Roberto Perricone

Glutathione: A key player in autoimmunity

Increasing attention in the physiopathology of inflammatory/immunomediated diseases has been focused on the role of reactive oxygen species (ROS), oxygen-based molecules possessing high chemical reactivity and produced by activated neutrophils during the inflammatory response. During chronic inflammation, when sustained production of ROS occurs, antioxidant defences can weaken, resulting in a situation termed oxidative stress. Moreover, antioxidant defence systems have been demonstrated to be constitutively lacking in patients affected with chronic degenerative diseases, especially inflammatory/immunomediated. Glutathione, a tripeptide, is the principal component of the antioxidant defence system in the living cells. Glutathione has been demonstrated to have diverse effects on the immune system, either stimulating or inhibiting the immunological response in order to control inflammation. The study of interactions between glutathione and the immune system has attracted many investigators. Altered glutathione concentrations may play an important role in many autoimmune pathological conditions prevalently elicited, detrimed and maintained by inflammatory/immune response mediated by oxidative stress reactions. The role of glutathione in autoimmunity will be reviewed herein.

Angiogenesis in rheumatoid arthritis: A disease specific process or a common response to chronic inflammation?

Angiogenesis is the formation of new blood vessels from existing vessels. During RA new blood vessels can maintain the chronic inflammatory state by transporting inflammatory cells to the site of inflammation and supplying nutrients and oxygen to the proliferating inflamed tissue. The increased endothelial surface area also creates an enormous capacity for the production of cytokines, adhesion molecules, and other inflammatory stimuli, simultaneously the propagation of new vessels in the synovial membrane allows the invasion of this tissue supporting the active infiltration of synovial membrane into cartilage and resulting in erosions and destruction of the cartilage. This angiogenic phenotype is promoted by several pro-angiogenic molecules, the most potent of which is vascular endothelial growth factor (VEGF). Although angiogenesis is recognized as a key event in the formation and maintenance the infiltration of synovial membrane during RA, it is unclear whether angiogenesis should be considered a specific feature of the disease or a common inflammation driven process. However the emergence of biological therapies, such as anti TNF blockade, has suggested that there are features of the inflammatory response that are not general but contextual to the specificity of the tissue where inflammation occurs, and point out the relevant role of tissue-resident stromal cells in determining the site at which inflammation occurs and the specific features of chronic inflammation such as that occurs in RA.

NK cells in autoimmunity: A two-edg'd weapon of the immune system☆

Natural killer (NK) cells are part of the innate-immune system and respond rapidly to a variety of insults via cytokine secretion and cytolytic activity. Their main function is first line of innate immunity across viral, bacterial and parasitic infections. NK-cells are not solely killers but can also act as regulators of adaptive immunity. It is evident from literature that NK-cells are deeply involved in autoimmunity, but the question is how and why they act as a two edged weapon. Number of circulating NK-cells can be frequently altered depending on the disease taken into consideration. Cytokine milieu, the microenvironment in which they mature and other stimuli acting on different cell surface receptors may differently trigger NK-cells response and influence their role in autoimmune diseases. Functional differences between NK-cells at different anatomical sites, the adaptability of NK-cells effector responses and genetic factors may also explain differences in such responses. Thus, NK-cell alterations may be associated with increased autoimmunity and the modulation in the number of circulating NK-cells seems to be a primary event rather than an active inflammation/drug administration consequence during inflammatory/autoimmune processes, playing a fundamental role in the pathogenesis of a number of autoimmune diseases.

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.

GM-CSF and Pregnancy: Evidence of Significantly Reduced Blood Concentrations in Unexplained Recurrent Abortion Efficiently Reverted by Intravenous Immunoglobulin Treatment

Problem: Certain Th‐2 cytokines and granulocyte–macrophage colony‐stimulating factor (GM‐CSF) are propitious for the success of pregnancy and recurrent spontaneous abortion (RSA) is often characterized by a failure of Th‐2 type responses. These considerations as well as the use of intravenous immunoglobulin (IVIg) in RSA induced us to evaluate the levels of GM‐CSF in normal pregnancies, in pregnant women affected with unexplained RSA and the effects of IVIg treatment.

