Eleonora Ballanti

Complement and autoimmunity

The complement system is a component of the innate immune system. Its main function was initially believed to be limited to the recognition and elimination of pathogens through direct killing or stimulation of phagocytosis. However, in recent years, the immunoregulatory functions of the complement system were demonstrated and it was determined that the complement proteins play an important role in modulating adaptive immunity and in bridging innate and adaptive responses. When the delicate mechanisms that regulate this sophisticated enzymatic system are unbalanced, the complement system may cause damage, mediating tissue inflammation. Dysregulation of the complement system has been involved in the pathogenesis and clinical manifestations of several autoimmune diseases, such as systemic lupus erythematosus, vasculitides, Sjögren’s syndrome, antiphospholipid syndrome, systemic sclerosis, dermatomyositis, and rheumatoid arthritis. Complement deficiencies have been associated with an increased risk to develop autoimmune disorders. Because of its functions, the complement system is an attractive therapeutic target for a wide range of diseases. Up to date, several compounds interfering with the complement cascade have been studied in experimental models for autoimmune diseases. The main therapeutic strategies are inhibition of complement activation components, inhibition of complement receptors, and inhibition of membrane attack complex. At present, none of the available agents was proven to be both safe and effective for treatment of autoimmune diseases in humans. Nonetheless, data from preclinical studies and initial clinical trials suggest that the modulation of the complement system could constitute a viable strategy for the treatment of autoimmune conditions in the decades to come.

Role of the complement system in rheumatoid arthritis and psoriatic arthritis: Relationship with anti-TNF inhibitors

The complement system is an essential component of innate immunity and also plays an important role in modulating adaptive immunity. It comprises more than 30 plasma and membrane-bound proteins and can be activated through three pathways: the classical, the alternative and the lectin pathways. Its activation contributes to the pathogenesis of several autoimmune and inflammatory conditions. The evidence of complement activation in synovial fluid of Rheumatoid Arthritis (RA) patients is abundant, while few data exist in Psoriatic Arthritis (PsA) patients. Levels of complement proteins are generally depressed in the synovial fluid of patients with RA, reflecting consumption of complement. On the other hand, elevated levels of several complement cleavage products have been observed in synovial fluid. Involvement of complement in the pathogenesis of RA was also confirmed in animal models of arthritis: mice deficient for complement proteins are protected against the development of collagen-induced arthritis and administration of the anti-C5 monoclonal antibody prevents the onset of this arthritis. In the last decade anti-tumor necrosis factor agents have shown to be effective for the treatment of both RA and PsA and some studies suggest that the interaction between TNFα and complement system may contribute to the pathogenesis of these diseases. Reduction of the complement activation could be one of the mechanism by which TNFα-inhibitors exert their effectiveness in inflammatory arthritides. Because of these findings, complement could be an attractive therapeutic target both in RA and in PsA.

Complement system and rheumatoid arthritis: relationships with autoantibodies, serological, clinical features, and anti-TNF treatment

Autoantibodies (rheumatoid factor, RF; anti-citrullinated-protein antibodies, ACPA) and complement system are involved in rheumatoid arthritis (RA). ACPA and anti-TNF agents are capable of in vitro modulating complement activity. We investigated the relationships between complement, autoantibodies, and anti-TNF treatment in vivo. One-hundred fourteen RA patients (89F/25M), diagnosed according to 1987 ACR criteria, and 30 healthy controls were enrolled. Serological analysis included ESR, CRP, complement C3, C4 and CH50, RF and ACPA (ELISA, cut-off>20U/ml). Split-products (SP) of C3 and B were studied by immunoelectrophoresis/counterimmunoelectrophoresis. Seventy-six patients started anti-TNF treatment and were studied at baseline and after 22 weeks. Disease activity was measured with DAS28 and response to therapy with EULAR criteria. At baseline, RA patients showed significantly higher levels of C3 and C4 than controls (C3 127.9±26.5 vs 110±25mg/dl, P=0.0012; C4 29.7±10.2 vs 22.7±8.3mg/dl, P=0.0003). No differences in C3, C4 and CH50 levels were observed between ACPA+ (n=76) and ACPA- (n=38) patients. After 22 weeks of anti-TNF, C3, C4 and RF were significantly reduced (P<0.003, <0.005 and <0.04, respectively) and RF changes showed negative correlation with CH50. SP of C3 and B were observed neither at baseline nor after 22 weeks. DAS28 significantly improved after 22 weeks. Patients showing higher baseline C3 or lower reduction of C3 levels after 22 weeks had a worse EULAR outcome (χ2=22.793, P<0.001). RF levels seem to correlate with complement CH50. The presence of high levels of C3 in RA patients may reflect a pro-inflammatory status and represent a negative prognostic factor for anti-TNF therapy.

