Maria Chiara Gerardi

Citrullination and autoimmunity

Autoimmune diseases are characterized by the bodys own immune system attack to the self-tissues, a condition enabled, in predisposed subjects, by the reduction of self-tolerance. A central role has been recently recognized to post-translational modifications, since they can promote generation of neo-(auto)antigens and in turn an autoimmune response. During the last years great attention has been paid to citrullination, because of its role in inducing anti-citrullinated proteins/peptide antibodies (ACPA), a class of autoantibodies with diagnostic, predictive and prognostic value for Rheumatoid Arthritis (RA). Nonetheless, citrullination has been reported to be a process present in a wide range of inflammatory tissues. Indeed, citrullinated proteins have been detected also in other inflammatory arthritides and in inflammatory conditions other than arthritides (polymyositis, inflammatory bowel disease and chronic tonsillitis). Moreover, environmental exposure to cigarette smoke and nanomaterials of air pollution may be able to induce citrullination in lung cells prior to any detectable onset of inflammatory responses, suggesting that protein citrullination could be considered as a sign of early cellular damage. Accordingly, citrullination seems to be implicated in all those para-physiological processes, such as cells death pathways, in which intracellular calcium concentration raises to higher levels than in physiologic conditions: hence, peptidylarginine deiminases enzymes are activated during apoptosis, autophagy and NETosis, processes which are well-known to be implicated in autoimmunity. Taken together, these data support the hypothesis that rather than being a disease-dependent process, citrullination is an inflammatory-dependent condition that plays a central role in autoimmune diseases.

Serum Levels of Asymmetric Dimethylarginine and Apelin as Potential Markers of Vascular Endothelial Dysfunction in Early Rheumatoid Arthritis

Objectives. Impaired endothelial function represents the early stage of atherosclerosis, which is typically associated with systemic inflammatory diseases like rheumatoid arthritis (RA). As modulators of endothelial nitric oxide synthase expression, asymmetric-dimethylarginine (ADMA) and apelin might be measured in the blood of RA patients to detect early atherosclerotic changes. We conducted a prospective, case-control study to investigate serum ADMA and apelin profiles of patients with early-stage RA (ERA) before and after disease-modifying antirheumatic drug (DMARD) therapy. Methods. We enrolled 20 consecutively diagnosed, treatment-naïve patients with ERA and 20 matched healthy controls. Serum ADMA and apelin levels and the 28-joint disease activity scores (DAS28) were assessed before and after 12 months of DMARDs treatment. All patients underwent ultrasonographic assessment for intima-media tickness (IMT) evaluation. Results. In the ERA group, ADMA serum levels were significantly higher than controls at baseline (P = 0.007) and significantly decreased after treatment (P = 0.012 versus controls). Baseline serum apelin levels were significantly decreased in this group (P = 0.0001 versus controls), but they were not significantly altered by treatment. IMT did not show significant changes. Conclusions. ERA is associated with alterations of serum ADMA and apelin levels, which might be used as biomarkers to detect early endothelial dysfunction in these patients.

Mavrilimumab: an evidence based review of its potential in the treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) management has greatly improved with the development of biologic disease modifying antirheumatic drugs, but a proportion of patients do not improve despite the biologic drugs currently available. We need new biologic agents with novel mechanisms of action for the treatment of refractory patients. Recent evidence has shown that granulocyte-macrophage colony-stimulating factor (GM-CSF) is involved in the pathogenesis of RA. GM-CSF can exacerbate RA and elevated levels of this cytokine have been observed in synovial fluid from RA patients. Antagonism of GM-CSF can strikingly reduce established disease in mouse models of arthritis. Mavrilimumab, a human monoclonal antibody to GM-CSF receptor α, is a competitive antagonist of GM-CSF signaling. Phase I and II studies have shown good clinical response with a good safety profile in patients with mild to moderate RA, suggesting encouraging effects of mavrilimumab for the treatment of RA. This paper reviews the preclinical and clinical data evaluating the safety, tolerability, and efficacy of mavrilimumab in the treatment of RA.