High levels of peripheral blood NK cells in women suffering from recurrent spontaneous abortion are reverted from high-dose intravenous immunoglobulins.

To determine the levels of peripheral blood natural killer (NK) cells in healthy women and recurrent aborters, and the effect of intravenous immunoglobulins (IVIGs) on these levels.

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.

Intravenous immunoglobulin therapy in pregnant patients affected with systemic lupus erythematosus and recurrent spontaneous abortion

OBJECTIVES We aimed to test the maternal and fetal outcome of SLE patients who suffered from recurrent spontaneous abortion (RSA) treated with intravenous immunoglobulin (IVIg) alone during pregnancy and whether the clinical response to IVIg treatment is accompanied by modifications of SLE-associated antibodies and of complement levels. METHODS Twelve SLE-RSA pregnant patients were treated with high-dose IVIg and compared with 12 SLE-RSA pregnant patients treated with prednisolone and NSAIDs. They were evaluated for the clinical response [lupus activity index-pregnancy (LAI-P) scale] and for ANA, anti-dsDNA, anti Ro/SS-A or La/SS-B, aCL, LAC, C4, C3 before and during pregnancy, and before and after each treatment course. Pregnancy outcome in the two groups was also evaluated. RESULTS The groups characteristics were homogeneous at the beginning of pregnancy. A beneficial clinical response following IVIg treatment was noted in all patients and mean LAI-P decreased from 0.72 +/- 0.43 at the beginning of pregnancy to 0.13 +/- 0.19 at the end of pregnancy (P < 0.0001). Antibodies and complement levels tended to normalize in most of the patients. These clinical and laboratory improvements were significant with respect to the control group. Pregnancy was successfully carried out in 12/12 (100%) SLE-RSA patients with a mean Apgar score of 8.92. Three patients in the control group got aborted (25%). CONCLUSIONS IVIg has a high response rate among SLE-RSA pregnant patients and may be considered safe and effective.

Anti-thyroid antibodies and antiphospholipid syndrome: evidence of reduced fecundity and of poor pregnancy outcome in recurrent spontaneous aborters.

Problem:  To determine the presence of anti‐thyroid antibodies in patients with primary antiphospholipid syndrome (APS) [antiphospholipid antibodies (aPL) + recurrent spontaneous abortion (RSA)], compare APS alone with APS and thyroid autoimmunity for fecundity and for pregnancy outcome.

Efficacy and Safety of Subcutaneous Anti-Tumor Necrosis Factor-Alpha Agents, Etanercept and Adalimumab, in Elderly Patients Affected by Psoriasis and Psoriatic Arthritis: An Observational Long-Term Study

Background: In elderly patients the management of psoriasis is challenging due to contraindications and a higher risk of side effects. Objective: Our retrospective study aimed to evaluate the long-term efficacy and safety profile of subcutaneous anti-tumor necrosis factor (anti-TNF) agents in elderly psoriatic patients. Methods: The study included 89 patients (aged ≥65 years) with plaque-type psoriasis and psoriatic arthritis treated with the subcutaneous anti-TNF-α agents etanercept or adalimumab as monotherapy for a long-term continuous period. Results: Efficacy results were consistent and stable over long-term observation, as expressed by mean Psoriasis Area and Severity Index (PASI) score variation, percentage of patients achieving PASI50 and PASI75 and by the improvement of articular indices, pain visual analogue scale (Pain-VAS) and 44-Joint Disease Activity Score (DAS44-ESR). The proportion of patients achieving PASI50 was 91.80 and 82.14% at week 156 with etanercept and adalimumab treatment, respectively, while the proportion of patients achieving PASI75 was 83.61 and 71.43% at week 156 when treated with etanercept and adalimumab, respectively. The mean DAS44-ESR score decreased from 5.80 to 0.89 and from 3.43 to 1.44 at week 156 and the mean Pain-VAS score decreased from 75.10 to 3.15 and from 71.30 to 18.26 at week 156 with etanercept and adalimumab treatment, respectively. Both treatment adherence and safety profile were good. Conclusions: Our study demonstrates that subcutaneous anti-TNF-α agents are appropriate in the long-term management of elderly patients.