SIRT1 activation protects against autoimmune T cell-driven retinal disease in mice via inhibition of IL-2/Stat5 signaling.

Sirtuins are a mammalian family of NAD(+)-dependent histone deacetylases that regulate cell function and survival as well as regulating cell responses under inflammatory conditions. SIRT1 activator treatment in vitro using mouse pLN cells, normal human and ocular Behçet's disease donor PBMC resulted in suppressed T cell proliferation and pro-inflammatory cytokine production. Our data suggest a novel mechanism by which SIRT1 activators contribute to suppression of T cell proliferation by both down regulating STAT5A/B expression and suppression of pSTAT5A/B signaling in response to IL-2. Experimental autoimmune uveoretinitis (EAU) in B10.RIII mice is an antigen-specific cell-mediated model of human intra-ocular inflammatory disease. Infiltrating CD4(+) T cells in the retina secrete both IFN-γ and IL-17 and are accompanied by inflammatory granulocytes and macrophages which together result in retinal destruction. Oral SIRT1 activator treatment administered to EAU mice suppressed disease with an accompanying reduction in retinal leukocytic infiltrate, suppressed antigen-specific T cell responses and marked suppression of innate and adaptive pro-inflammatory cytokine production in the eye including IL-6, IL-17A and IFN-γ. In vivo SIRT1 activator treatment also suppressed production of IL-17A, IL-17F, IL-6, TGFß and IL-22 by pLN cells. Oral SIRT1 activator treatment administered to mice during the efferent phase (days7-14) of EAU was effective at suppressing disease. These observations demonstrate that SIRT1 activation is anti-inflammatory in nature and future targeted activation of SIRT1 shows promise as a potential treatment for non-infectious intra-ocular disorders such as uveitis associated with Behçets disease.

Long-term clinical outcomes and factors predictive of relapse after 5-aminosalicylate or sulfasalazine therapy in patients with intestinal Behcet disease.

BACKGROUND: Currently, 5-aminosalicylic acid (5-ASA)/sulfasalazine is used to empirically treat patients with intestinal Behcet disease (BD) without clear clinical evidence. In this study, we investigated long-term clinical outcomes and predictors of clinical relapse in patients with intestinal BD receiving 5-ASA/sulfasalazine maintenance therapy. METHODS: We reviewed the medical records of all the patients with intestinal BD, who received 5-ASA/sulfasalazine therapy in a single tertiary academic medical center between March 1986 and January 2011. The cumulative probabilities of clinical relapse after remission were calculated using the Kaplan-Meier method. Predictors of clinical relapse were identified by univariate analysis using the log-rank test and by multivariate analysis using Cox proportional hazards regression models. RESULTS: Among the 143 patients enrolled, 46 (32.2%) had a clinical relapse while they were being treated with 5-ASA/sulfasalazine therapy. The cumulative relapse rates at 1, 3, 5, and 10 years after remission were 8.1%, 22.6%, 31.2%, and 46.7%, respectively. By multivariate analysis, a younger age (<35 y) at the time of diagnosis, higher C-reactive protein level (≥1.5 mg/dL), and a higher disease activity index for intestinal Behcet disease score (≥60) at the time of 5-ASA/sulfasalazine initiation were independent predictors of relapse in patients with intestinal BD receiving 5-ASA/sulfasalazine maintenance therapy. CONCLUSIONS: This study has shown that 5-ASA/sulfasalazine therapy has a positive effect in maintaining remission in patients with intestinal BD. However, a younger age (<35 y), higher C-reactive protein level (≥1.5 mg/dL), and a higher disease activity index for intestinal Behcet disease score (≥60) were associated with a poor response to 5-ASA/sulfasalazine therapy, making careful observation and intensive treatment necessary in these risk groups.

Response rates to medical treatments and long-term clinical outcomes of nonsurgical patients with intestinal Behçet disease.

