Paula I. Burgos

Stage-Specific Role of Interferon-Gamma in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

The role of interferon (IFN)-γ in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), has remained as an enigmatic paradox for more than 30 years. Several studies attribute this cytokine a prominent proinflammatory and pathogenic function in these pathologies. However, accumulating evidence shows that IFN-γ also plays a protective role inducing regulatory cell activity and modulating the effector T cell response. Several innate and adaptive immune cells also develop opposite functions strongly associated with the production of IFN-γ in EAE. Even the suppressive activity of different types of regulatory cells is dependent on IFN-γ. Interestingly, recent data supports a stage-specific participation of IFN-γ in EAE providing a plausible explanation for previous conflicting results. In this review, we will summarize and discuss such literature, emphasizing the protective role of IFN-γ on immune cells. These findings are fundamental to understand the complex role of IFN-γ in the pathogenesis of these diseases and can provide basis for potential stage-specific therapy for MS targeting IFN-γ-signaling or IFN-γ-producing immune cells.

Inhibition of angiogenesis by platelets in systemic sclerosis patients

IntroductionSystemic sclerosis (SSc) is a chronic autoimmune disease characterized by microvascular damage, inflammation, and fibrosis. It has become increasingly evident that platelets, beyond regulating hemostasis, are important in inflammation and innate immunity. Platelets may be an important source of proinflammatory and profibrotic cytokines in the vascular microenvironment. In this study, we sought to assess the contribution of platelet-derived factors in patients with SSc to the angiogenesis of human dermal microvascular endothelial cells (DMVECs) in a tubule formation assay and to characterize the secretion of profibrotic and proinflammatory cytokines in these platelets.MethodsWe analyzed platelets obtained from 30 patients with SSc and 12 healthy control subjects. Angiogenesis was evaluated in vitro with a DMVEC tubule formation assay on Matrigel and platelet-derived angiogenic factors such as vascular endothelial growth factor (VEGF), 165b isoform (VEGF165b), and cytokine secretion was evaluated. Platelet serotonin content was also determined.ResultsWhen DMVECs were incubated with SSc platelet releasates, tubule formation was significantly inhibited (p < 0.01, t test), and higher expression of endothelin-1 in these cells was observed compared with control subjects (p < 0.05, Mann–Whitney U test). In SSc platelet releasates, VEGF165b was significantly higher (p < 0.05, t test), and the VEGF165b/VEGF ratio was increased compared with that of control subjects. Higher secretion of transforming growth factor β (p < 0.01, t test) and CD40L (p < 0.01, t test) was observed compared with control subjects. Also, intraplatelet serotonin levels were lower in platelets obtained from patients with diffuse SSc compared with patients with limited SSc and control subjects (p < 0.05, t test).ConclusionsOur findings suggest that antiangiogenic factors such as VEGF165b, together with proinflammatory and profibrotic factors secreted by platelets, can contribute to the progression of peripheral microvascular damage, defective vascular repair, and fibrosis in patients with SSc.

Immune Response Modulation by Vitamin D: Role in Systemic Lupus Erythematosus.

Vitamin D plays key roles as a natural immune modulator and has been implicated in the pathophysiology of autoimmune diseases, including systemic lupus erythematosus (SLE). This review presents a summary and analysis of the recent literature regarding immunoregulatory effects of vitamin D as well as its importance in SLE development, clinical severity, and possible effects of supplementation in disease treatment.

First Latin American clinical practice guidelines for the treatment of systemic lupus erythematosus: Latin American Group for the Study of Lupus (GLADEL, Grupo Latino Americano de Estudio del Lupus)–Pan-American League of Associations of Rheumatology (PANLAR)

Systemic lupus erythematosus (SLE), a complex and heterogeneous autoimmune disease, represents a significant challenge for both diagnosis and treatment. Patients with SLE in Latin America face special problems that should be considered when therapeutic guidelines are developed. The objective of the study is to develop clinical practice guidelines for Latin American patients with lupus. Two independent teams (rheumatologists with experience in lupus management and methodologists) had an initial meeting in Panama City, Panama, in April 2016. They selected a list of questions for the clinical problems most commonly seen in Latin American patients with SLE. These were addressed with the best available evidence and summarised in a standardised format following the Grading of Recommendations Assessment, Development and Evaluation approach. All preliminary findings were discussed in a second face-to-face meeting in Washington, DC, in November 2016. As a result, nine organ/system sections are presented with the main findings; an ‘overarching’ treatment approach was added. Special emphasis was made on regional implementation issues. Best pharmacologic options were examined for musculoskeletal, mucocutaneous, kidney, cardiac, pulmonary, neuropsychiatric, haematological manifestations and the antiphospholipid syndrome. The roles of main therapeutic options (ie, glucocorticoids, antimalarials, immunosuppressant agents, therapeutic plasma exchange, belimumab, rituximab, abatacept, low-dose aspirin and anticoagulants) were summarised in each section. In all cases, benefits and harms, certainty of the evidence, values and preferences, feasibility, acceptability and equity issues were considered to produce a recommendation with special focus on ethnic and socioeconomic aspects. Guidelines for Latin American patients with lupus have been developed and could be used in similar settings.