Restoration of peripheral blood natural killer and B cell levels in patients affected by rheumatoid and psoriatic arthritis during etanercept treatment.

Etanercept (ETN) is an anti‐tumour necrosis factor (TNF)‐α agent used in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Few studies focused on the effects of anti‐TNF‐α on peripheral blood cells. We aimed to evaluate peripheral blood cells in RA and PsA patients during ETN treatment and to explore their relationships with disease activity. RA (n = 82) and PsA (n = 32) patients who started ETN were included into the study and evaluated prospectively before the beginning of ETN therapy and after 14, 22, 54 and 102 weeks. Patients were studied in terms of disease activity score on 28 joints (DAS28), clinical response and laboratory findings. Natural killer (NK) cells, B cells and T cells were characterized by immunophenotyping. Both the RA and the PsA patients showed reduced NK and B cell count before ETN treatment compared with controls. A negative correlation was demonstrated between DAS28 and B cell count in RA patients at baseline. Sustained significant increase of NK and B cells up to normal levels was observed in RA and PsA patients along ETN treatment. Increase of NK cell count was associated with a good–moderate clinical response to ETN in both RA and PsA patients. During ETN treatment peripheral blood NK and B cells levels were restored in RA and PsA patients. Correlations between NK and B cells with disease activity were observed, suggesting that those effects could be mediated by ETN treatment.

Vasculitides and the Complement System: a Comprehensive Review.

Systemic vasculitides are a group of rare diseases characterized by inflammation of the arterial or venous vessel wall, causing stenosis or thrombosis. Clinical symptoms may be limited to skin or to other organs or may include multiple manifestations as systemic conditions. The pathogenesis is related to the presence of leukocytes in the vessels and to the IC deposition, which implies the activation of the complement system (CS) and then the swelling and damage of vessel mural structures. The complement system (CS) is involved in the pathogenesis of several autoimmune diseases, including systemic vasculitides. This enzymatic system is a part of the innate immune system, and its function is linked to the modulation of the adaptive immunity and in bridging innate and adaptive responses. Its activation is also critical for the development of natural antibodies and T cell response and for the regulation of autoreactive B cells. Complement triggering contributes to inflammation-driven tissue injury, which occurs during the ischemia/reperfusion processes, vasculitides, nephritis, arthritis, and many others diseases. In systemic vasculitides, a group of uncommon diseases characterized by blood vessel inflammation, the contribution of CS in the development of inflammatory damage has been demonstrated. Treatment is mainly based on clinical manifestations and severity of organ involvement. Evidences on the efficacy of traditional immunosuppressive therapies have been collected as well as data from clinical trials that involve the modulation of the CS. In particular in small-medium-vessel vasculitides, the CS represents an attractive target. Herein, we reviewed the pathogenetic role of CS in these systemic vasculitides as urticarial vasculitis, ANCA-associated vasculitides, anti-glomerular basement membrane disease, cryoglobulinaemic vasculitides, Henoch-Schönlein purpura/IgA nephropathy, and Kawasaki disease and therefore its potential therapeutic use in this context.

The autoimmune side of hereditary angioedema: Insights on the pathogenesis

Hereditary angioedema (HAE) is an autosomal dominant disease resulting from the deficiency of C1 inhibitor (C1-INH), a glycosylated serine protease inhibitor that plays a regulatory role in the complement system (CS), the contact system and the intrinsic coagulation cascade. HAE disease severity is highly variable and may be influenced by genetic polymorphisms as well as by other factors, such as gender hormone-mediated effects. In HAE, the potential inadequate clearance of immune-complexes (IC) in the presence of reduced levels of CS components and in turn an excess of IC in the tissues results in inflammatory damage and release of autoantigens that may trigger an autoimmune response. Occasional reports link HAE with autoimmune conditions and only few studies have been conducted on large patient populations with controversial results. Although several immunoregulatory disorders have been documented, the prevalence of defined autoimmune diseases in patients with HAE remains debated. The occurrence of autoimmune conditions in HAE patients may worsen the disease severity enhancing the complexity of the comprehensive care.