BACKGROUND: The aims of this study were to evaluate the efficacy of medical treatments and to identify factors to predict clinical outcome of intestinal Behçet disease (BD) during medical treatment. METHODS: We performed a retrospective review of the medical records of 93 patients who were diagnosed and medically treated with intestinal BD at Severance Hospital, Seoul, Korea from 1992 to 2007. A therapeutic response was evaluated 8 weeks after the initiation of medical treatment, and cumulative recurrence and surgery rates were also assessed during long-term follow-up. RESULTS: The initial remission rate at 8 weeks after treatment was 66.7%. During the follow-up period, cumulative recurrence rates for intestinal BD were 24.9% at 2 years and 43.0% at 5 years. The recurrence rate was significantly higher in patients with apparent gastrointestinal symptoms at their initial presentation, volcano-type and deep intestinal ulcers, and those who failed to achieve complete remission during the initial treatment. Cumulative rates for surgery were 6.7% at 2 years and 15.1% at 5 years. The typical type of ulcers was the only predictive factor for the likelihood of surgery. CONCLUSIONS: Our study demonstrates that a considerable number of patients experience disease relapse during follow-up despite a high-remission rate after medical treatment for intestinal BD. Careful observation and intensive treatment should be carried out, especially in patients without complete remission after initial treatment, with deep and volcano-shaped ulcers, or with apparent gastrointestinal symptoms at the time of diagnosis.

Low prevalence of NOD2 SNPs in Behçet's disease suggests protective association in Caucasians.

OBJECTIVE: It has been shown previously that three nucleotide-binding oligomerization domain containing 2 (NOD2) variants (Arg702Trp, Gly908Arg and Lue1007fs) are associated with Crohn's disease (CD), a disorder clinically resembling Behçet's disease (BD). We studied the frequency of these variants in BD patients. METHODS: DNA samples of 200 BD patients [59 Caucasians, 139 Middle Easterns (MEs) of Arab descent and 2 Asians] and 520 healthy controls (444 Caucasians and 76 MEs) were genotyped using a Taqman assay. RESULTS: Both the Arg702Trp and Leu1007fs (frameshift) variants were significantly less frequently present among BD patients compared with healthy controls (0.5 vs 5.8%; P < 1.10(-5) and 0.0 vs 1.8%; P < 0.007, respectively). In the Caucasian subpopulation, Arg702Trp was significantly less frequent in the BD group as compared with the controls (P = 0.04); whereas in the ME subpopulation, a trend was observed (P < 0.06). CONCLUSIONS: Of the three CD-associated single nucleotide polymorphisms, one of the variant NOD2 alleles, was found to be present significantly less in Caucasian BD patients.

Association between polymorphisms of FCRL3, a non-HLA gene, and Behçet's disease in a Chinese population with ophthalmic manifestations.

PURPOSE: Studies have shown a strong association of human leukocyte antigens-B51 (HLA-B51) with Behçet's disease (BD). However, little is known about the association of non-HLA genes with BD. The polymorphisms of the Fc receptor-like 3 gene (FCRL3), -169C/T, -110A/G, +358C/G, and +1381A/G, have been reported to be associated with several autoimmune diseases. This study was designed to determine whether the polymorphisms of FCRL3 were associated with susceptibility to BD in a Chinese population mainly with ocular involvement. METHODS: A case-control study was performed in 245 Chinese BD patients and 289 controls. Four single nucleotide polymorphisms (SNPs; -169C/T, -110A/G, +358C/G, and +1381A/G) in FCRL3 were detected using polymerase chain reaction restriction fragment length polymorphisms (PCR-RFLP). HLA-B51 genotyping was performed by the PCR sequence specific primers method as described previously. RESULTS: The results showed a significantly higher frequency of the G allele at the -110 site in BD patients compared with that in controls (corrected p=0.044, 75.3% versus 67.5%, chi2=7.72). Haplotype CGCG frequency was significantly higher in patients than in controls (corrected p=0.0096) whereas haplotype TACG frequency was significantly lower in patients compared with controls (corrected p=0.032). There was no relationship between clinical signs and FCRL3 polymorphisms. No significant difference was observed between patients and controls after HLA-B51 stratification concerning the four SNPs. CONCLUSIONS: Our study suggests that the -110 G allele and the haplotype CGCG of FCRL3 are positively associated with BD in a Chinese population and that the haplotype ATCG might be a protective haplotype for BD.

