Neurogenic in rheumatology

Matthias Seidel, Chief Rheumatology, Schmerzklinik Basel

Muscoloskelettal Symposium, March 31st 2017 Neurogenic inflammation

Describes the mechanism of the central or peripheral nervous system that modulates or perhaps initiates inflammatory and potentially autoimmune events Adjuvant-induced arthritis in rats is prevented after ligation of the spinal cord or peripheral nerves

Courtright and Kuzell 1965 Pittcock 2002 Inflammatory neurotransmitters and neuropeptides

•SubstanceP • CGRP • • • Nerve Growth Factor (NGF) Tachykinins

Arg-Pro-Lys-Pro-Gln-Glin-Phe-Gly-Leu-Met-NH2 neurokinin A

Hys-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH2 neurokinin B

Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH2 neurokinin K Asp-Ala-Asp-Ser-Ser-Ile-Glu-Lys-Gln-Val-Ala-Leu-Leu-Lys-Ala-Leu-Tyr-Gly-His-Gly-

Gln-Ile-Ser-His-Lys-Arg-His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH2 neuropeptide y Asp-Ala-Gly-His-Gly-Gln-Ile-Ser-His-Lys-Arg-His-Lys-Thr-Asp-Ser-Phe-Val-Gly-

Leu-Met-NH2 Substance P

• Expressed in the spinal ganglion • Released after stimulation of primary nociceptive neurons • After repetitive stimulation and antidromal transport release at the nociceptor with vasodilataion and edema

Seidel et. al. 2007 Substance P and the immune system

• B and T lymphocytes, macrophages, mastcells and astrocytes: express substance P receptors • Polymorph mononuclear leukocytes: induce expression of chemotactic IL-8 and phagocytosis • Macrophages: stimulation of phagocytosis • Neutrophil granulocytes: chemotaxis, aggregation and production of superoxides, expression of ICAM-1 • Lymphocytes: induction of proliferation Sacerdote and Levrini 2012 Substance P in rheumatic diseases

Seidel et. al. 2007 Substance P (NK-1) antagonists spantide I and spantide II Low receptor selectivity, reduced efficacy, partial agonistic effect, neurotoxicity, release of histamin from mast cells SDZNKT34311 and LY303875 Significant reduction of neurpathy pain after oral or intrathecal application CGP49823 Significant anxiolytic effect SR140333 Reduced the severity of experimental colitis in rats, and redued infarct area after focal cerebral ischimia GR205171 and MK-0869 Antiemetic effects after bei chemotherapy in ferrets GR205171 Reduced experiment arthritis in rats Nerve Growth Factor (NGF)

Seidel on file 2000 Nerve Growth Factor (NGF)

• -NGF biologically active form • receptors: p75 with low affinity and TrkA with high affinity • upon binding of NGF: internalisation of NGF-TrkA- complex and translocation to the nucleus • activiation of NF-B

Seidel et. al. 2009 Norman and McDermott 2017 Andrews NGF in rheumatic diseases

Seidel et al. 2009 CD68, NGF, NK1 und NK3 in OA synovial tissue

CD68 NGF

NK1 NK3

Seidel on file NGFi as therapeutic option?

• NT-3 infusion in adult rats in TrkA-positive/ TrkC-negative nociceptive neurons reduced: • expression of TrkA-mRNA • binding of NGF to ist receptor • the amount of SP-mRNA and SP-Protein • Significant analgetic effect ALE-0540 (TrkA antagonist) in experimental models with neuropathic and heat-induced pain • NGF injected into humans causes chronic pain syndromes NGFi in OA

• Tanezumab: humanized mAb • Fulranumab: humanized mAb • REGN475/SAR164877: fully human mAb • Medi-578: single chain mAb variable fragment • ABT-110: humanized mAb • AR-786: TrkA selective small molecule

Schnitzler and Marks 2015

Tanezumab in OA

Lane et al, 2010

Conclusions

• Neuron-derived nediators regulate peripheral pain and inflammation • Substance P is a proinflammatory neuro/cytokine • NGF is a key molecule in pain perception • NGFi are promising tools as NSAID alternatives • Several pitfalls need to be solved for daily praxis Thank you!

Danke!

Merci!

Grazie!