Remission and low disease activity in a cohort of real-life patients with rheumatoid arthritis treated with first-line antitumour necrosis factor

Objectives This retrospective study used various indices to evaluate remission and low disease activity in ‘real life’ patients with rheumatoid arthritis (RA), given antitumour necrosis factor (anti-TNF) as a first-line treatment; changes in concomitant steroid and conventional synthetic disease-modifying antirheumatic drug (csDMARD) treatment were also assessed. Methods Remission and low disease activity were analysed in patients with RA treated with anti-TNF using the 28-joint Disease Activity Score (DAS28), Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI). Remission and low disease activity were recorded after 6 months, 1 year and 2 years, along with concomitant prednisone and csDMARD treatment. Results A total of 271 patients with RA were included in the study. After 6 months, remission rates were 18.0%, 20.3% and 23.0% as assessed by CDAI, SDAI and DAS28, respectively. After 1 year and 2 years, respectively, remission rates were 18.4% and 15.9% using CDAI, 21.8% and 17.3% using SDAI, and 22.1% and 17.3% using DAS28. Low disease activity was achieved in 30–40% of patients, depending on the indices used. There was a significant reduction in the number of patients on prednisone and csDMARDs during anti-TNF treatment. Conclusion Remission with first-line anti-TNF treatment is an achievable goal in clinical practice, allowing a reduction in concomitant csDMARD and prednisone treatment.

Humoral Factors in the Skin

The literature of the last 20 years in relation to oxidative stress (OS) is extremely abundant (>25,000 articles). This chapter attempts to give just the basis of OS and suggestions about the relevant literature on the matter. This chapter describes the essential elements of OS, starting from its formation, propagation, and the control exercised by enzymatic and nonenzymatic systems. The most common pathways to produce the reactive species (RS) and the molecules undergoing their oxidizing action will be considered together with the most important cellular defense mechanisms. The aim of this chapter is to describe the baseline concepts to investigators and medical doctors that need to approach the problem of OS leaving a much more precise definition to the reported literature.

FRI0222 Impact of a Multidisciplinary Approach in Enteropathic Spondiloarthritis: Usefulness of a Combined Assessment in Prevalence, Characteristics, Diagnostic Delay and Outcomes

Background Prevalence of Enteropathic-related Spondyloarthritis (SpAe) in inflammatory bowel disease (IBD) shows marked variations (18-45%) and may be underestimated by gastroenterologists. Objectives In a prospective study, in a combined GastroIntestinal and RHeumAtologic “GiRha” clinic of the University of Rome “Tor Vergata”, prevalence and characteristics of joint manifestations in inflammatory bowel disease (IBD) patients were evaluated. diagnostic delay and therapeutic modifications were also assessed. Methods The study prospectively enrolled patients affected by IBD who presented muscolo-skeletal pain between November 2012 and July 2014. Disease activity in SpA patients was assessed using the ASDAS-CRP, BASDAI, BASFI, DAS44-CRP and HAQ-S. Results SpAe was detected in 101 patients. In 65 cases this was a new diagnosis. Other rheumatologic diagnosis were: Osteoarthritis (30.3%), Fybromialgia (6.9%), Psoriatic Arthritis (4.3%), Rheumatoid Arthritis (3.2%) and Gout (1.6%). Prevalence of other extraintestinal manifestations (psoriasis, uveitis, primary sclerosing cholangitis and erythema nodosum) resulted higher in SpAe patients than that in IBD non-SpAe patients (p=0.04). 56.4% SpAe patients showed a high disease activity (ASDAS ≥2.1). 22.8% had axial involvement, peripheral involvement in 57.4% and a combination of peripheral and axial involvement in 19.8% of cases. Axial SpAe patients were preferentially male and showed increased ESR and CRP levels compared with peripheral SpAe patients. Peripheral SpAe patients showed higher DAS levels compared with that in both axial and axial+peripheral SpAe patients. The diagnostic delay (time between the onset of joint symptoms and first rheumatological encounter) was calculated for all SpAe patients. Patients with disease onset between 2000-2009 had a reduced diagnostic delay compared with those with joint onset in 1980-1989 and 1990-1999. The diagnostic delay was further reduced for those patients with joint onset after 2010 (Figure 1). A higher percentage of IBD patients were treated with disease-modifying anti-rheumatic drugs (p=0.04), anti-COX2 (p<0.0001) and anti-TNF drugs (p=0.001) after the rheumatological assessment. Clinical outcome demonstrate improuvement of disease activity after 6 months of combined aproach: ASDAS and DAS changed from 2.8±0.9 at baseline to 1.4±0.5 and 2.5±0.8 at baseline to 1.8±0.8 respectively. Conclusions Multidisciplinary care facilitates the diagnosis and the management of rheumatic disorders in IBD offering a comprehensive treatment approach. Disclosure of Interest None declared