Nathalie Saidenberg-Kermanach

Rheumatoid arthritis: from autoimmunity to synovitis and joint destruction.

Rheumatoid arthritis is an autoimmune disease characterized by the production of two known antibodies - rheumatoid factor and anti-citrullinated peptide antibody (ACPA) - against common autoantigens that are widely expressed within and outside the joints. The interactions between genes and environment are crucial in all stages of the disease, involving namely genes from major histocompatibility complex locus, and antigens such as tobacco or microbes (e.g. Porphyromonas gingivalis). T and B cells are activated as soon as the earliest phases of the disease, rheumatoid arthritis appearing as a Th1 and Th17 disease. Inflammatory cytokines have a considerable importance in the hierarchy of the processes involved in RA. The joint destruction seen in RA is caused not only by cytokine imbalances, but also by specific effects of the Wnt system and osteoprotegerin on osteoclasts and by matrix production dysregulation responsible for cartilage damage. Both innate and adaptative immunity demonstrated their respective cornerstone position in rheumatoid arthritis, since targeted treatments has been efficiently developed against TNF-α, IL-6 receptor, IL-1β, CD20 B cells and T-cell/Dendritic cell interactions.

Efficacy of interleukin-10 gene electrotransfer into skeletal muscle in mice with collagen-induced arthritis.

Gene therapy is very promising in the treatment of rheumatoid arthritis (RA). Electrotransfer is a recent method reported to enhance in vivo intramuscular DNA transfection. Interleukin‐10 (IL‐10) has antiinflammatory effects in RA and in collagen‐induced arthritis (CIA), a murine model of RA. In order to improve our strategy of gene therapy, we used electrotransfer to enhance penetration into skeletal muscle with CIA of plasmids encoding IL‐10.

Syngeneic fibroblasts transfected with a plasmid encoding interleukin-4 as non-viral vectors for anti-inflammatory gene therapy in collagen-induced arthritis.

No effective long‐term treatment is available for rheumatoid arthritis. Recent advances in gene therapy and cell therapy have demonstrated efficiency in collagen‐induced arthritis (CIA). Interleukin‐4 (IL‐4) is already known to be efficient in CIA in systemic injection or administered by gene therapy. This study was designed to evaluate the effect of a non‐viral gene therapy of CIA, involving injection of syngeneic fibroblasts transfected with a plasmid encoding for IL‐4.

Interleukin-4 Cellular Gene Therapy and Osteoprotegerin Decrease Inflammation-Associated Bone Resorption in Collagen-Induced Arthritis

To evaluate the respective action of IL-4, an anti-inflammatory cytokine, and OPG, an inhibitor of bone resorption, on the inflammatory process and the associated bone resorption in collagen-induced arthritis (CIA). After CIA induction, DBA/1 mice were treated with OPG or with IL-4 DBA/1 transfected fibroblasts or both OPG + IL-4. CIA significantly improved in IL-4 groups. OPG had no effect on arthritis clinical scores but histologic scores were reduced in OPG, IL-4, and OPG + IL-4 groups vs. nontreated CIA mice. OPG increased significantly BMD and decreased by 45% D-pyridinolin levels. Moreover association of IL-4 and OPG exerted an additive effect of BMD and resorption marker (−68%). Production of IFN-γ in the supernatants of spleen cells was reduced in IL-4 treated mice. OPG had a moderate effect on IFN-γ, but potentiated the inhibitory effect of IL-4. OPG and IL-4 prevent bone loss in CIA-mice model and could have additive effects on IFN-γ secretion.

Budget impact model of rituximab after failure of one or more TNFα inhibitor therapies in the treatment of rheumatoid arthritis

OBJECTIVES To estimate the budget impact implied by the introduction of rituximab after failure of one or more anti-TNFalpha therapies in the perspective of the French health care system. METHODS A Markov model reproduced the course, over 4years, of patients treated either by infliximab, etanercept, adalimumab or RTX, after failure of one or more anti-TNFalpha therapies, in a multicentric study. A sensitivity analysis was developed to account for patients in 3rd and subsequent lines of treatment who are expected to consume more healthcare resources. RESULTS When RTX is not used, total annual medical cost is euro16,555 per patient, euro13,206 of which are dedicated to drug acquisition. When RTX is the only treatment in use, these costs decrease respectively to euro11,444 and euro7469. Total savings per patient and per year is euro5000. Over 4 years, total savings for the targeted population reach euro118M. In the sensitivity analysis, the difference between H2 and H2-coeff 2 (20%) reaches euro5,400,000 in total direct costs during the first year of simulation. This difference decreases along the period, to reach euro2,400,000 the fourth year of simulation, and is due to the fact that rituximab acquisition costs are independent from the treatment line. CONCLUSION If TNFalpha inhibitors were the only treatment available, the annual global cost of treatment would be euro16,555 per patient versus euro11,444 for patients treated exclusively with rituximab. RTX is expected to produce important savings (-31%) if used after failure of one or more TNFalpha therapies. This is mainly due to its lower drug acquisition cost. These savings could increase with the development of rituximab in earlier stages of treatment.

Screening for latent tuberculosis in anti-TNF-α candidate patients in a high tuberculosis incidence setting.

BACKGROUND Screening for latent tuberculosis infection (LTBI) using a protocol comprising chest X-ray and tuberculin skin test (TST) interpreted with medical history, Sc1, reduces LTBI reactivation on treatment with anti-tumour necrosis factor-alpha (anti-TNF-α). In the district of Seine-Saint-Denis, France, where tuberculosis (TB) incidence ranges from 30 to >100/100 000 person-years, however, Sc1 might be insensitive as a screening tool. We adopted another protocol, Sc2, comprising Sc1 plus two additional tests: the QuantiFERON(®)-TB Gold In-Tube (QFT-GIT) and chest computed tomography (CT). METHODS We screened 123 consecutive patients with inflammatory rheumatic diseases (IRDs), candidates for anti-TNF-α treatment, and evaluated the impact of Sc2 vs. Sc1 on the prescription of prophylactic anti-tuberculosis treatment. RESULTS Sc2 led to a diagnosis of LTBI in 69 patients vs. 59 when using Sc1: eight were QFT-GIT-positive. Diagnosis was based on CT findings in two patients. QFT-GIT had higher diagnostic accuracy than TST, but no single diagnostic test could detect all patients at high risk for LTBI reactivation (respectively 30.2% and 37.5% of patients positive with only TST or QFT-GIT). CT detected TB sequelae in 3/46 rheumatoid arthritis patients who were negative to all tests. CONCLUSIONS Testing with both TST and QFT-GIT seems the safest strategy for detecting LTBI in patients with IRD from populations with high incidence of TB. Systematic screening with CT warrants further evaluation.