Treatment with Dexamethasone and Monophosphoryl Lipid A Removes Disease-Associated Transcriptional Signatures in Monocyte-Derived Dendritic Cells from Rheumatoid Arthritis Patients and Confers Tolerogenic Features.

Tolerogenic dendritic cells (TolDCs) are promising tools for therapy of autoimmune diseases, such as rheumatoid arthritis (RA). Here, we characterize monocyte-derived TolDCs from RA patients modulated with dexamethasone and activated with monophosphoryl lipid A (MPLA), referred to as MPLA-tDCs, in terms of gene expression, phenotype, cytokine profile, migratory properties, and T cell-stimulatory capacity in order to explore their suitability for cellular therapy. MPLA-tDCs derived from RA patients displayed an anti-inflammatory profile with reduced expression of co-stimulatory molecules and high IL-10/IL-12 ratio, but were capable of migrating toward the lymphoid chemokines CXCL12 and CCL19. These MPLA-tDCs induced hyporesponsiveness of autologous CD4+ T cells specific for synovial antigens in vitro. Global transcriptome analysis confirmed a unique transcriptional profile of MPLA-tDCs and revealed that RA-associated genes, which were upregulated in untreated DCs from RA patients, returned to expression levels of healthy donor-derived DCs after treatment with dexamethasone and MPLA. Thus, monocyte-derived DCs from RA patients have the capacity to develop tolerogenic features at transcriptional as well as at translational level, when modulated with dexamethasone and MPLA, overcoming disease-related effects. Furthermore, the ability of MPLA-tDCs to impair T cell responses to synovial antigens validates their potential as cellular treatment for RA.

Mycophenolate Mofetil Therapy in Refractory Inflammatory Eye Disease.

PURPOSE: To study the efficacy and incidence of treatment-related side effects of mycophenolate mofetil (MMF) therapy in patients with noninfectious inflammatory eye diseases. METHODS: Retrospective cohort study of 27 Chilean patients treated for noninfectious inflammatory eye diseases using MMF therapy over a 10-year period. Main outcome measures were: ability to control ocular inflammation and to taper prednisone to ≤10 mg daily (treatment success); incidence of treatment-related side effects. RESULTS: The proportion of patients with sustained control of inflammation was 81.48% at 6 months. Additionally 55.56% and 22.22% of patients succeeded in tapering their prednisone to 5-10 mg/day and <5 mg/day, at 6 months. Two patients developed a neoplasia during MMF therapy; however, this cohort is too small to interpret the significance of this relation to MMF treatment. CONCLUSIONS: MMF seems to be an effective corticosteroid-sparing agent with an acceptable safety profile.

Catalytic autoantibodies against myelin basic protein (MBP) isolated from serum of autistic children impair in vitro models of synaptic plasticity in rat hippocampus.

Autoantibodies from autistic spectrum disorder (ASD) patients react with multiple proteins expressed in the brain. One such autoantibody targets myelin basic protein (MBP). ASD patients have autoantibodies to MBP of both the IgG and IgA classes in high titers, but no autoantibodies of the IgM class. IgA autoantibodies act as serine proteinases and degrade MBP in vitro. They also induce a decrease in long-term potentiation in the hippocampi of rats either perfused with or previously inoculated with this IgA. Because this class of autoantibody causes myelin sheath destruction in multiple sclerosis (MS), we hypothesized a similar pathological role for them in ASD.

Clinical parameters and biomarkers for anti-TNF treatment prognosis in rheumatoid arthritis patients.