Treat to target in systemic lupus erythematosus: a commentary

Treat to target (T2T) strategies have proved to be useful in several chronic disorders, including Rheumatoid Arthritis. In systemic lupus erythematosus (SLE), T2T strategy has been proposed in order to control disease activity, improve health-related quality of life, and reduce morbidity and mortality. Remission would be the main target, but a low disease activity state (LDAS) could be an acceptable alternative. However, due to SLE protean manifestations, the operational definitions of both remission and LDAS are still in progress. The definitions of these targets, remission and LDAS, should include a validated disease activity index, the treatments allowed, and the minimum length of time the target should be maintained. Furthermore, achieving these targets should result in better disease outcomes such as reducing damage accrual. This review addresses the current state regarding these possible targets in SLE and the impact of achieving them in intermediate and long-term outcomes of this disease.

Treatment Algorithms for Patients with Systemic Lupus Erythematosus: Comment on the Article by Muangchan et al.

We read with interest the thought-provoking article by Muangchan et al, published recently in Arthritis Care & Research, in which the authors proposed different algorithms for the treatment of systemic lupus erythematosus (SLE) patients (1). We would respectfully like to offer some comments. To begin with, we were a bit surprised that the authors chose to only include physicians who were involved in SLE randomized-controlled trials (RCTs) for the development of these algorithms; it can be argued that these physicians are not representative of the universe of specialists treating patients with SLE across the world. Rheumatologists not involved in RCTs may have a different perception of what is the best for these patients. Furthermore, in a multisystemic disease like lupus, other specialists (nephrologists, dermatologists, and neurologists, among others) could have contributed to these algorithms. Also important is the fact that the bulk of the participants (77%) were from North America; this could have significantly impacted on the selection of specific treatment options. Regarding the development of the algorithms per se, we were surprised at the participants’ low retention rate from the first to the third round, i.e., from the original 37 participants in the first round to 13 (35.1%) in the third round. Furthermore, respondents indicated agreement (

Tobacco promotes exacerbated inflammatory features in dendritic cells of Chilean rheumatoid arthritis patients

70%) in only 6 of the 16 organs (37.5%) for which algorithms were constructed. Taking these facts altogether causes us to wonder how valid these algorithms really are. As to the specificities of the algorithms, we do take exception with the fact that hydroxychloroquine was not considered a first-line therapy for some SLE manifestations when in fact there is ample evidence that antimalarials should be used in all SLE patients, unless there is a contraindication because they have proven to prevent disease flares (2) and damage accrual (3), and to prolong survival (4,5). A second concern regarding the algorithms is the fact that the patients’ race/ethnicity was not considered. This is an important point, given that data from clinical trials, particularly in lupus nephritis, suggest that ethnicity and geographic region may influence treatment response (6,7). When comparing the efficacy of mycophenolate mofetil (MMF) and intravenous cyclophosphamide (IVC) as induction therapy for lupus nephritis by race and ethnicity, more African descendants and Hispanic patients responded to MMF than IVC, while response rates with MMF and IVC were comparable in Asians and whites (6,7). Therefore, race/ethnicity should be taken into account when therapeutic decisions are made, particularly in lupus nephritis. In conclusion, the algorithms presented by Muangchan et al (1) constitute, in our view, the opinion of a relatively reduced number of lupus experts, and therefore they should be interpreted and applied with great caution. Given the heterogeneity of the disease, the fact that mild/moderate, severe, or life-threatening lupus manifestations may occur concomitantly, clinicians treating these patients need to, first and foremost, exercise their clinical judgement.

Factors affecting quality of life in patients with systemic lupus erythematosus: important considerations and potential interventions

BACKGROUND The dual potential to promote tolerance or inflammation when facing self-antigens makes dendritic cells (DCs) fundamental players in autoimmunity. There is an association between smoking and DCs maturation in patients with rheumatoid arthritis (RA). However, ethnicity is a key factor in autoimmune disorders. AIM To evaluate phenotypic and functional alterations of DCs obtained from Chilean patients with RA as compared to healthy controls (HC). In second term, to compare the inflammatory behaviour of DCs between smoker and non-smoker patients. MATERIAL AND METHODS Monocyte-derived DCs and T-cells were obtained from blood samples isolated from 30 HC and 32 RA-patients, 14 of which were currently smokers and 18 non-smokers. Several maturation surface markers were evaluated in DCs, including HLA-DR, CD40, CD80, CD83 and CD86. Furthermore, autologous co-cultures of DCs and T-cells were carried out and then T-cell proliferation, and expansion of Th1, Th17 and Tregs were analysed. RESULTS Compared with HC, RA-patients displayed increased HLA-DR expression in DCs, which was manifested mainly in patients with moderate-to- high disease activity scores (DAS28). Furthermore, RA-patients presented a stronger Th17-expansion and a correlation between DAS28 and Th1-expansion. Both effects were mainly observed in patients in remission or with a low DAS28. Moreover, smoker RA-patients displayed enhanced HLA-DR and CD83 expression in DCs as well as an exacerbated Th17-expansion and a correlation between DAS28 and Th1-expansion. CONCLUSIONS These findings suggest that smoking enhances the inflammatory behaviour of DCs and the consequent Th1 and Th17-mediated response in patients with RA.