mainstay for the diagnosis of SSc-ILD, but there is a growing interest in lung ultrasound. Recently, the correlation between severity of fibrosis and some peripheral blood biomarkers has been described. Nonselective immunosuppressors are still the main treatment for ILD, with cyclophosphamide (CYC) most widely used to obtain remission. Novel therapies towards specific molecular and cellular targets have been suggested; in particular, rituximab (RTX) has shown promising results, but further research is needed. It is of paramount importance to define the severity of the disease and the risk of progression in order to define the need for treatment and the treatment intensity. We propose the division of the treatment strategies at our disposal to induce remission into three categories: high intensity (haematopoietic stem cell transplantation), medium intensity (CYC and RTX) and low intensity (azathioprine (AZA) and mycophenolate mofetil (MMF)). After obtaining remission, maintenance treatment with AZA or MMF should be started. In this review we explore new advances in the pathogenesis, diagnosis and treatment of SSc-ILD. Early diagnosis of ILD is possible, and is mandatory to improve the prognosis of the disease http://ow.ly/P28JH

Immunosuppression for interstitial lung disease in systemic sclerosis

The efficacy of immunosuppressors in the treatment of systemic sclerosis-interstitial lung disease is still matter of controversy. In this review we will analyse the evidence that immunosuppressors, despite not being able to reverse fibrotic changes, may help in slowing disease progression. Induction treatment with cyclophosphamide should be started as soon as possible in patients at risk for progression. Mycophenolate mofetil and rituximab have to be considered in patients who are unable to tolerate cyclophosphamide. After remission, maintenance treatment with mycophenolate mofetil or azathioprine should be started in order to preserve the benefits achieved during the induction treatment.

Assessment, Definition, and Classification of Lower Limb Ulcers in Systemic Sclerosis: A Challenge for the Rheumatologist

Objective. To evaluate pathogenesis and clinical features of lower limb ulcers in systemic sclerosis (SSc) and to propose a classification that could be used in clinical practice. Methods. Charts of 60 patients with SSc who had lower limb cutaneous lesions were reviewed. All patients had videocapillaroscopy and arterial and venous lower limb color Doppler ultrasonography (US). Arteriography was performed if occlusive peripheral arterial disease was suspected. Results. The 554 lesions were classified as hyperkeratosis, ulcers, and gangrenes. There were 341 (61.6%) hyperkeratoses, 208 (37.5%) ulcers, and 5 (0.9%) gangrenes. Ulcers were divided into pure ulcers, ulcers associated with hyperkeratosis, and ulcers secondary to calcinosis. Involvement of arterial and venous macrocirculation as determined by color Doppler US was observed in 17 (18.3%) and 18 (30%) patients, respectively. Seventeen out of 37 patients with pure ulcers (45.9%) presented neither venous insufficiency nor hemodynamically significant macrovascular arterial disease. In these patients, pure ulcers were most likely caused by isolated SSc-related microvascular involvement (pure microvascular ulcers). The only significant risk factor for development of pure microvascular ulcers in the multivariate analysis was the history of lower limb ulcers (OR 26.67, 95% CI 2.75–259.28; p < 0.001). Conclusion. Results of our study indicate that lower limb ulcers in SSc often have a multifactorial pathogenesis that may be difficult to manage. Further studies are needed to validate the proposed classification and to assess the most appropriate management of lower limb ulcers in SSc.

Angiostatic and angiogenic chemokines in systemic sclerosis: an overview

In systemic sclerosis (SSc), the dysregulation of several molecular pathways seem to have a role in the disease pathogenesis. Either angiogenesis and vasculogenesis are disturbed and impaired, and an imbalance between angiogenic and angiostatic factors may be involved in the genesis and maintenance of vasculopathy. Aberrant immune system activation and function involves both B and T cells, as well as many different chemokines and cytokines. Particularly, chemokines are central to the initiation and maintenance of inflammatory responses as well as angiogenesis and fibrosis. Increased expression of several chemokines as CXCL4 (platelet factor 4), CXCL8 (IL8), CXCL5 (ENA-78), CCL5 (RANTS), CXCL9 (MIG), CCL24, CXCL10 IP-10), CXCL12, CXCL16 (SRPSDX), CCL2 (MCP-1), CCL19 (MIP-3β/ELC), CCL24 (Eotaxin 2), suggests a complex mechanism by which many immune cell types, including T cells, macrophages and neutrophils are recruited to the skin in SSc patients. Many of these chemokines have redundant roles, possibly to ensure recruitment of specific cell types. Several studies have shown a synergistic effect of combinations of these chemokines in cell recruitment, emphasizing the importance of understanding global chemokine expressions. urthermore, chemokines can be detected in peripheral blood compared with cytokines or growth factors. The utility of cytokines as biomarkers has been investigated but longitudinal studies are necessary to clarify their clinical utility for the evaluation of disease activity, therapeutic effects on skin sclerosis or interstitial lung disease and risk stratification of SSc patients. An effective therapeutic agent, able to interfere with complex chemokine networks, is warranted to attenuate perivascular inflammation, dysregulated angiogenesis and the evolution of skin and internal organ fibrosis, is the most ambitious goal for the scientific research of the future.