Tumor necrosis factor (TNF) plays a pivotal role in the pathogenesis of rheumatoid arthritis (RA). This finding has led to the development of TNF blockers for RA treatment. However, response to these therapies is heterogeneous with success in only two thirds of patient. Some clinical aspects useful in the attempt to predict the response to TNF inhibitors is the promptness and the magnitude of the response at the first weeks and a low basal disease activity, while comorbidities, tobacco, glucocorticoids treatment, and high basal radiological score correlate with a poorer response. The role of TNF promoter polymorphisms in clinical response to anti-TNF therapies is controversial. A correlation between the presence of high baseline titers of rheumatoid factor (RF) and decreased response to anti-TNF treatment has been reported. Most studies show decreased RF titers during anti-TNF treatment mainly in patients who responded to treatment. There is no consensus about the usefulness of basal anti-citrullinated protein antibodies (ACPA) levels, and a decrease in ACPA titers as predictor of clinical response to anti-TNF therapy. Despite some promising markers identified to fulfill this role, currently the predictive value of single markers seems not strong enough to predict treatment response in an individual RA patient.

Acute herpes simplex virus 1 pneumonitis in a patient with systemic lupus erythematosus.

A woman with severe and longstanding systemic lupus erythematosus presented with a 1-week history of fever up to 38°C and pain in her right flank. Computed tomography scan of the chest revealed interstitial infiltrates and multiple nodules. Bronchoalveolar lavage did not show any inflammatory cells. Gram stain and cultures for aerobic and anaerobic bacteria, fungi, and Nocardia; acid-fast staining; polymerase chain reaction for tuberculosis, cytomegalovirus, herpesvirus 6, and parvovirus B19; and IF staining for pneumocystic and Legionella antigen were all negative. Transbronchial biopsy was nondiagnostic. Open lung biopsy with polymerase chain reaction and immunohistochemistry analyses revealed herpes simplex virus 1 infection. Acyclovir therapy was initiated and was followed by significant improvement. Herpes simplex virus 1 infection (although unusual) should be considered in patients with systemic lupus erythematosus with an atypical clinical presentation.

Weak CD4+ T-cell responses to citrullinated vimentin in rheumatoid arthritis patients carrying HLA-DR9 alleles.

Citrullinated vimentin (cVIM) is one of the antigens specifically targeted by anti-citrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA) patients. The association between ACPA and certain HLA-DRB1 alleles, those coding for the shared epitope (SE), suggests that this response could be T-cell mediated. HLA-DR9 alleles, which do not code for the SE, have recently been associated with ACPA (+) RA. The objective of this work was to study CD4+ T cell responses to cVIM in RA patients and healthy controls carrying HLA-DR9 alleles. Fourteen RA patients and ten healthy controls previously genotyped for HLA-DRB1 were studied for the presence of serum anti-cVIM antibodies by Western blot and ELISA. Peripheral blood mononuclear cells were stimulated with native vimentin and cVIM, and CD4+ T cells proliferation was assessed by flow cytometry. Citrulline-specific CD4+ T cells proliferation was found not only in RA patients but also in healthy controls. Although most patients carrying HLA-DR9 alleles present anti-cVIM antibodies, HLA-DR9 alleles were associated with weaker cVIM-driven CD4+ T-cell responses among RA patients. These results suggest that HLA-DR9 alleles could exert a protective effect on the recognition of cVIM epitopes by CD4+ T cells. In this context, other citrullinated proteins may break T and B cell tolerance, with cVIM only acting as a cross-reactive target for ACPA.

Anti-TNF therapy in patients with rheumatoid arthritis decreases Th1 and Th17 cell populations and expands IFN-γ-producing NK cell and regulatory T cell subsets.

The aim of this work was to study the effect of anti-TNF treatment on CD4+ Th1, Th17 and regulatory T cells (Tregs), together with CD8+ T cells and NK cells from rheumatoid arthritis (RA) patients. For this purpose, 18 RA patients received adalimumab during 16weeks and their peripheral blood lymphocytes were assessed by flow cytometry at the beginning and at the end of the study. We found that the proportion of Th17 cells was directly correlated with Th1 cells, but inversely correlated with IFN-γ-producing NK cells. A decrease was observed in Th1, Th17 cells and IFN-γ-producing CD8+ T cells by anti-TNF therapy. Conversely, the proportion of Tregs increased, as did the percentage of IFN-γ-producing NK cells. We postulate that a rise in IFN-γ production due to recovery of NK cells' function, together with expanded Tregs, contribute to decrease the Th17 response in anti-TNF-treated RA patients.