Standard and novel therapeutic approaches to Behçet's disease.

Behçet's disease (BD), a systemic inflammatory disorder of unknown aetiology, is characterised by recurrent attacks of oral aphthous ulcers, genital ulcers, skin lesions, uveitis or other manifestations affecting the blood vessels, gastrointestinal tract, and respiratory and central nervous systems. Although the treatment of BD is empirical, in recent years, it has been shown that early and effective treatment of acute inflammatory lesions and prevention of relapses can help to reduce the disease burden and improve outcome. Randomised, controlled trials are limited in BD, but those that have been conducted have documented favourable effects of colchicine, ciclosporin, azathioprine, thalidomide, dapsone, depot methylprednisolone, rebamipide, sucralfate, benzathine benzylpenicillin, interferon-alpha-2a and etanercept for various BD manifestations. Anti-inflammatory and/or immunosuppressive treatments should be tailored according to the disease severity and prognostic factors. More potent drugs, such as azathioprine, ciclosporin, interferon-alpha and infliximab, are effective in the suppression of more severe systemic features as well as mucocutaneous manifestations of BD. Although no randomised, controlled trials are yet available, results of open studies with both interferon-alpha and infliximab are promising for those patients with disease resistant to conventional immunosuppressive treatments. Multicentre, multi-disciplinary and long-term trials aiming to assess the efficacy of interventions in both the treatment of acute inflammatory attacks and the prevention of relapses are required in order to provide more generalisable results that can lead to better management plans.

Mucosal adjuvants and anti-infection and anti-immunopathology vaccines based on cholera toxin, cholera toxin B subunit and CpG DNA.

Mucosal immunisation may be used both to protect the mucosal surfaces against infections and as a means for immunological treatment of peripheral immunopathological disorders through the induction of systemic antigen-specific tolerance ('oral tolerance'). The development of mucosal vaccines, whether for prevention of infectious diseases or for oral tolerance immunotherapy, requires efficient antigen delivery and adjuvant systems that can help to present the appropriate vaccine or immunotherapy antigens to the mucosal immune system. The most potent (but also toxic) mucosal adjuvants are cholera toxin (CT) and the closely related Escherichia coli heat-labile enterotoxin (LT), and much effort and significant progress have been made recently to generate toxicologically acceptable derivatives of these toxins with retained adjuvant activity. Among these are the non-toxic, recombinantly produced cholera toxin B-subunit (CTB). CTB is a specific protective antigen component of a widely registered oral cholera vaccine as well as a promising vector for either giving rise to mucosal anti-infective immunity or for inducing peripheral anti-inflammatory tolerance to chemically or genetically linked foreign antigens administered mucosally. CT and CTB have also recently been used as combined vectors and adjuvants for markedly promoting ex vivo dendritic cell (DC) vaccination with different antigens and also steering the immune response to the in vivo-reinfused DCs towards either broad Th1 + Th2 + CTL immunity (CT) or Th2 or tolerance (CTB). Another type of mucosal adjuvants is represented by bacterial DNA or synthetic oligodeoxynucleotides containing CpG-motifs, which especially when linked to CTB have been found to effectively stimulate both innate and adaptive mucosal immune responses. The properties and clinical potential of these different classes of adjuvants are being discussed.

Treatment of Behçet's disease--an update.