Hypovitaminosis D in recent onset rheumatoid arthritis is predictive of reduced response to treatment and increased disease activity: a 12 month follow-up study

BackgroundVitamin D displays immunomodulatory activities and has been proposed as a potential player in the pathogenesis of rheumatoid arthritis (RA). A negative association between serum 25(OH) vitamin D levels and RA activity was demonstrated but longitudinal studies investigating the role of vitamin D levels in predicting RA activity and response to treatment are lacking. Therefore, this study was designed to test the hypothesis of an association between serum 25(OH) vitamin D levels at RA diagnosis and disease activity evaluated by clinimetric, laboratory and ultrasound (US) parameters and to detect the prevalence of remission and response to treatment after 12 months follow-up.MethodsThis is a longitudinal, retrospective study on data obtained from thirty-seven patients with early RA treatment-naïve. Serum inflammatory markers, auto-antibodies and 25(OH) vitamin D levels were obtained at baseline. Hypovitaminosis D was diagnosed for 25(OH) vitamin D levels < 20 ng/ml. Tender joint count (TJCs), swollen joint count (SJCs), Visual Analog Scales (VAS), Disease Activity Score (DAS) 28 score were assessed at baseline and 12 months after diagnosis. Joints synovitis and power-Doppler were evaluated at baseline and 12 months later.ResultsAt baseline mean 25(OH) vitamin D levels were 24.4 ± 11.9 ng/ml; 35% of study subjects had hypovitaminosis D which strongly associated with higher RA activity and lower prevalence of remission and response to treatment (all p-values < 0.001). The percentage of patients not presenting a reduction of the US synovitis score after 12 months from diagnosis was significantly higher among patients with hypovitaminosis D than in those with normal serum 25(OH) vitamin D at baseline.ConclusionsIn patients with early RA and basal hypovitaminosis D after 12 months follow-up reduction of disease activity and percentage of remission and response to treatment were significantly lower than those observed in patients with normal vitamin D levels. These results provide further support to the immunomodulatory action of vitamin D in RA and suggest a role of basal vitamin D status in the prediction of disease evolution. Vitamin D measurement and possibly vitamin D supplementation should be considered an additional option in the management of early RA patients.

The Microbiome in Connective Tissue Diseases and Vasculitides: An Updated Narrative Review

Objective To provide a narrative review of the most recent data concerning the involvement of the microbiome in the pathogenesis of connective tissue diseases (CTDs) and vasculitides. Methods The PubMed database was searched for articles using combinations of words or terms that included systemic lupus erythematosus, systemic sclerosis, autoimmune myositis, Sjögrens syndrome, undifferentiated and mixed CTD, vasculitis, microbiota, microbiome, and dysbiosis. Papers from the reference lists of the articles and book chapters were reviewed, and relevant publications were identified. Abstracts and articles written in languages other than English were excluded. Results We found some evidence that dysbiosis participates in the pathogenesis of systemic lupus erythematosus, systemic sclerosis, Sjögrens syndrome, and Behçets disease, but there are still few data concerning the role of dysbiosis in other CTDs or vasculitides. Conclusions Numerous studies suggest that alterations in human microbiota may be involved in the pathogenesis of inflammatory arthritides as a result of the aberrant activation of the innate and adaptive immune responses. Only a few studies have explored the involvement of dysbiosis in other CTDs or vasculitides, and further research is needed.