The presence of anti-citrullinated protein antibodies (ACPA) does not affect the clinical response to adalimumab in a group of RA patients with the tumor necrosis factor (TNF) α-308 G/G promoter polymorphism.

The introduction of antitumor necrosis factor (TNF) agents has improved the outcome for many patients with rheumatoid arthritis (RA). To date, the only replicated genetic predictor of anti-TNF response is the -308 G > A single-nucleotide polymorphism in the TNF promoter region. The presence of the -308 TNF G/G genotype appears to be a marker of good response to anti-TNF treatment. Anti-citrullinated protein antibodies (ACPA) have been linked with erosive disease, and have been established as the single most reliable prognostic factor in clinical practice. To test the hypothesis that the ACPA status may affect the -308 G/G patients rate of response to TNF blockade, we prospectively investigated a group of 52 RA patients with the -308 G/G genotype who were ACPA (+) or ACPA (-). All patients were treated with adalimumab, and the clinical response was studied using the Disease Activity Score in 28 joints (DAS28) at 24 weeks of treatment. Over 85% of patients were DAS28 responders in both groups. No significant differences were found between patients from both groups, according to the DAS28 criteria of response at week 24 (p = 0.79). In conclusion, our findings suggest that the ACPA status does not affect the clinical response to anti-TNF therapy in -308 TNF G/G patients.

Antibodies against the voltage-dependent anion channel (VDAC) and its protective ligand hexokinase-I in children with autism.

Autistic children show elevated serum levels of autoantibodies to several proteins essential for the function of normal brains. The voltage-dependent anion channel (VDAC) and hexokinase-I, a VDAC protective ligand, were identified as targets of this autoimmunity in autistic children. These autoantibodies were purified using immunoaffinity chromatographic techniques. Both antibodies induce apoptosis of cultured human neuroblastoma cells. Because VDAC and hexokinase-I are essential for brain protection from ischemic damage, the presence of these autoantibodies suggests a possible causal role in the neurologic pathogenesis of autism.

Comparison of the clinical efficacy of two different immunosuppressive regimens in patients with chronic vogt-koyanagi-harada disease.

PURPOSE: To prospectively compare 2 immunosupressive regimens in patients with active Vogt-Koyanagi-Harada disease in spite of systemic glucocorticoid treatment. METHODS: Forty-four patients were diagnosed between 1998 and 2005. Twenty-one developed chronic intraocular inflammation in spite of glucocorticoid treatment and were randomized to receive either prednisone and azathioprine (AZA) (n = 12) or prednisone and cyclosporine (CyA) (n = 9). RESULTS: In the AZA group Tyndall score decreased from 1.21 +/- 1.10 to 0.29 +/- 0.62 (p < .01), and visual acuity (LogMAR) improved from 0.32 +/- 0.35 to 0.09 +/- 0.16 (p < .001). In the CyA group Tyndall score decreased from 1.67 +/- 1.08 to 0.16 +/- 0.51 (p < .001), and visual acuity improved from 0.41 +/- 0.40 to 0.25 +/- 0.42 (p < .001). Patients in the AZA group needed a significantly higher average prednisone dose and total cumulative dose than those in the CyA group, p < .01 for each comparison. CONCLUSIONS: Both regimens showed a good clinical efficacy, but CyA seems to be a better glucocorticoid-sparing agent than AZA.

B cells from rheumatoid arthritis patients show important alterations in the expression of CD86 and FcgammaRIIb, which are modulated by anti-tumor necrosis factor therapy.

