[Pregnancy in patients with rheumatoid arthritis and inflammatory spondylarthropathies]

The activity of a rheumatic disease can be influenced by pregnancy and puerperium. Prospective studies have shown an improvement in joint involvement in rheumatoid arthritis in two thirds to three quarters of pregnancies. After birth, an exacerbation is common. In spondylarthropathies there is no relevant change in disease activity. The fetal outcome is not impaired in patients with rheumatoid arthritis and inflammatory spondylarthropathies. Every pregnancy in women with a rheumatic disease should be considered as high-risk, and such pregnancies require close collaboration between rheumatologists and obstetricians.

Expression profiling in spondyloarthropathy synovial biopsies highlights changes in expression of inflammatory genes in conjunction with tissue remodelling genes

Background: In the spondyloarthropathies, the underlying molecular and cellular pathways driving disease are poorly understood. By undertaking a study in knee synovial biopsies from spondyloarthropathy (SpA) and ankylosing spondylitis (AS) patients we aimed to elucidate dysregulated genes and pathways. Methods RNA was extracted from six SpA, two AS, three osteoarthritis (OA) and four normal control knee synovial biopsies. Whole genome expression profiling was undertaken using the Illumina DASL system, which assays 24000 cDNA probes. Differentially expressed candidate genes were then validated using quantitative PCR and immunohistochemistry. Results: Four hundred and sixteen differentially expressed genes were identified that clearly delineated between AS/SpA and control groups. Pathway analysis showed altered gene-expression in oxidoreductase activity, B-cell associated, matrix catabolic, and metabolic pathways. Altered «myogene» profiling was also identified. The inflammatory mediator, MMP3, was strongly upregulated (5-fold) in AS/SpA samples and the Wnt pathway inhibitors DKK3 (2.7-fold) and Kremen1 (1.5-fold) were downregulated. Conclusions: Altered expression profiling in SpA and AS samples demonstrates that disease pathogenesis is associated with both systemic inflammation as well as local tissue alterations that may underlie tissue damaging modelling and remodelling outcomes. This supports the hypothesis that initial systemic inflammation in spondyloarthropathies transfers to and persists in the local joint environment, and might subsequently mediate changes in genes directly involved in the destructive tissue remodelling.

Matters Arising: Role of HLA genes in familial spondyloarthropathy

Said-Nahal and colleagues report an intriguing finding of an association with HLA-DR4 independent of B27 in families with ankylosing spondylitis (AS),1 a finding highlighted by an accompanying editorial.2 The approach of studying B27 positive and B27 negative haplotypes may prove powerful in identifying further cis or trans encoded genes involved in AS. However, the reported association of DR4 with AS is quite a surprising finding given that no difference was noted in B27-DR4 haplotype frequencies in patients and ethnically matched healthy controls. Many previous studies have not reported any such association,3–9 including a similar preliminary study by the same authors.10 Although these studies were mainly case-control studies, population stratification is highly unlikely to cause a false negative finding if the effect size of the reported association with DR4 is as high as Said-Nahal and colleagues describe...

Monitoring of human CD4 T cell responses in metastatic melanoma and arthritic patients