OBJECTIVES: To report the experience of the investigators and review the major treatment trials conducted for Behçet's disease (BD). METHODS: A MEDLINE literature review from 1970 to date was performed on the drugs prescribed for the treatment of BD. Open and controlled clinical studies and indications for the treatment of affected organs are analyzed. RESULTS: Glucocorticoids are indicated for the treatment of BD, although no controlled studies have been reported. The combination of corticosteroids and immunosuppressant drugs is used when vital organs are involved. Nonsteroidal anti-inflammatory drugs are of little value in arthritis. In controlled trials, colchicine was efficacious for erythema nodosum and arthritis, particularly in women. Cyclosporine A has a rapid action and when combined with azathioprine is effective in patients with severe uveitis and extraocular manifestations. Chlorambucil is indicated for uveitis and meningoencephalitis. In controlled studies, azathioprine prevented unilateral uveitis from becoming bilateral and improved extraocular symptoms. Pulse cyclophosphamide combined with corticosteroids improves severe systemic vasculitis. Interferon alpha benefits ocular and extraocular manifestations, but controlled studies are lacking. Methotrexate is indicated for uveitis and arthritis, and sulfasalazine improves gastrointestinal vasculitis. In controlled trials, thalidomide was effective for mucocutaneous manifestations, but on its discontinuation the disease exacerbated. Orogenital manifestations are treated with local application of corticosteroids or other medications. CONCLUSIONS: Combination therapy is not always efficacious in controlling inflammation. The goal of management is to treat early to avoid recurrences and irreversible damage to the vital organs. With proper management of BD, loss of useful vision was reduced from 75% to 20% of the affected eyes. However, less favorable results are seen for central nervous system and large artery and vein involvement.

Expression of Th2 cytokines decreases the development of and improves Behçet's disease-like symptoms induced by herpes simplex virus in mice.

In the etiology of Behçet's disease (BD), viral infection has long been postulated as a contributing factor, and viral involvement has been demonstrated. However, viral infection alone is not sufficient to explain the pathogenesis of BD, and some evidence suggests that immunologic abnormalities are also important. To study the possible role of immune regulation in the development of BD-like symptoms induced by herpes simplex virus inoculation in ICR mice, macrophages were deleted by use of liposome-encapsulated clodronate (lip-Cl(2)MDP). Treatment with lip-Cl(2)MDP suppressed the development of BD-like symptoms, and this suppression was correlated with the induction of interleukin-4 expression in mouse spleens. When the Th2 adjuvant ovalbumin (OVA)-alum was injected into mice with BD-like symptoms, their cutaneous symptoms improved. Adoptive transfer with splenocytes from OVA-alum-injected mice also resulted in improvement. These findings suggest that up-regulated Th2 cytokine expression can attenuate the development of and improve some BD-like symptoms.

Effect of prophylactic benzathine penicillin on mucocutaneous symptoms of Behçet's disease.

BACKGROUND: Recent studies point out a probable role of streptococcal antigens in the pathogenesis of Behçet's disease (BD). This has led to the proposal of benzathine penicillin as a therapeutic modality in BD. OBJECTIVE: A prospective study was conducted to compare the efficacy of colchicine and colchicine + benzathine penicillin treatments on mucocutaneous manifestations of BD. METHODS: 60 patients (group I) were given colchicine alone and 94 (group II) were given colchicine + benzathine penicillin. Frequency, number, duration and severity of oral aphthous ulcers, genital ulcers and erythema nodosum were determined before and after treatment. RESULTS: In group I, all parameters of oral ulcers and the frequency and healing time of genital ulcers and erythema nodosum decreased significantly. In group II, all parameters of oral aphthous ulcers, genital ulcers and erythema nodosum were significantly improved. When treatment results in the two groups were compared, the decrements in the frequency and duration of oral ulcers and erythema nodosum and the frequency of genital ulcers were significantly greater in group II than in group I (p < 0.05). CONCLUSION: We conclude that prophylactic benzathine penicillin combined with colchicine is more effective in controlling mucocutaneous manifestations of BD than colchicine alone.