Laetitia Sparsa

Innate immunity triggers IL-32 expression by fibroblast-like synoviocytes in rheumatoid arthritis

IntroductionInterleukin-32 (IL-32) is a recently described cytokine that is a strong inducer of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, IL-1β, IL-6, and IL-8. The expression of this cytokine is highly increased in the rheumatoid synovium and correlated with the severity of joint inflammation. Little is known regarding the innate immune-related regulation of IL-32 by fibroblast-like synoviocytes (FLSs). We therefore investigated the effect of innate immune stimulation by ligands of Toll-like receptor (TLR)2, TLR3, and TLR4, and cytokines such as TNF-α and interferon (IFN)-γ, on IL-32 expression by FLSs.MethodsFLSs were isolated from patients with rheumatoid arthritis (RA) according to the ACR criteria. Quantitative RT-PCR, confocal analysis, and ELISA were performed to evaluate IL-32 mRNA induction and IL-32 release by FLSs stimulated with TLR2 (BLP), TLR3 (poly I:C), and TLR4 (lipopolysaccharide) ligands, TNF-α and IFN-γ.ResultsTLR2, -3, and -4 ligands as well as IFN-γ and TNF-α induced IL-32 β, γ and δ mRNA expression by RA FLSs. Mature IL-32 was expressed intracellularly and released by cells stimulated with the various activators. The IL-32α isoform was expressed intracellularly in response to TNF-α and poly I:C and not released in culture supernatants. Stimulation of FLS with TNF-α, BLP, lipopolysaccharide, or poly I:C concomitant with IFN-γ increased IL-32 expression compared with stimulation with IFN-γ alone.ConclusionsIL-32 synthesis by FLSs is tightly regulated by innate immunity in rheumatoid arthritis. Thus TNF-α, IFN-γ, double-strand RNA, hyaluronic acid, or other damage-associated molecular patterns (DAMPs), highly secreted in synovial tissues of RA patients, might trigger IL-32 secretion by FLSs. IL-32 might therefore represent a relevant therapeutic target in RA.

Exposure to abatacept or rituximab in the first trimester of pregnancy in three women with autoimmune diseases.

The use of biological therapies for treating autoimmune diseases is increasing. These therapies are sometimes administered to pregnant women as part of a planned therapeutic regimen or to women with unexpected or unplanned pregnancies. The safety of biological therapies in this setting is a major issue. Here, we describe three young pregnant patients with autoimmune disorders: two patients with rheumatoid arthritis and one with idiopathic thrombotic thrombocytopenic purpura. These patients were exposed to rituximab (anti-CD20 monoclonal antibody) or abatacept (fusion protein CTLA4Ig) during the first trimester of their pregnancies. No significant adverse effects or complications were observed during the pregnancies, and all three patients delivered healthy newborns. In the rituximab cases, this result might be explained in part by the very low transplacental maternofetal transfer of rituximab during the first trimester of pregnancy. Despite these favorable outcomes, the use of these two biological agents must follow international recommendations. Their use is not currently allowed during pregnancy except in cases where the potential benefit to the mother justifies the potential risk to the fetus. In the case of exposure to the single agent rituximab during the first trimester, current data suggest that the low risk to the fetus may be outweighed by the potential benefit to the mother.

Jessner–Kanof disease induced by leflunomide: a dermal variant of cutaneous lupus?

Leflunomide can have adverse effects, but cases of subacute cutaneous lupus have more rarely been described. This drug, through its immunomodulatory effect, can favor the appearance of a Th2 lymphocyte immune response inducing lupus. A recent study has suggested that Jessner–Kanof disease (JKD) could be a dermal form of lupus. We report a case of subacute cutaneous lupus induced by leflunomide with anti-Ro/SSA Ab and unusual histological presentation, identical to that of JKD. Leflunomide can induce cutaneous lupus characterized by exclusively dermal involvement and histologically comparable to JKD. This observation therefore suggests that JKD could be a dermal variant of lupus. This prompted a revision of the classification of cutaneous lupus, which has until now been divided into acute, subacute and chronic forms but could equally be classed as epidermal, dermal and hypodermal. The last point of interest in our observation is the efficacy of a combination of chloroquine and anakinra, which led to complete remission of the articular and cutaneous symptoms after the failure of corticotherapy.

Long-term efficacy and safety of antitumour necrosis factor alpha treatment in rhupus: an open-label study of 15 patients

Background The efficacy of antitumour necrosis factor alpha (anti-TNF-α) treatment is well recognised in rheumatoid arthritis (RA) but remains controversial in systemic lupus erythematosus (SLE). Therefore, the role of anti-TNF-α treatment in ‘Rhupus’, a disease sharing features of RA and SLE, is still debated. Objective To evaluate the efficacy and tolerance of anti-TNF-α in patients with rhupus. Methods Fifteen patients with rhupus with Disease Activity Score 28 (DAS 28) >3.2 despite conventional disease-modifying anti-rheumatic drugs were included in an open-label study. Patients were monitored at months (M) 3, 6, 12, 24 and 60 with SLE Disease Activity Index (SLEDAI) and DAS 28. Statistical analyses were performed using Bayesian methods and Prob >97.5% was considered significant. Results Twelve patients were treated with etanercept for a median duration of 62.5 (range: 6–112) months and three patients by adalimumab during 36.0 (range: 4–52) months. At baseline, median DAS 28 and SLEDAI were 5.94 (4.83–8.09) and 6 (4–8), respectively. DAS 28 and SLEDAI decreased significantly after 3 months, respectively, to 3.70 (1.80–6.42) and 4 (0–6) (Prob >99.9%, for both). These changes persisted at M6, M12, M24 and M60 (Prob >99.9%, for all). Median prednisone dose decreased significantly from 15 (5–35) mg/day to 5 (0–20) mg/day after 6 months and over the follow-up (Prob >99.9%, for all). Tolerance was acceptable, with a severe infection rate of 3.0 per 100 patient-years. Conclusion This pilot study suggests that anti-TNF-α is effective in patients with rhupus with refractive arthritis and has an acceptable safety profile.