Riccardo Capecchi

Two Takayasu arteritis patients successfully treated with rituximab

Takayasu arteritis (TA) is a rare form of chronic large vessel vasculitis of unknown origin involving the aorta and its major branches. Recently, the involvement of B lymphocytes in TA has been suggested, and active refractory TA patients were successfully treated with B cell depletion therapy (BCDT). We report two cases of patients with TA successfully treated with anti-CD20 monoclonal antibody (rituximab). The favorable outcome of rituximab treatment in our patients also support the view that BCDT can be a useful option for refractory TA, and its potential should be evaluated in controlled trials.

IL-1 family cytokines and receptors in IgG4-related disease.

Abstract Background/aim: The IgG4‐related disease (IgG4‐RD) is a fibroinflammatory condition that can affect almost any organ, often associated with eosinophilia and increased levels of IgE and IgG4. Overexpression in tissues of Th2‐related cytokines but also of IFN‐&ggr; has been reported. Given the major role of Il‐1 family cytokines in inducing and regulating inflammation, and the paucity of data so far available in IgG‐RD, we performed a comprehensive analysis of IL‐18, related IL‐1 family cytokines and soluble receptors in these patients. Patients and Methods: Fifteen patients fulfilling the criteria for the diagnosis of IgG4‐RD and 80 blood donors as control were recruited. Cytokines of the IL‐1 family (IL‐1&agr;, IL‐1&bgr;, IL‐33, IL‐18), soluble receptors (sIL‐1R1, sIL‐1R2, sIL‐1R3, ST2/sIL‐1R4) and antagonists (IL‐1Ra, IL‐18 binding protein ‐IL‐18 BP‐) were measured in sera by multiarray ELISA assay. Free IL‐18 was calculated as the amount of IL‐18 not inhibited by IL‐18 BP. Results: Half of the patients had a multiorgan disease, mainly affecting retroperitoneum, lymph nodes and pancreas. sIL‐1R1 (p = 0.0001), sIL‐1R2 (p = 0.0024), ST2/sIL‐1R4 (p = 0.002) were significantly increased in IgG4‐RD sera compared with healthy controls; sIL‐R3 was significantly lower in patients vs controls (p = 0,0006). Conclusions: The increased levels of the soluble forms of the two IL‐1 receptors IL‐1R1 and IL‐1R2 suggest the need to dampen IL‐1‐mediated inflammation at the tissue level. Elevated circulating ST2/sIL‐1R4 levels may represent the marker of an ongoing protective mechanism, but their contribution to organ damage cannot be excluded. On the whole, the data suggest a tight control of IL‐1 family cytokines signalling in IgG4‐RD.

Salivary Gland Pathology in IgG4-Related Disease: A Comprehensive Review

IgG4-related disease (IgG4-RD) is a rare fibroinflammatory condition that can affect almost any organ, characterized by swollen lesions and often by eosinophilia and elevated serum IgG4 concentrations. The diagnosis of IgG4-RD is a challenging task: in fact, single or multiple organs can be affected and clinical, serological, and histological findings can be heterogeneous. In IgG4-RD, the involvement of salivary glands is observed in 27% to 53% of patients. Several organ-specific conditions, now recognized as different manifestations of IgG4-related sialadenitis (IgG4-RS), were viewed in the past as individual disease entities. The study of salivary glands may sometimes be complex, because of the number of pathological conditions that may affect them, often with overlapping clinical pictures. Integration of different imaging techniques is often required in the case of swelling of salivary glands, even though biopsy remains the gold standard for a definite diagnosis of IgG4-RS. Thus, in this review, we discuss new insights in the pathogenesis of IgG4-RD, focusing on its clinical aspects and the tools that are currently available for a correct differential diagnosis when the salivary glands are involved.

A6.10 Anti citrullinated peptides/proteins antibodies induce secretion of CCL5/rantes by fibroblast like synoviocytes

Background Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder, characterised by a progressive joint damage, caused by a cellular infiltrate localised in the synovia. In RA, fibroblast like synoviocytes (FLS) acquire an aggressive phenotype and contribute to joint destruction also producing a variety of pro-inflammatory cytokines. In the pathogenesis of RA a pivotal role is played by fibroblast like synoviocytes (FLS), that produce cytokines that perpetuate inflammation. One of the serological markers of RA are anti citrullinated protein antibodies (ACPA), a family of autoantibodies recognising a wide variety of antigens all characterised by the deimination of arginine into citrulline. Among the different citrullinated targets, ACPA can bind viral citrullinated peptides (VCPs) and histone citrullinated peptides (HCPs). Despite their strict association with RA, so far little is known about the role of ACPA in the pathogenesis of the disease. Objective The aim of this work was to analyse the effects of anti VCPs and HCPs antibodies on in vitro cultured FLS. Methods FLS from RA and non RA patients were isolated from synovial fluid and used for experiments at 4–5th passage. Anti-VCPs and anti-HCPs antibodies were purified by affinity chromatography from RA patients sera and IgG from normal subjects were used as control antibodies. Anti-VCPs and –HCPs antibodies were incubated on subconfluent FLS; cells and supernatants were recovered at different time points. RANTES protein was quantified in the supernatants by sandwich ELISA and RANTES gene expression was evaluated by RT-PCR. To investigate intracellular signalling after ACPA stimulation, specific MAP kinase, already known to be activated during CCL5/RANTES production, were studied. Results Anti-VCPs and anti-HCPs from 5 RA patients induce RNA expression and secretion of RANTES from FLS as compared with normal IgG (p < 0.001). No differences were observed between RA and non RA FLS. FLS stimulation with ACPA seems to induce phosphorylation of ERK, JNK and p38. Conclusions These results suggest a novel mechanism potentially involved in damage induced by ACPA, mediated by the production of RANTES in FLS. ACPA might play a role in activation and chemotaxis of T cells in synovial tissue with a perpetuation in inflammation and immune response. Studies are in progress to clarify the intracellular pathways implicated in the synthesis of RANTES induced by ACPA in FLS and to define the target of ACPA on FLS surface.

CCL5/RANTES in ANCA-associated small vessel vasculitis

(Figure 1). This case illustrates several therapeutic issues that can arise in the management of TB in the context of anti-TNF therapy. As was clearly demonstrated in our patient, withdrawal of infliximab and use of TB treatment can result in a flare-up of the underlying rheumatic disease and/or an excessive inflammatory response conducive to IRIS (3). This syndrome was first described before the HIV epidemic as a paradoxical response to TB treatment, but it drew wide attention in the AIDS era (4). Although the incidence of IRIS after discontinuation of anti-TNF therapy is not known, based on the limited number of reported cases (Table 1) (3, 5–8) and on a survey on behalf of the Infectious Diseases Society of America Emerging Infections Network (9) it seems that IRIS is not common in this context and when it occurs it responds well to treatment. However, the development of breakthrough TB in our patient, despite the administration of active anti-tuberculous treatment, indicates that resumption and continuation of anti-TNF agents after diagnosis of TB may render tuberculosis refractory to treatment, especially in patients with signs of active disease. Thus, when we are faced with the therapeutic dilemma to withdraw or continue an anti-TNF agent in patients who develop TB, we should consider the risks and benefits of each approach. The first approach may result in flare-up of rheumatic disease and/or IRIS. The second approach, however, may result in TB treatment failure. The limited experience presented here, in conjunction with the high mortality rate reported in patients with anti-TNF-associated TB (9), raises awareness that the administration of any of the currently available anti-TNF agents may not be safe in cases of active TB and should be withheld until completion of TB treatment. References