INTRODUCTION: Several molecules help preserve peripheral B cell tolerance, but when altered, they may predispose to autoimmunity. This work studied the expression of the costimulatory molecule CD86 and the inhibitory receptor for IgG immune complexes FcgammaRIIb (CD32b), on B cells from rheumatoid arthritis (RA) patients, and the influence of anti-tumor necrosis factor (TNF) therapy. METHODS: Peripheral B cells from 18 RA patients and 13 healthy donors were characterized using flow cytometry. Eleven patients who underwent a six-month adalimumab therapy were further assessed for phenotypic changes on their B cells. RESULTS: RA patients exhibited a high percentage of naïve and memory B cells expressing CD86. In contrast, expression of FcgammaRIIb was significantly reduced on RA memory B cells and plasmablasts as compared to healthy donors, probably due to downregulation of this receptor when differentiating from naïve to memory cells. These alterations on FcgammaRIIb were associated with high levels of anti-citrullinated vimentin autoantibodies. In addition, treatment with adalimumab normalized the expression of CD86 on memory B cells and reduced the expression of FcgammaRIIb, mainly on naïve B cells. CONCLUSIONS: Our findings show that peripheral B cells from RA patients have an altered expression of key molecules, such as CD86 and FcgammaRIIb. Because this latter receptor is required for feedback inhibition, a deficient expression might contribute to humoral autoimmune responses. Furthermore, these molecules are likely to be influenced by inflammatory factors, since they were modulated by TNF inhibition.

[Retrospective review of 44 Chilean patients with Behçet disease]. / Enfermedad de Behçet en Chile: Análisis clínico de 44 casos.

BACKGROUND: Behçet's disease (BD) is a rare multisystemic inflammatory disease that is potentially disabling and may cause death. AIM: To describe the characteristics of BD patients from two Chilean centers. PATIENTS AND METHOD: Retrospective review of the clinical records of patients with BD attended in two rheumatology services between 1985 and 2007. The "Behçet's Disease Research Committee of Japan" (BDCJ) and the "International Study Group for Behçet's Disease" (ISG) diagnostic criteria were applied. RESULTS: We found 44 cases (25 males), diagnosed as BD. The mean age at the onset of symptoms was 26+/- 12 years. According to BDCJ criteria, 13 patients had complete BD, 24 had incomplete BD and 7 had a suspected BD. Thirty two patients fulfilled the ISG criteria. Forty two patients (95%) had oral ulcers, 33 (75%) had genital ulcers and 29 (66%) had ophthalmological involvement. Eleven and three patients had symptoms of central and peripheral nervous system involvement, respectively. No gender differences were detected. CONCLUSIONS: The clinical characteristics of these patients were similar to those described abroad, except for a higher frequency of peripheral nervous system involvement and a lower rate of arthritis.

Enfermedad de Behçet en Chile: Análisis clínico de 44 casos / Retrospective review of 44: Chilean patients with Behçet disease

Background: Behget's disease (BD) is a rare multisystemic inflammatory disease that is potentially disabling and may cause death. Aim: To describe the characteristics of BD patients from two Chilean centers. Patients and method: Retrospective review of the clinical records of patients with BD attended in two rheumatology services between 1985 and 2007. The "Behget's Disease Research Committee of Japan" (BDCJ) and the "International Study Group for Behget's Disease" (ISG) diagnostic criteria were applied. Results: We found 44 cases (25 males), diagnosed as BD. The mean age at the onset of symptoms was 26± 12 years. According to BDCJ criteria, 13 patients had complete BD, 24 had incomplete BD and 7 had a suspected BD. Thirty two patients fulfilled the ISG criteria. Forty two patients (95 percent) had oral ulcers, 33 (75 percent) had genital ulcers and 29 (66 percent) had ophthalmological involvement. Eleven and three patients had symptoms of central and peripheral nervous system involvement, respectively. No gender differences were detected. Conclusions: The clinical characteristics of these patients were similar to those described abroad, except for a higher frequency of peripheral nervous system involvement and a lower rate of arthritis.

Azathioprine in the management of autoimmune uveitis.

