New Directions in Therapy for Sjogren’s Syndrome

Robert I. Fox, MD., Ph.D.Scripps-Ximed

La Jolla, CA robertfoxmd@mac.com

(all slides on my website www.robertfoxmd.com)

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 biologics as measured by ESSDAI (clinical significance >3 units improvement) in SS patients with early disease

• Rituximab• Belimumab• Abatacept• Tocilizumab

Background-2The 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 mTor and AKT pathways

Background-3The functional circuit in SS

1. Mucosal Surface(inflammatory cytokines and metalloproteinase)

1. Mucosal Surface(inflammatory cytokines and metalloproteinase)

2. MidbrainVth Nucleus

(lymphocytes and glial cells)

2. MidbrainVth Nucleus

(lymphocytes and glial cells)

4. Gland(lymphs, cytokines, metalloproteinase)

4. Gland(lymphs, cytokines, metalloproteinase)

3. Vascular(iNOS, CAMs, Chemokines)

3. Vascular(iNOS, CAMs, Chemokines)

BrainCortex

Nociception (pain)glial cells and

corticcal neurons

BrainCortex

Nociception (pain)glial cells and

corticcal neurons

These sites and their cytokines correlate with systemic manifestations

We must understand these sites to treat “benign” symptoms

Does this apply to Sjogren’s syndrome?

• Patients with early SS had corneal pain that decreased completely with topical anesthesia*

• Patients with chronic SS showed only a partial (30% decrease) in eye pain after topical anesthetic*

• Functional MRI (fMRI) 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

• The thrombospondin (-/-) mouse (TSP null) or the TGF-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-• Activated TGF-promotes Treg and inhibits Th-17 (IFN-• Thus, TSP (null) has high levels of Th-17, IL-17 and IFN-

Thrombospondin (-/-) mouse model of SS

4 wks

Lacrimal gland biopsies

The mouse has ANA+, SS-A+TSP null can not activate TGF-In absence TGF-continuous Th-17TGF- and cytokine activation stimulates mTor/AKT

WT Tsp-/-

24 wks

0

Neuroplasticity in Pain Processing1-3

1. Woolf CJ, Salter MW. Science. 2000;288:1765-1768. 2. Basbaum AI, Jessell TM. The perception of pain. In: Kandel ER, et al, eds.

Principles of Neural Science. 4th ed. 2000:479.3. Cervero F, Laird JMA. Pain. 1996;68:13-23.

Stimulus Intensity

100

Pain state Normal

Allodynia

Hyperalgesia3

80

60

40

20

innocuous noxious

Pa

in S

en

sa

tio

n

Thrombospondin (-/-)Mouse at 24 wksWhere a trivial stimuliCauses pain response

Wild type

A pain stimuli that is innocuous in Wild Typedoes cause nociceptive pain in tsp (-/-) mouse model

The Pain Threshold is Lowered in the Tsp (-/-) mouse

•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 inflammatory signals that go to nociceptive cortex

WT TSP (-/-)

mTor and AKT activated in response to “lower stimuli”in the tsp (-/-) mouse

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

EmotionalEmotional PhysiologicalPhysiological

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 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 site of cytokine/neurokine

interaction• Receptors and neurokines from microglial

cells are therapeutic targets

Summary-3

• Novel targets include mTor and AKT pathways

• These mTor/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

• fMRI indicates that nociceptive pain is the cause of benign symptoms in SS that do not correlate with acute phase reactants

Moulton et*. Al used fMRI in SS patients with chronic ocular painusing fMRI 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. PloS one 2012;7:e44643.

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 atAdditional Targets of Interests

Chemokines and their receptors (CCR) on vascular cells and lymphocytesTLR receptors: SLAC-15 that links Toll receptor and type 1 IFNMethylation modulators and siRNANeural mediator circuits:• Receptors on cornea--substance P (TRPV1), VIP and CGRP pain receptors• TRPM8, TRPA1, 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

EmotionalEmotional PhysiologicalPhysiological

Similar pattern ofFos-ir in PVH neurons

in response to distinct stressors

We need to examine microglial pathways

• Upon activation, microglia (M1 and M2) secrete inflammatory mediators that contribute to the resolution or to further enhancement of damage in the central nervous system (CNS).

• Particularly, the role of thephosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and glycogen synthase kinase-3

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

• Activation of microglial cells through mTor/AKT

• In absence of thrombospondin, constitutive activation of Th17 and IFN-activates microglial cells

• Nociceptive (pain) pathway occurs through smad3 and non-smad pathways that involve mTor/AKT pathways in cranial nerve V