New Directions in Therapy for Sjogrens Syndrome Robert

  • Slides: 23
Download presentation
New Directions in Therapy for Sjogren’s Syndrome Robert I. Fox, MD. , Ph. D.

New Directions in Therapy for Sjogren’s Syndrome Robert I. Fox, MD. , Ph. D. Scripps-Ximed La Jolla, CA [email protected] com (all slides on my website www. robertfoxmd. com)

Background Benign Symptoms • These do not correlate well with acute phase reactants •

Background Benign Symptoms • These do not correlate well with acute phase reactants • They are more similar to “neuropathic” symptoms and involve “nociceptive” pain circuits • Nociceptive pain is caused when special nerve endings—called nociceptors –are activated and follow a particular pathway to cortex of brain

Use of Biologics in Systemic Manifestations of SS We have had modest success with

Use of Biologics in Systemic Manifestations of SS We have had modest success with biologics as measured by ESSDAI (clinical significance >3 units improvement) in SS patients with early disease • • Rituximab Belimumab Abatacept Tocilizumab

Background-2 The functional Circuit • To understand “benign symptoms” and develop better therapies—we must

Background-2 The functional Circuit • To understand “benign symptoms” and develop better therapies—we must review the concept of the functional circuit in SS • the interaction of immune activation on microglial cells and associated neurons • New targets include m. Tor and AKT pathways

Background-3 The functional circuit in SS 1. Mucosal Surface (inflammatory cytokines and metalloproteinase) 4.

Background-3 The functional circuit in SS 1. Mucosal Surface (inflammatory cytokines and metalloproteinase) 4. Gland (lymphs, cytokines, metalloproteinase) 2. Midbrain Vth Nucleus (lymphocytes and glial cells) 3. Vascular (i. NOS, CAMs, Chemokines) These sites and their cytokines correlate with systemic manifestations Brain Cortex Nociception (pain) glial cells and corticcal neurons We must understand these sites to treat “benign” symptoms

Does this apply to Sjogren’s syndrome? • Patients with early SS had corneal pain

Does this apply to Sjogren’s syndrome? • Patients with early SS had corneal pain that decreased completely �with topical anesthes • Patients with chronic SS showed only a partial (30% decrease) in eye pain after topical anesthetic* • Functional MRI (f. MRI) showed nocioceptive pattern—called phantom pain amplification *Rosenthal et al

To study the mechanism of neurogenic or nociceptive pain we must use animal model-1

To study the mechanism of neurogenic or nociceptive pain we must use animal model-1 • The thrombospondin (-/-) mouse (TSP null) or the TGF-b receptor mutation both develop SS like disease • The mouse develops both oral and ocular lesions • The mouse develops ANA and SS-A antibodies • Thrombospondin is a matrix protein that plays a role in activation of latent TGF-b • Activated TGF-b promotes Treg and inhibits Th-17 (IFN-g) • Thus, TSP (null) has high levels of Th-17, IL-17 and IFN-g

Thrombospondin (-/-) mouse model of SS 4 wks WT 24 wks Lacrimal gland biopsies

Thrombospondin (-/-) mouse model of SS 4 wks WT 24 wks Lacrimal gland biopsies Tsp-/- The mouse has ANA+, SS-A+ TSP null can not activate TGF-b In absence TGF-b , continuous Th-� 17 TGF-b and cytokine activation stimulates m. Tor/AKT

The Pain Threshold is Lowered in the Tsp (-/-) mouse A pain stimuli that

The Pain Threshold is Lowered in the Tsp (-/-) mouse A pain stimuli that is innocuous in Wild Type does cause nociceptive pain in tsp (-/-) mouse model Thrombospondin (-/-) Mouse at 24 wks Where a trivial stimuli Causes pain response Wild type • Ocular chemical stress model of nociceptive pain • Le Bars D, Animal models of nociception. Pharmacological reviews 2001; 53: 597 -652.

