Roberta Gualtierotti

Updating on the pathogenesis of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease whose pathogenesis is multifactorial lying on genetic, environmental factors and on abnormalities of both the innate and the adaptive immune system. The induction, maintenance and progression of the disease are a multi-step process that may take long time eventually leading to tissue injury. Several genes have been associated to SLE susceptibility; each of them displaying a small effect suggesting the need of an association. However, the gene-gene and gene-environment interactions are still matter of research. Environmental factors, both external such as physical and infectious agents and internal such as gender and hormonal profile, may influence the disease manifestation. SLE is characterized by a complex array of immune abnormalities affecting both the innate and the adaptive immunity. All these processes play a role in the defective clearance of chromatin material that is overexposed to the afferent limb of the immune system leading to an autoimmune response facilitated by defective regulatory mechanisms. The production of a wide panel of autoantibodies represents the ultimate events responsible for tissue aggression. Finally, tissue damage is influenced by the presence of local factors responsible for the final aggressivity of the lesions and of the clinical manifestations.

Prognostic model based on nailfold capillaroscopy for identifying Raynaud's phenomenon patients at high risk for the development of a scleroderma spectrum disorder: PRINCE (Prognostic Index for Nailfold Capillaroscopic Examination)

OBJECTIVE To construct a prognostic index based on nailfold capillaroscopic examinations that is capable of predicting the 5-year transition from isolated Raynauds phenomenon (RP) to RP secondary to scleroderma spectrum disorders (SSDs). METHODS The study involved 104 consecutive adult patients with a clinical history of isolated RP, and the index was externally validated in another cohort of 100 patients with the same characteristics. Both groups were followed up for 1-8 years. Six variables were examined because of their potential prognostic relevance (branching, enlarged and giant loops, capillary disorganization, microhemorrhages, and the number of capillaries). RESULTS The only factors that played a significant prognostic role were the presence of giant loops (hazard ratio [HR] 2.64, P = 0.008) and microhemorrhages (HR 2.33, P = 0.01), and the number of capillaries (analyzed as a continuous variable). The adjusted prognostic role of these factors was evaluated by means of multivariate regression analysis, and the results were used to construct an algorithm-based prognostic index. The model was internally and externally validated. CONCLUSION Our prognostic capillaroscopic index identifies RP patients in whom the risk of developing SSDs is high. This model is a weighted combination of different capillaroscopy parameters that allows physicians to stratify RP patients easily, using a relatively simple diagram to deduce the prognosis. Our results suggest that this index could be used in clinical practice, and its further inclusion in prospective studies will undoubtedly help in exploring its potential in predicting treatment response.

Improving outcome prediction of systemic sclerosis from isolated Raynaud’s phenomenon: role of autoantibodies and nail-fold capillaroscopy

OBJECTIVE A simple weighted prognostic algorithm, based on capillaroscopy and autoantibodies, is developed to classify patients at different risk of transition from isolated RP to SSc within 5 years from the screening visit. METHODS Two hundred and eighty-eight of 768 patients with isolated RP who underwent capillaroscopy were recruited. The prognostic contributions of capillaroscopic findings (giant loops, haemorrhages and the number of capillaries) and SSc-associated autoantibodies (ACAs, anti-topo I and ANAs) were assessed in a semi-parametric regression models suitable for competing risks. A prognostic index was built by a bagging technique. A structured tree approach was used to extract simple classificatory rules that can be directly interpreted. RESULTS Thirty-four transitions from isolated RP to SSc and 42 to other CTDs were observed. All of the chosen variables had a substantial prognostic impact. A complex non-linear prognostic pattern was observed for capillaries, with the risk of developing SSc increasing as the number of loops decreased. The presence of ANAs had a strong impact on prognosis [hazard ratio (HR) = 9.70], which was increased by the presence of ACA (HR = 3.94; P < 0.001). A weighted prognostic classification for the development of SSc was constructed using capillary number, giant loops and ANAs. The prognostic discrimination was satisfactory (Harrells C-index = 0.86). CONCLUSION Our prognostic model is based on easy-to-obtain features (i.e. the number of capillaries, giant loops and ANAs) and could be used to facilitate clinical decision making in the screening phase, and may also have important implications for stratifying patients into risk groups for future clinical assessment.

Complement functional tests for monitoring eculizumab treatment in patients with atypical hemolytic uremic syndrome

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy characterized by hemolysis, platelet consumption, and renal injury. Eculizumab, a mAb that blocks complement activity, has been successfully used in aHUS.

Feasibility of Different Capillaroscopic Measures for Identifying Nailfold Microvascular Alterations

OBJECTIVE To ascertain the most reliable and relevant capillaroscopic measurements of nailfold videocapillaroscopy (NVC) by analyzing their inter- and intraobserver agreement and predictive value. METHODS We studied 217 subjects (110 with Raynauds phenomenon under ongoing evaluation, and 107 with connective tissue diseases) by evaluating the number of capillaries, intercapillary distances, avascular areas, capillary disorganization, capillary loop length, capillary width, percentage of minor abnormalities (tortuous, crossed, or enlarged capillaries), and major abnormalities (giant, bushy, meandering, or branching capillaries), microhemorrhage, skin transparency, and subpapillary plexus visibility. Every finger of both hands was examined. All of the measurements were made by 2 observers under blinded conditions. RESULTS A total of 877 nailfold images were analyzed. The number of capillaries/mm, interpeak distance, and avascular areas were poorly discriminant, with no statistical differences between their areas under the receiver operating characteristic curve; their reproducibility and repeatability were good, except for the intercapillary distance. Minor abnormalities were observed in 75% of the cases and major abnormalities in 34%; the inter- and intraobserver agreement concerning the major abnormalities was almost perfect. There was very good inter- and intraobserver agreement regarding the analysis of capillary disorganization and hemorrhages. CONCLUSIONS This study shows that NVC can be useful in quantitatively and reproducibly recording various parameters. We suggest that combining the parameters showing the greatest reliability and prognostic value may be the best means of analyzing NVC images.

