Long-term anti-tumor necrosis factor antibody therapy in rheumatoid arthritis patients sensitizes the pituitary gland and favors adrenal androgen secretion.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Straub
Rainer H
RH
Department of Internal Medicine, University Hospital Regensburg, Regensburg, Germany. rainer.straub@klinik.uni-regensburg.de
Pongratz
Georg
G
Schölmerich
Jürgen
J
Kees
Frieder
F
Schaible
Thomas F
TF
Antoni
Christian
C
Kalden
Joachim R
JR
Lorenz
Hanns-Martin
HM
D019326:17-alpha-Hydroxyprogesterone / Q000097:blood; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D000735:Androstenedione / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D000069285:Infliximab; D015850:Interleukin-6 / Q000097:blood; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D010902:Pituitary Gland / Q000187:drug effects*; D010913:Pituitary-Adrenal System / Q000187:drug effects; D011239:Prednisolone / Q000627:therapeutic use; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
D000911:Antibodies, Monoclonal; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D000735:Androstenedione; D019326:17-alpha-Hydroxyprogesterone; D000324:Adrenocorticotropic Hormone; D011239:Prednisolone; D000069285:Infliximab; D006854:Hydrocortisone