Measurement of Serum Klotho in Systemic Sclerosis

Background The aim of our study was to evaluate the serum concentration of klotho in a cohort of systemic sclerosis (SSc) patients compared to that of healthy controls and to correlate its levels with the degree and the kind of organ involvement. Methods Blood samples obtained from both patients and controls were collected and analysed by an ELISA test for the determination of human soluble klotho. Scleroderma patients were evaluated for disease activity through clinical, laboratory, and instrumental assessment. Results Our cohort consisted of 81 SSc patients (74 females, mean age 63.9 ± 13.1 years) and 136 healthy controls (78 females, mean age 50.5 ± 10.7 years). When matched for age, serum klotho concentration significantly differed between controls and patients (p < 0.001). However, in SSc patients, we did not find any significant association between serum klotho and clinical, laboratory, and instrumental findings. Lower serum levels of klotho were detected in 4 patients who were anticitrullinated peptide antibody (ACPA) positive (p = 0.005). Conclusions Our data show a lower concentration of klotho in the serum of SSc patients compared to that of healthy controls, without any significant association with clinical manifestations and laboratory and instrumental findings. The association between serum klotho and ACPA positivity requires further investigation.

Novel Pharmaceutical Options For Treating Fibromyalgia.

ABSTRACT Fibromyalgia is a chronic disorder whose symptoms have a devastating effect on patients’ lives as they limit their ability to engage in everyday working and social activities, and make it difficult to maintain normal relationships with family, friends and employers. None of the currently available drugs are fully effective against the whole spectrum of symptoms of pain, fatigue, sleep disturbances and depression, but increasing efforts by the pharmaceutical industry have led to the introduction of new investigational drugs and new formulations of older drugs, as well as studies of the possibility of applying drugs currently used for other diseases. The aim of this review is to summarise the data relating to the new therapeutic options that have become available over the last few years.

In sickness and in health: the peculiar occurrence of polymyalgia rheumatica in married cohabiting couples-a case series and review of the literature

Polymyalgia rheumatica (PMR) is an inflammatory rheumatic disorder in elderly people. It is frequently associated with giant-cell arteritis (GCA), although it is still debated if they are the same disease or two distinct pathologies. The etiology of PMR remains challenging, although current knowledge supports the role of both genetic and environmental factors. Among these, there is evidence that infectious agents could trigger the disease’s onset in some cases. We describe the peculiar case where PMR occurred in two Italian married and cohabiting couples and provide a review of the literature for similar cases. This is the first reported occurrence of PMR in two conjugal pairs in Italy. Moreover, in the second case, the wife presented PMR associated with GCA. To date, seven cases of PMR and two of GCA in married couples are described in the literature. The occurrence of PMR in both a husband and a wife supports the pathogenetic role of an environmental factor.

Frequency of Antibodies to Mutated Citrullinated Vimentin in Chronic Obstructive Pulmonary Disease: Comment on the Article by Demoruelle et al

Figure 2 of our article showed that there may be some differences in those with the longest followup. Further, and as we noted in the original article, the large number of statistical tests necessitated cautious interpretation. We did not mean to imply that there was no possibility of such an increased risk with longer followup—it is plausible that with longer followup, differences may emerge, and we hope that future work takes this into consideration.

Interstitial lung disease in systemic autoimmune rheumatic diseases: a comprehensive review

ABSTRACT Background: Interstitial lung diseases (ILDs) are among the most serious complications associated with systemic rheumatic diseases, and lead to significant morbidity and mortality; they may also be the first manifestation of connective tissue diseases (CTDs). The aim of this narrative review is to summarise the data concerning the pathogenesis of CTD/ILD and its distinguishing features in different rheumatic diseseas. Areas covered: The pathogenesis, clinical aspects and treatment of ILD associated with rheumatic systemic diseases and CTDs were reviewed by searching the PubMed, Medline, and Cochrane Library databases for papers published between 1995 and February 2017 using combinations of words or terms. Articles not written in English were excluded. Expert commentary: The management of CTD–ILD is challenging because of the lack of robust data regarding the treatments used, the heterogeneity of the diseases themselves, and the scarcity of well-defined outcome measures. Treatment decisions are often made clinically on the basis of functional, radiographic progression, and exacerbating factors such as age and the burden of comorbidities. Given the complexities of diagnosis and the paucity of treatment trials, the management of CTD patients with ILD requires multidisciplinary collaboration between rheumatologists and pulmonologists in CTD-ILD clinics.