PURPOSE: To evaluate the role of azathioprine as an immunosuppressive for steroid-resistant autoimmune uveitis (AIU). METHODS: Patients using oral prednisolone for active AIU without clinical response were recruited. A standard protocol of oral prednisolone and azathioprine was used. RESULTS: Twenty-seven patients participated in the study: 3 with anterior uveitis, 1 pars planitis, 4 idiopatic panuveitis, 8 Vogt-Koyonagi-Harada syndrome, 3 Behcet disease, and 8 choroidoretinopathies. Complete response was observed in 92%. Eleven patients had well-tolerated minor side effects. CONCLUSION: Azathioprine is safe and effective in controlling steroid-resistant AIU.

Infliximab can induce a prolonged clinical remission and a decrease in thyroid hormonal requirements in a patient with SAPHO syndrome and hypothyroidism.

SAPHO syndrome is a rare entity that compromises the skeletal system (arthritis-osteitis) and is associated with various dermatological conditions such as palmoplantaris pustulosis (PPP) and acne. We present the case of a 39-year-old man with invalidating arthritis derived from a SAPHO syndrome and hypothyroidism (after radioiodine treatment for a Graves' disease). Due to the severity and refractoriness of his disease, we decided to use infliximab. He showed a prompt and prolonged response of his joint and cutaneous manifestations after three doses of a tumor necrosis factor alpha (TNF-alpha) blocker. Interestingly, he also decreased his levothyroxine requirements after TNF-alpha blockade therapy.

[Role of Azathioprine in steroid resistant non infectious ocular inflammatory diseases]. / Eficacia de la azatioprina en la enfermedad ocular inflamatoria no infecciosa resistente a tratamiento esteroidal sistémico.

BACKGROUND: Topical and systemic steroids are the first line of treatment of non infectious inflammatory ocular disease. Immunosuppresants are reserved as a second line treatment. AIM: To evaluate the role of Azathioprine (AZA) as a coadyuvant immunosuppressive treatment for non infectious ocular inflammatory diseases (OIDs) resistant to systemic steroid therapy in a retrospective, noncomparative interventional case series. PATIENTS AND METHODS: Patients using oral Prednisone due to an active or recurrent OID, without clinical response, and not receiving any other immunosuppressive treatment were studied. A standard protocol of oral Prednisone (0.5 mg/kg/ day) and oral AZA (2-3 mg/kg/day) during one year was used. Ocular and systemic monthly evaluations were done including relapse rate, steroid dosage, inflammatory score and visual acuity. RESULTS: Thirty patients (10 male) aged 18-75 years (mean 44 years) were studied. Three had bilateral anterior uveitis, one had pars planitis, four had diffuse uveitis, eight Vogt-Koyanahi-Harada syndrome, three Behget's disease, three necrotizing scleritis and eight had retinochoroidopathy A complete initial response was observed in 26 patients (87%). The time of response was between 1 to 6 months (mean 2.65 months). Seventeen percent of these had a relapse 6 to 12 months after AZA was started. In 61 %, visual acuity improved. The ocular inflammatory score decreased in 86.5%. Eleven patients had mild controlled side effects that did not require discontinuation of AZA. CONCLUSIONS: Combined systemic steroid and oral AZA therapy is safe and effective in controlling steroid resistant non infectious inflammatory ocular diseases.

Eficacia de la azatioprina en la enfermedad ocular inflamatoria no infecciosa resistente a tratamiento esteroidal sistémico / Role ofAzathioprine in steroid resistant non infectious ocular inflammatory diseases