At the level of the Vth nerve (Tsp -/- mouse) • Microglial cells translate

At the level of the Vth nerve (Tsp -/- mouse) • Microglial cells translate inflammatory signals that go to nociceptive cortex WT TSP (-/-) m. Tor and AKT activated in response to “lower stimuli” in the tsp (-/-) mouse

Of interest, the same regions are activated with physiologic or emotional stressors Emotional Physiological

Of interest, the same regions are activated with physiologic or emotional stressors Emotional Physiological Similar pattern of Fos-ir in cortical neurons in response to distinct stressors

Summary-1 • Functional circuit needs to be considered when assessing “benign” symptoms of corneal

Summary-1 • Functional circuit needs to be considered when assessing “benign” symptoms of corneal or oral pain • Symptoms of oral/ocular pain do not correlate with markers of systemic inflammation (ESR/CRP) because the events are contained within the brainstem and cortex

Summary-2 • Afferents go to midbrain regions of Cranial Vth • Microglial cells are

Summary-2 • Afferents go to midbrain regions of Cranial Vth • Microglial cells are site of cytokine/neurokine interaction • Receptors and neurokines from microglial cells are therapeutic targets

Summary-3 • Novel targets include m. Tor and AKT pathways • These m. Tor/AKT

Summary-3 • Novel targets include m. Tor and AKT pathways • These m. Tor/AKT pathways also implicated in chronic pain and depression—so we must collaborate with these neurochemists

Summary-4 • Cortical “memory” of nociceptive pain is well described in neurologic literature •

Summary-4 • Cortical “memory” of nociceptive pain is well described in neurologic literature • f. MRI indicates that nociceptive pain is the cause of benign symptoms in SS that do not correlate with acute phase reactants

Moulton et*. Al used f. MRI in SS patients with chronic ocular pain using

Moulton et*. Al used f. MRI in SS patients with chronic ocular pain using f. MRI of nociceptive pain have been studied Cortical regions that activate with ocular pain signal at “benign stimuli levels” occur only in chronic SS patients with severe pain *Moulton EA, Becerra L, Rosenthal P, Borsook D. An Approach to Localizing Corneal Pain Representation in Human Primary Somatosensory Cortex. Plo. S one 2012; 7: e 44643.

Summary-5 • We have made advances in “systemic inflammation” and these are encouraging •

Summary-5 • We have made advances in “systemic inflammation” and these are encouraging • For “drug licensing” we will also need to improve the patient’s “quality of life” symptoms of dryness, pain and fatigue • We need for “autoimmune” divisions to work with “neuro-chemistry” research divisions

We are also looking at Additional Targets of Interests Chemokines and their receptors (CCR)

We are also looking at Additional Targets of Interests Chemokines and their receptors (CCR) on vascular cells and lymphocytes TLR receptors: SLAC-15 that links Toll receptor and type 1 IFN Methylation modulators and si. RNA Neural mediator circuits: • Receptors on cornea--substance P (TRPV 1), VIP and CGRP pain receptors • TRPM 8, TRPA 1, and CGRP in trigeminal ganglion neurons • Trigeminal ganglion neurons- MCP-1, MIP-2, • CCR and CCL at the blood brain barrier

CCR and Blood Brain Barrier

CCR and Blood Brain Barrier

Similar pattern of Fos-ir in PVH neurons in response to distinct stressors Emotional Physiological

Similar pattern of Fos-ir in PVH neurons in response to distinct stressors Emotional Physiological

We need to examine microglial pathways • Upon activation, microglia (M 1 and M

We need to examine microglial pathways • Upon activation, microglia (M 1 and M 2) secrete inflammatory mediators that contribute to the resolution or to further enhancement of damage in the central nervous system (CNS). • Particularly, the role of the phosphatidylinositol 3 -kinase (PI 3 K)/Akt/mammalian target of rapamycin (m. TOR) and glycogen synthase kinase-3

The tsp-null mouse allows us to look at the interaction of peripheral inflammation and

The tsp-null mouse allows us to look at the interaction of peripheral inflammation and microglial cells • Activation of microglial cells through m. Tor/AKT • In absence of thrombospondin, constitutive activation of Th 17 and IFN-g activates microglial cells • Nociceptive (pain) pathway occurs through smad 3 and non-smad pathways that involve m. Tor/AKT pathways in cranial nerve V