Rheumatoid Factors: Clinical Applications

Rheumatoid factors are antibodies directed against the Fc region of immunoglobulin G. First detected in patients with rheumatoid arthritis 70 years ago, they can also be found in patients with other autoimmune and nonautoimmune conditions, as well as in healthy subjects. Rheumatoid factors form part of the workup for the differential diagnosis of arthropathies. In clinical practice, it is recommended to measure anti-cyclic citrullinated peptide antibodies and rheumatoid factors together because anti-cyclic citrullinated peptide antibodies alone are only moderately sensitive, and the combination of the two markers improves diagnostic accuracy, especially in the case of early rheumatoid arthritis. Furthermore, different rheumatoid factor isotypes alone or in combination can be helpful when managing rheumatoid arthritis patients, from the time of diagnosis until deciding on the choice of therapeutic strategy.

Potential Effect of Anti-Tumour Necrosis Factor-Alpha Treatment on Reducing the Cardiovascular Risk Related to Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that affects about 1% of the adult population. RA sufferers not only have a high chronic disease burden, but may also experience increased cardiovascular disease (CVD) and mortality as the prevalence of myocardial infarction (MI) is 4 times higher in RA patients than in general population, and there is ample evidence showing that coagulation processes are active in RA. Fibrin accumulation in the synovium is one of the most striking pathological features of rheumatoid synovitis and characteristic RA antibodies such as anti-citrullinated protein antibodies (ACPA) can cross-react with epitopes exposed on fibrin and fibrinogen molecules, and thus impair fibrinolysis. The inflammation, coagulation and fibrinolytic systems are modulated by a common mechanism that includes the involvement of proinflammatory cytokines, such as tumour necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6). It has long been recognised that extensive cross-talk takes place between the coagulation pathway and the inflammatory process at various levels, and there is growing evidence that this interaction may be relevant to arthritis. Large-scale, long-term studies have shown that anti-TNF-alpha treatment improves the clinical and laboratory measures of disease activity, and reduces local and systemic inflammation. TNF-alpha blockade may therefore also reduce the impaired coagulation and cardiovascular risk associated with RA. This review provides an overview of the pathophysiological role of TNF-alpha in thrombotic mechanisms and the evidence so far available indicating that anti-TNF-alpha treatment can modify cardiovascular risk in RA.

Autoantibodies to coagulation factors: From pathophysiology to diagnosis and therapy

Autoantibodies may develop against coagulation factors altering their function or promoting their rapid clearance. In non-congenitally deficient patients, they are usually in association with autoimmune diseases, malignancies, pregnancy or advanced age. The possible development of coagulation factor autoantibodies should be considered when a patient presents with bleeding symptoms without any prior bleeding diathesis. The most common disorder associated with coagulation factor autoantibodies is acquired factor VIII deficiency, which is characterized by hemorrhages involving soft tissues, muscles and skin; hemarthroses are less frequent than in the inherited form. Acquired deficiencies of von Willebrand factor and factor XIII due to autoantibodies are emerging conditions. Autoantibodies to the other coagulation factors may be associated with a wide spectrum of clinical manifestations ranging from minimal or no bleeding to life-threatening conditions. The diagnostic approach begins with global coagulation tests: prothrombin time (PT) and activated partial thromboplastin time (aPTT). In case of prolonged times, mixing studies (typically using normal plasma in a 1:1 proportion) should be performed. Specific factor and inhibitor assays, assessment of lupus anticoagulant and eventually enzyme immunoassays for specific anti-factor antibodies complete the evaluation. A prompt diagnosis of specific coagulation factor inhibitors is mandatory for starting an appropriate treatment aimed at overcoming the deficient factor, in case of bleeding, and, if possible, at the suppression of the autoantibodys production.

A systematic overview on the use and relevance of capillaroscopy in systemic sclerosis.

Capillaroscopy is a non-invasive and safe technique that allows the detection and quantification of the early microvascular abnormalities that characterize secondary Raynaud’s phenomenon. The well-established role of capillaroscopy for the early diagnosis of systemic sclerosis, its inclusion in the classification criteria, combined with its predictive value for clinical complications of the disease and its potential for monitoring disease progression and treatment response, makes nailfold capillaroscopy an important assessment in clinical practice and research. Capillaroscopy provides a unique window into the microcirculation and its application in diseases in which a microvascular component is suspected; it also may provide new insights into their pathophysiology and natural history.

Cutting-Edge Issues in Coronary Disease and the Primary Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is the most frequent cause of venous and arterial thrombotic events in young patients. The brain arterial tree is primarily affected, but coronary ischemic manifestations are also relatively frequent. Coronary involvement was suggested to be closely related to the accelerated atherosclerosis linked to the underlying disease in APS associated to systemic autoimmune diseases, in particular, systemic lupus erythematosus. However, arterial ischemic events can occur in primary APS—with no other systemic disorders—even in the absence of traditional cardiovascular risk factors and overt atherosclerosis. From a biological point of view, this finding speaks in favor for a pro-coagulant activity of anti-phospholipid antibodies rather than for their role in atherosclerotic plaque formation. On the other hand, the clinical challenge is to avoid the risk to misdiagnose young patients with potentially life-threatening symptoms, such as myocardial infarction (MI). In fact, the occurrence of nonspecific symptoms related to coronary ischemic events is frequently misdiagnosed because of its rarity in young patients. This issue is well illuminated by two cases of MI in young patients reported in the manuscript together with a systematic review of the associations and implications of coronary ischemic events in APS.