Straub Rainer H, Pongratz Georg, Schölmerich Jürgen, Kees Frieder, Schaible Thomas F, Antoni Christian, Kalden Joachim R, Lorenz Hanns-Martin
Department of Internal Medicine, University Hospital Regensburg, Regensburg, Germany.
Arthritis Rheum. 2003 Jun;48(6):1504-12. doi: 10.1002/art.11036.
New insights into the role of tumor necrosis factor (TNF) in the pathogenesis of rheumatoid arthritis (RA) have expanded our understanding about the possible mechanisms by which anti-TNF antibody therapy reduces local synovial inflammation. Beyond local effects, anti-TNF treatment may modulate systemic antiinflammatory pathways such as the hypothalamic-pituitary-adrenal (HPA) axis. This longitudinal anti-TNF therapy study was designed to assess these effects in RA patients.
RA patients were given 5 infusions of anti-TNF at weeks 0, 2, 6, 10, and 14, with followup observation until week 16. We measured serum levels of interleukin-6 (IL-6), adrenocorticotropic hormone (ACTH), 17-hydroxyprogesterone (17[OH]progesterone), cortisol, cortisone, androstenedione (ASD), dehydroepiandrosterone (DHEA), and DHEA sulfate in 19 RA patients.
Upon treatment with anti-TNF, we observed a fast decrease in the levels of serum IL-6, particularly in RA patients who did not receive parallel prednisolone treatment (P = 0.043). In these RA patients who had not received prednisolone, the mean serum ACTH levels sharply increased after every injection of anti-TNF, which indicates a sensitization of the pituitary gland (not observed for the adrenal gland). During treatment, the ratio of serum cortisol to serum ACTH decreased, which also indicates a sensitization of the pituitary gland (P < 0.001), and which was paralleled by constant cortisol secretion. The adrenal androgen ASD significantly increased relative to its precursor 17(OH)progesterone (P = 0.013) and relative to cortisol (P = 0.009), which indicates a normalization of adrenal androgen production. The comparison of patients previously treated with prednisolone and those without previous prednisolone revealed marked differences in the central and adrenal level of this endocrine axis during long-term anti-TNF therapy.
Long-term therapy with anti-TNF sensitizes the pituitary gland and improves adrenal androgen secretion in patients who have not previously received prednisolone treatment. These changes are indicative of normalization of the HPA axis and must therefore be considered as evidence of an additional antiinflammatory influence of anti-TNF treatment in patients with RA.
对肿瘤坏死因子（TNF）在类风湿关节炎（RA）发病机制中作用的新认识，拓展了我们对抗TNF抗体疗法减轻局部滑膜炎症可能机制的理解。除局部作用外，抗TNF治疗可能调节全身抗炎途径，如下丘脑 - 垂体 - 肾上腺（HPA）轴。这项纵向抗TNF治疗研究旨在评估RA患者中的这些效应。
RA患者在第0、2、6、10和14周接受5次抗TNF输注，并随访观察至第16周。我们测定了19例RA患者血清白细胞介素 - 6（IL - 6）、促肾上腺皮质激素（ACTH）、17 - 羟孕酮（17[OH]孕酮）、皮质醇、可的松、雄烯二酮（ASD）、脱氢表雄酮（DHEA）和硫酸脱氢表雄酮的水平。
抗TNF治疗后，我们观察到血清IL - 6水平迅速下降，尤其是在未接受平行泼尼松龙治疗的RA患者中（P = 0.043）。在这些未接受泼尼松龙治疗的RA患者中，每次注射抗TNF后，血清ACTH平均水平急剧升高，这表明垂体致敏（肾上腺未观察到）。治疗期间，血清皮质醇与血清ACTH的比值下降，这也表明垂体致敏（P < 0.001），且与皮质醇持续分泌平行。肾上腺雄激素ASD相对于其前体17(OH)孕酮显著增加（P = 0.013），相对于皮质醇也显著增加（P = 0.009），这表明肾上腺雄激素产生正常化。先前接受泼尼松龙治疗的患者与未接受过泼尼松龙治疗的患者比较显示，在长期抗TNF治疗期间，该内分泌轴的中枢和肾上腺水平存在显著差异。
长期抗TNF治疗使未接受过泼尼松龙治疗的患者垂体致敏，并改善肾上腺雄激素分泌。这些变化表明HPA轴正常化，因此必须被视为抗TNF治疗对RA患者具有额外抗炎作用的证据。