SUMMARY : Detailed knowledge of the different components of the immune system is required for the development of new immunotherapeutic strategies. CD4 T lymphocytes represent a highly heterogeneous group of cells characterized by various profiles of cytokine production and effector vs. regulatory functions. They are central players in orchestrating adaptive immune responses: unbalances between the different subtypes can lead either to aggressive autoimmune disorders or can favour the uncontrolled growth of malignancies. In this study we focused on the characterization of human CD4 T cells in advanced stage melanoma patients as well as in patients affected by various forms of autoimmune inflammatory spondyloarthropathies. In melanoma patients we report that a population of FOXP3 CD4 T cells, known as regulatory T cells, is overrepresented in peripheral blood, and even more in tumor-infitrated lymph nodes as well as at tumor sites, as compared to healthy donors. In tumor-infiltrated lymph nodes, but not in normal lymph nodes or in peripheral blood, FOXP3 CD4 T cells feature a highly differentiated phenotype (CD45RA-CCR7+/-), which suggests for a recent encounter with their cognate antigen. FOXP3 CD4 T cells have been described to be an important component of the several known immune escape mechanisms. We demonstrated that FOXP3 CD4 T cells isolated from melanoma patients exert an in vitro suppressive action on autologous CD4 T cells, thus possibly inhibiting an efficient anti-tumor response. Next, we aimed to analyse CD4 T cells at antigen-specific level. In advanced stage melanoma patients, we identified for the first time, using pMHCII multimers, circulating CD4 T cells specific for the melanoma antigen Melan-A, presented by HLA-DQB1 *0602. Interestingly, in a cohort of melanoma patients enrolled in an immunotherapy trails consisting of injection of a Melan-A derived peptide, we did not observe signif cant variations in the ex vivo frequencies of Melan-A specific CD4 T cells, but important differences in the quality of the specific CD4 T cells. In fact, up to 50% of the ex vivo Melan-A/DQ6 specific CD4 T cells displayed a regulatory phenotype and were hypoproliferative before vaccination, while more effector, cytokine-secreting Melan-A/DQ6 specific CD4 T cells were observed after immunization. These observations suggest that peptide vaccination may favourably modify the balance between regulatory and effector tumor-specific CD4 T cells. Finally, we identified another subset of CD4 T cells as possible mediator of pathology in a group of human autoimmune spondyloarthropathies, namely Th17 cells. These cells were recently described to play a critical role in the pathogenesis of some marine models of autommunity. We document an elevated presence of circulating Th17 cells in two members of seronegative spondyloarthropathies, e.g. psoriatic arthritis and ankylosing spondylitis, while we do not observe increased frequencies of Th17 cells in peripheral blood of rheumatoid arthritic patients. In addition, Th17 cells with a more advanced differentiation state (CD45RA-CCR7-CD27-) and polyfunctionality (concomitant secretion of IL-17, IL-2 and TNFα) were observed exclusively in patients with seronegative spondylarthropathies. Together, our observations emphasize the importance of CD4 T cells in various diseases and suggest that immunotherapeutic approaches considering CD4 T cells as targets should be evaluated in the future.

Espondiloartropatias seronegativas y viceversa

Introducción. Las Espondiloartropatias Seronegativas (EAS) son un grupo de enfermedades interrelacionadas que presentan compromiso inflamatorio articular y hallazgos extraarticulares. Por otra parte, las Enfermedades Autoinmunes (EAI) son un síndrome clínico caracterizado por la pérdida de la tolerancia inmune. Se encuentra en ellas activación de células B o T, conllevando a daño tisular en ausencia de cualquier otra causa. No existe evidencia sustancial para considerar las EAS como EAI, pero si pueden ser consideradas como enfermedades autoinflamatorias. Dado que la poliautoinmunidad es una de las más importantes características de las EAI, nuestro propósito fue investigar la relación entre EAS y EAI. Materiales y métodos. 2 grupos fueron analizados. Primero, evaluamos la presencia de EAI en una cohorte de pacientes con EAS (n=148). Segundo, examinamos la presencia de EAS en un grupo bien definido de pacientes con EAI (n=1077), incluyendo artritis reumatoide (AR), lupus eritematosos sistémico (LES) y síndrome de Sjögren (SS) Resultados. En el grupo de EAS, dos pacientes presentaron SS (1.4%) y 5 hipotiroidismo autoinmune (HAI) (3.5%). No se encontraron otras EAI en este grupo. La prevalencia de EAI en EAS fue 4.86%. En el grupo de EAI, 5 pacientes presentaron EAS (0.46%). Conclusión. Este estudio no sugiere relación entre EAS y EAI, reforzando la evidencia a favor de que las EAS corresponden más a enfermedades autoinflamatorias que a EAI