Background: Topical and systemic steroids are the first line of treatment of non infectious inflammatory ocular disease. Immunosuppresants are reserved as a second line treatment. Aim: To evaluate the role ofAzathioprine (AZA) as a coadyuvant immunosuppressive treatment for non infectious ocular inflammatory diseases (OIDs) resistant to systemic steroid therapy in a retrospective, noncomparative interventional case series. Patients and methods: Patients using oral Prednisone due to an active or recurrent OID, without clinical response, and not receiving any other immunosuppressive treatment were studied. A standard protocol of oral Prednisone (0.5 mg/kg/ day) and oral AZA (2-3 mg/kg/day) during one year was used. Ocular and systemic monthly evaluations were done including relapse rate, steroid dosage, inflammatory score and visual acuity. Results: Thirty patients (10 male) aged 18-75 years (mean 44 years) were studied. Three had bilateral anterior uveitis, one had pars planitis, four had diffuse uveitis, eight Vogt-Koyanahi-Harada syndrome, three Behget's disease, three necrotizing scleritis and eight had retinochoroidopathy A complete initial response was observed in 26 patients (87 percent). The time of response was between 1 to 6 months (mean 2.65 months). Seventeen percent of these had a relapse 6 to 12 months after AZA was started. In 61 percent, visual acuity improved. The ocular inflammatory score decreased in 86.5 percent. Eleven patients had mild controlled side effects that did not require discontinuation of AZA. Conclusions: Combined systemic steroid and oral AZA therapy is safe and effective in controlling steroid resistant non infectious inflammatory ocular diseases.

Prostate cancer cell proliferation in vitro is modulated by antibodies against glucose-regulated protein 78 isolated from patient serum.

Circulating autoantibodies against the glucose-regulated protein of 78 kDa (GRP78) are present at high levels in prostate cancer patients and are a biomarker of aggressive tumor behavior. We purified the anti-GRP78 IgGs and examined their effect on 1-LN, PC-3, DU145, and LnCap human prostate cancer cells. We also evaluated its effects on the breast cancer MDA-MB231 and melanoma DM413 cell lines. The anti-GRP78 antibody binds only to cells expressing GRP78 on the surface, to a site also recognized by its physiologic agonist, activated alpha(2)-macroglobulin (alpha(2)M*). This antibody is completely specific for a peptide, including the primary amino acid sequence CNVKSDKSC, which contains a tertiary structural motif mimicking an epitope in GRP78. Tertiary structural analysis suggested the linear GRP78 primary amino acid sequence LIGRTWNDPSVQQDIKFL (Leu(98)-Leu(115)) as the putative binding site, containing the tertiary structual arrangement described above, which was confirmed experimentally. The anti-GRP78 antibodies from prostate cancer patients recognize almost exclusively this epitope. We produced animal antibodies against both these peptides, and they are able to mimic the effects of the human antibody. Our experiments also suggest this epitope as highly immunogenic, thereby explaining the specificity of the immune response against this epitope in GRP78, observed in humans. Using 1-LN cells as a model, we show that anti-GRP78 IgG purified from the sera of these patients mimics the proproliferative effects induced by alpha(2)M* via the common receptor, GRP78. Furthermore, increasing concentrations of human anti-GRP78 IgG show a dose-dependent protective effect on apoptosis induced by tumor necrosis factor alpha.

[Effectiveness of infliximab in patients with Behçet syndrome and severe uveoretinitis. Report of five cases]. / Eficacia del infliximab en pacientes con síndrome de Behçet portadores de úveo-retinitis grave.

The efficacy and safety of repeated administration of infliximab was evaluated in five patients (two men, three women) with Behçet syndrome accompanied by severe uveoretinitis. Ocular and extra ocular inflammation was suppressed in all patients during the observation period without any serious adverse reactions. The results in these patients suggests that TNF-á blockade is effective in patients with severe ocular Behçet syndrome.

Eficacia del infliximab en pacientes con síndrome de Behçet portadores de úveo-retinitis grave / Effectiveness of infliximab in patients with Behçet syndrome and severe uveoretinitis. Report of five cases

The efficacy and safety of repeated administration of infliximab was evaluated in five patients (two men, three women) with Behçet syndrome accompanied by severe uveoretinitis. Ocular and extra ocular inflammation was suppressed in all patients during the observation period without any serious adverse reactions. The results in these patients suggests that TNF-α blockade is effective in patients with severe ocular Behçet syndrome.