A rare case of Candida glabrata spondylodiscitis: case report and literature review

BACKGROUND Spondylodiscitis is an infection of the vertebral column, the incidence of which is increasing due to an increase in the susceptible population and improved ascertainment. This disease has been associated with a wide range of microorganisms. Fungal spondylodiscitis is uncommon (0.5-1.6%) and strongly associated with immunosuppression and diabetes (Gouliouris et al., 2010). A rare case of Candida glabrata spondylodiscitis in a non-neutropenic diabetic patient is reported herein, along with a review of the literature. CASE REPORT A case of C. glabrata spondylodiscitis of L3-L4 metameres was diagnosed. The diagnosis was obtained through open biopsy of an abscess and culture examination. The patient was treated with anidulafungin and surgical debridement of the lesion. CONCLUSIONS The diagnosis of spondylodiscitis is often delayed or missed. Physicians should consider this entity in the differential diagnosis of lumbar pain in order to initiate an appropriate therapy to prevent spinal cord lesions and disability. This is particularly relevant in the case of a fungal aetiology, as there is a recognized global shift towards invasive candidiasis due to non-albicans Candida species, in particular C. glabrata, which has variable susceptibility to antifungal drugs.

Systemic sclerosis and primary biliary cholangitis: An overlapping entity?

Systemic sclerosis (SSc) is a complex autoimmune disease that may lead to skin and internal organ fibrosis. Based on skin involvement, two subsets of the disease are recognized (limited cutaneous SSc and diffuse cutaneous SSc). The new 2013 American College of Rheumatology/European League against Rheumatism classification criteria allow to identify SSc patients at the early stage of the disease that allows new research avenues. The aetiology of the disease is still unknown, but it has an important autoimmune basis and its association with other autoimmune diseases has been reproducibly reported. Among them, primary biliary cholangitis is considered the most common liver disease in SSc. The aim of this review is to provide an overview on recent findings about SSc associated to primary biliary cholangitis. Although the aetiology of the two diseases is still unknown, data suggest that these two disorders share the expression of fibrogenic cytokines, involved both in generation and function of T lymphocytes subpopulation (Th17 cells) and regulatory T lymphocytes. In addition, the relationships between SSc and primary biliary cholangitis may be closer as suggested by the presence of primary biliary cholangitis–specific antibodies in SSc patients and vice versa. Recent findings confirm a prevalence of overt primary biliary cholangitis in about 2% of SSc population, in particular in patients with limited cutaneous SSc and positive anticentromere antibodies. The prevalence increases if also patients with only primary biliary cholangitis–specific antibodies are considered. Data regarding SSc prevalence in primary biliary cholangitis patients have also been recently clarified. Altogether, stimulating results are moving the field forward regarding the relationships of these two autoimmune and fibrotic disorders that may belong to an overlapping entity.

Stiff Skin Syndrome

Stiff skin syndrome (SSS) is clinically characterized by stone-hard skin bound firmly to the underlying tissues, leading to a secondary limitation of joint mobility, often associated mild overlying hypertrichosis, and postural and thoracic wall abnormalities. First manifestations of SSS are usually observed between birth and early childhood with rock-hard skin that is most prominent in areas with abundant fascia such as on the buttocks and thighs, and the disease progresses until the skin of the entire body becomes fibrotic with subsequent growth retardation and joint contractures. SSS is a diagnosis of exclusion, with a distinctive clinical presentation without pathognomonic laboratory or pathological findings. The clinical differential diagnosis of stone-hard and thickened skin areas includes systemic sclerosis, scleroderma, eosinophilic fasciitis, and scleromyxedema. In SSS patients, an overexpression of ECM proteins was detected, whereas no inflammatory infiltrates or upregulation of pro-fibrotic cytokines were found. Data in the literature suggest that fibrosis in SSS might be independent from inflammation. SSS exhibits a spectrum of histopathologic findings and different disease stages might also account for controversial results.