Effectiveness and safety of infliximab in rheumatoid arthritis: analysis from a Canadian multicenter prospective observational registry.

OBJECTIVE: To describe the profile of rheumatoid arthritis (RA) patients treated with infliximab in Canadian routine care and to assess the real-world effectiveness and safety of infliximab. METHODS: Biologics-naive RA patients from the Biologic Treatment Registry Across Canada were stratified based on their enrollment year. Effectiveness was assessed with the changes in clinical/laboratory parameters and patient-reported outcomes and the achievement of minimal disease activity and remission. Safety was assessed with the incidence of treatment-emergent adverse events (AEs). RESULTS: Among 628 patients, 45.9%, 34.6%, and 19.6% were enrolled between 2002-2005, 2005-2008, and 2008-2011, respectively. Patients recruited in more recent years had significantly lower Disease Activity Score with a 28-joint count using the C-reactive protein level (DAS28-CRP), Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), swollen joint count in 28 joints, tender joint count in 28 joints, physician's global assessment of disease activity, patient's global assessment of disease activity, Health Assessment Questionnaire disability index, pain, erythrocyte sedimentation rate, and CRP level (P < 0.01 for all). Patient management also changed with a trend to initiate infliximab after failure of fewer disease-modifying antirheumatic drugs (DMARDs). Six-month treatment with infliximab resulted in statistically significant and clinically important improvements in all disease parameters examined, which were sustained over 36 months. The cumulative probability of achieving remission by 36 months, as defined by the DAS28, SDAI, and CDAI, was 56.2 (95% confidence interval [95% CI] 47.8-64.8), 31.0 (95% CI 23.8-39.8), and 36.2 (95% CI 28.5-45.3), respectively, which was significantly greater in patients with lower baseline disease activity. The profile and incidence of AEs were comparable to data previously reported for tumor necrosis factor α inhibitors. CONCLUSION: RA patient characteristics at infliximab initiation changed over time toward lower disease activity. Furthermore, a trend to treat patients with fewer DMARDs before initiation of infliximab was observed. However, treatment with infliximab was effective in significantly reducing disease activity independent of the treatment initiation year.

Microchimerism in the rheumatoid nodules of patients with rheumatoid arthritis.

OBJECTIVE: The rheumatoid nodule is a lesion commonly found on extraarticular areas prone to mechanic trauma. When present with inflammatory symmetric polyarthritis, it is pathognomonic of rheumatoid arthritis (RA), an autoimmune disease in which naturally acquired microchimerism has previously been described and can sometimes contribute to RA risk. Since RA patients harbor microchimerism in the blood, we hypothesized that microchimerism is also present in rheumatoid nodules and could play a role in rheumatoid nodule formation. This study was undertaken to investigate rheumatoid nodules for microchimerism. METHODS: Rheumatoid nodules were tested for microchimerism by real-time quantitative polymerase chain reaction (qPCR). The rheumatoid nodules of 29 female patients were tested for a Y chromosome-specific sequence. After HLA genotyping of patients and family members, rheumatoid nodules from 1 man and 14 women were tested by HLA-specific qPCR, targeting a nonshared HLA allele of the potential microchimerism source. Results were expressed as genome equivalents of microchimeric cells per 10(5) patient genome equivalents (GE/10(5)). RESULTS: Rheumatoid nodules from 21% of the female patients contained male DNA (range <0.5, 10.3 GE/10(5)). By HLA-specific qPCR, 60% of patients were microchimeric (range 0, 18.5 GE/10(5)). Combined microchimerism prevalence was 47%. A fetal or maternal source was identified in all patients who tested positive by HLA-specific qPCR. Unexpectedly, a few rheumatoid nodules also contained microchimerism without evidence of a fetal or maternal source, suggesting alternative sources. CONCLUSION: Our findings indicate that microchimerism is frequently present in the rheumatoid nodules of RA patients. Since microchimerism is genetically disparate, whether microchimerism in rheumatoid nodules serves as an allogeneic stimulus or allogeneic target warrants further investigation.

Modulation of dendritic cell function by naive and regulatory CD4+ T cells.

The consequences of interactions between dendric cells (DCs) and either naive CD4+ T cells or regulatory CD4+CD25+ T cells on the expression of proinflammatory IL-6 and anti-inflammatory IL-10 in DC were examined over a period of 12 h, spanning the time frame during which stable T cell-DC interactions shape the development of tolerance and immunity in vivo. We demonstrate that the basal production of IL-6 and IL-10, which is initiated following DC stimulation with LPS, is modified in distinctly different ways by interaction with the two T cell populations. Naive CD4 T cells skew DC cytokine production toward IL-6 and suppress IL-10, whereas CD4+CD25+ T cells have the opposite effect. CD8 T cells or memory CD4 T cells do not influence basal cytokine production by stimulated DC. The effect of CD4+CD25+ T cells is dominant in coculture with naive CD4 T cells as long as inflammatory LPS is absent; the addition of LPS abrogates the suppression of IL-6. However, the modulating influence of CD4+CD25+ T cells remains evident in the enhancement of IL-10 production. Thus, mutual interactions between DC and CD4+ T cell subpopulations following contact with pathogens are likely to influence the strength and quality of incipient immune responses in the local microenvironment.

TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.

We describe de novo generation of IL-17-producing T cells from naive CD4 T cells, induced in cocultures of naive CD4 T cells and naturally occurring CD4+ CD25+ T cells (Treg) in the presence of TLR3, TLR4, or TLR9 stimuli. Treg can be substituted by TGFbeta1, which, together with the proinflammatory cytokine IL-6, supports the differentiation of IL-17-producing T cells, a process that is amplified by IL-1beta and TNFalpha. We could not detect a role for IL-23 in the differentiation of IL-17-producing T cells but confirmed its importance for their survival and expansion. Transcription factors GATA-3 and T-bet, as well as its target Hlx, are absent in IL-17-producing T cells, and they do not express the negative regulator for TGFbeta signaling, Smad7. Our data indicate that, in the presence of IL-6, TGFbeta1 subverts Th1 and Th2 differentiation for the generation of IL-17-producing T cells.

CD25+ CD4+ T cells compete with naive CD4+ T cells for IL-2 and exploit it for the induction of IL-10 production.

Maintenance of homeostasis in the immune system involves competition for resources between T lymphocytes, which avoids the development of immune pathology seen in lymphopenic mice. CD25+ CD4+ T cells are important for homeostasis, but there is as yet no consensus on their mechanisms of action. Although CD25+ CD4+ T cells cause substantial down-regulation of IL-2 mRNA in responder T cells in an in vitro co-culture system, the presence of IL-protein can be demonstrated by intracellular staining. As a consequence of competition for IL-2, CD25+ CD4+ T cells further up-regulate the IL-2R alpha chain (CD25), a process that is strictly dependent on IL-2, whereas responder T cells fail to up-regulate CD25. Similarly, adoptive transfer into lymphopenic mice showed that CD25+ CD4+ T cells interfere with CD25 up-regulation on co-transferred naive T cells, while increasing their own CD25 levels. IL-2 sequestration by CD25+ CD4+ T cells is not a passive phenomenon but instead initiates--in conjunction with signals through the TCR--their differentiation to IL-10 production. Although IL-10 is not required for in vitro suppression, it is vital for the in vivo function of regulatory T cells. Our data provide a link explaining the apparent difference in regulatory mechanisms in vitro and in vivo.