Blockade of TNF-α rapidly inhibits pain responses in the central nervous system

Abstract

There has been a consistent gap in understanding how TNF-α neutralization affects the disease state of arthritis patients so rapidly, considering that joint inflammation in rheumatoid arthritis is a chronic condition with structural changes. We thus hypothesized that neutralization of TNF-α acts through the CNS before directly affecting joint inflammation. Through use of functional MRI (fMRI), we demonstrate that within 24 h after neutralization of TNF-α, nociceptive CNS activity in the thalamus and somatosensoric cortex, but also the activation of the limbic system, is blocked. Brain areas showing blood-oxygen level-dependent signals, a validated method to assess neuronal activity elicited by pain, were significantly reduced as early as 24 h after an infusion of a monoclonal antibody to TNF-α. In contrast, clinical and laboratory markers of inflammation, such as joint swelling and acute phase reactants, were not affected by anti-TNF-α at these early time points. Moreover, arthritic mice overexpressing human TNF-α showed an altered pain behavior and a more intensive, widespread, and prolonged brain activity upon nociceptive stimuli compared with wild-type mice. Similar to humans, these changes, as well as the rewiring of CNS activity resulting in tight clustering in the thalamus, were rapidly reversed after neutralization of TNF-α. These results suggest that neutralization of TNF-α affects nociceptive brain activity in the context of arthritis, long before it achieves anti-inflammatory effects in the joints.

Fig. 1.

Rapid reversal of pain induced BOLD signals after TNF-α blockade in patients with RA. (A and B) Area of BOLD signal based on fMRI scans elicited by joint compression (A) and finger tapping (B) in patients (n = 5) with RA before, 1, 14, and 42 d after administration of TNF-α blocking agent IFX. (C) VAS (reaching from 0 to 10) for arthritis-related pain before, 1, 14, and 42 d after administration of IFX; (D) DAS28 before, as well as 1, 14, and 42 d after administration of IFX; (E) swollen and (F) tender joint count based on the assessment of 28 joints. (G) Maps of BOLD activity in a single patient before (Top) as well as 1 (Middle) and 42 d (Bottom) after administration of IFX. Asterisks indicate significant difference to baseline (P < 0.05).

Fig. 2.

Mapping of BOLD changes after TNF-α blocking therapy. (A–C) Changes in the area size of the BOLD signal elicited by joint compression (blue bars) or finger tapping (red bars) comparing day 0 with day 1 (W2/W1) and day 0 with day 42 (W3/W1) after IFX treatment: overall (A) and specific for the contralateral (B) and ipsilateral hemisphere (C). (D and E) Changes in the area size of the BOLD signal elicited by joint compression (D) or finger tapping (E) comparing day 0 with day 1 (W2/W1) at the following brain regions: thalamus (Th), secondary (S2) and primary (S1), somatosensoric cortex, parietal cortex (Par), posterior cingulate cortex (PCC), anterior cingulate cortex (ACC), lateral (LPFC) and medial (MPFC) prefrontal cortex, anterior (AIns) and posterior (PIns) insular cortex, cerebellum (Cb), motor cortex (M1), and periaqueductal gray (PAG).

Fig. 3.

Reversible enhancement of central pain responses by TNF-α–mediated arthritis. Functional MRI of the brain of 10-wk-old WT and human TNFtg mice without and with human antiTNF-α antibody IFX (each n = 10). (A and B) 2D axial scans with heatmap (A) or superimposed on the corresponding anatomical image (B) show enhanced neuronal activity in the primary (S1) and secondary (S2) somatosensoric cortex, as well as in association cortex (RS) and the thalamus (Th) of TNFtg mice, which is reversible 24 h after IFX administration. (C) 3D reconstruction of functional brain activity. (D) Bar graphs showing area size (Left) and peak height (Right) of the BOLD signal in WT mice (blue) and TNFtg mice treated with either vehicle (red) or the human anti–TNF-α antibody IFX (green). Four key groups of brain regions (brainstem, thalamus, sensory cortex, and association cortex) involved in central nociception are shown. Asterisks indicate significant differences of WT to TNFtg plus those of TNFtg/IFX to TNFtg, with * and + indicating a P value of < 0.05 and ** and ++ a P value of < 0.025) (n = 10).

Fig. 4.

Temporal profiles and reversibility of TNF-α–induced changes of central pain response. (A) Temporal profiles showing the intensity of BOLD signals obtained by fMRI of 10-wk-old WT mice and human TNFtg mice treated either with vehicle or with human anti–TNF-α antibody IFX. Colors indicate peak height of the BOLD signal from very low (dark blue) to very high (red). The x axis indicates time with at total of three sequences, each of which comprises four pain stimuli (S1 to S4) with increasing intensity (40, 45, 50, 55 °C). The y axis reflects 32 different brain regions as follows: motor cortex (M1), cerebellum (Cb), ventral pallidum (VP), globus pallidus (GP), nucleus accumbens (Acb), striatum (CPu), periaqueductal gray (PAG), zona incerta (ZI), hypothalamus (HT), bed nucleus of stria terminalis (BST), amygdala (Amd), hippocampus (Hip), septal area (Sep), piriform cortex (Pir), perirhinal/ectorhinal cortex (Prh/Ect), entorhinal cortex (Ent), insular cortex (Ins), frontal association cortex (FrA), cingulate cortex (Cg), retrosplenial cortex (RS), secondary (S2) and primary somatosensory cortex (S1), ventral posterolateral/posteromedial thalamic nucleus (VPL/VPM), medial thalamus (MT), lateral posterior thalamic nucleus (LP), lateral (LG) and medial geniculate nucleus (MG), pretectal area (PTA), superior (SC) and inferior colliculus (IC), substantia nigra (SN), ventral tegmental area (VTA). (B) Curves showing average time-dependent changes of the amplitudes of BOLD signals in WT (blue), hTNFtg mice (red), and the latter treated with the human anti–TNF-α antibody IFX (green).