New Directions in Therapy for Sjogrens Syndrome

New Directions in Therapy for Sjogrens SyndromeRobert I. Fox, MD., Ph.D.Scripps-XimedLa Jolla, CA robertfoxmd@mac.com(all slides on my website www.robertfoxmd.com)GoalsRecognize that Sjogrens has benign and systemic manifestationsReview the concept of functional circuit that links the inflammation of the mucosal circuit to the brain cortical regions that sense painDiscuss the potential target of microglial cells and their cytokines/neurokines that may influence the perception of pain/dryness in SSBackground-1SS patients have Benign and Systemic SymptomsSystemic symptomsrash, arthritis, lung, kidney, lymphoma, hematologic--measured by ESSDAI which measures 12 organ domains. Although ESSDAI usually less than 10, it has scale 0-100.Improvement by at least 3.5 units is significantBenign symptomsdry and painful eyes/mouth, fatigue, cognitive, myalgiameasured by ESSPRIBackground-2Benign symptoms are leading cause of disability as identified by SS patients and poorly correlate with acute phase markers of inflammationThe failure to improve benign symptoms is the main reason why current therapies have failed in FDA trialsBackground-1Benign symptoms include:Dry and Painful eyesDry and Painful MouthFatigue, and Myalgia

Background-2Benign SymptomsThese do not correlate well with acute phase reactantsThey are more similar to neuropathic symptoms and involve nociceptive pain circuitsNociceptive pain is caused when special nerve endingscalled nociceptors are activated and follow a particular pathway to cortex of brain

Use of Biologics in Systemic Manifestations of SSWe have had modest success with biologics as measured by ESSDAI (clinical significance >3 units improvement) in SS patients with early diseaseRituximabBelimumabAbataceptTocilizumabBackground-2The functional CircuitTo understand benign symptoms and develop better therapieswe must review the concept of the functional circuit in SSthe interaction of immune activation on microglial cells and associated neuronsNew targets include mTor and AKT pathwaysBackground-3The functional circuit in SS1. Mucosal Surface(inflammatory cytokines and metalloproteinase)2. MidbrainVth Nucleus(lymphocytes and glial cells)4. Gland(lymphs, cytokines, metalloproteinase)3. Vascular(iNOS, CAMs, Chemokines)

BrainCortexNociception (pain)glial cells and corticcal neuronsThese sites and their cytokines correlate with systemic manifestationsWe must understand these sites to treat benign symptomsDoes this apply to Sjogrens 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 patterncalled phantom pain amplification

*Rosenthal et al To study the mechanism of neurogenic or nociceptive pain we must use animal model-1The thrombospondin (-/-) mouse (TSP null) or the TGF-b receptor mutation both develop SS like diseaseThe mouse develops both oral and ocular lesionsThe mouse develops ANA and SS-A antibodiesThrombospondin is a matrix protein that plays a role in activation of latent TGF-bActivated 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

Lacrimal gland biopsiesThe mouse has ANA+, SS-A+TSP null can not activate TGF-b In absence TGF-b , continuous Th-17TGF-b and cytokine activation stimulates mTor/AKT WTTsp-/-24 wks

Thrombospondin (-/-)Mouse at 24 wksWhere a trivial stimuliCauses pain responseWild typeA pain stimuli that is innocuous in Wild Typedoes cause nociceptive pain in tsp (-/-) mouse model

The Pain Threshold is Lowered in the Tsp (-/-) mouseOcular chemical stress model of nociceptive painLe Bars D, Animal models of nociception. Pharmacological reviews 2001;53:597-652.

Pathophysiology of Pain13PURPOSE OF THE SLIDETo introduce the concept of neuroplasticity that will appear throughout the presentation.

KEY POINTSNeuroplasticity is defined as the capacity of neurons to change their structure, function, or chemical profile.Plasticity may occur in multiple regions of the body during pain processing and contribute to the pain hypersensitivity observed in neuropathic pain. Thus, hypersensitivity is one expression of neuronal plasticity. Activation, modulation, and modification are all forms of plasticity that may contribute to pain hypersensitivity.

REFERENCEWoolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288:1765-1768.

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 stimuliin the tsp (-/-) mouseOf interest, the same regions are activated with physiologic or emotional stressors

EmotionalPhysiologicalSimilar pattern of Fos-ir in cortical neurons in response to distinct stressors

Summary-1Functional circuit needs to be considered when assessing benign symptoms of corneal or oral painSymptoms of oral/ocular pain do not correlate with markers of systemic inflammation (ESR/CRP) because the events are contained within the brainstem and cortexSummary-2Afferents go to midbrain regions of Cranial VthMicroglial cells are site of cytokine/neurokine interactionReceptors and neurokines from microglial cells are therapeutic targets

Summary-3Novel targets include mTor and AKT pathwaysThese mTor/AKT pathways also implicated in chronic pain and depressionso we must collaborate with these neurochemistsSummary-4Cortical memory of nociceptive pain is well described in neurologic literaturefMRI 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-5We have made advances in systemic inflammation and these are encouragingFor drug licensing we will also need to improve the patients quality of life symptoms of dryness, pain and fatigueWe need for autoimmune divisions to work with neuro-chemistry research divisions

Takayuki Sumida,MD.-PresidentIchiro Saito, DDS (Tokyo)Kaz Tsubota, MD (Tokyo)Bruce Beutler, Ph.D. (Scripps TSRI)Ari Theofilopoulos (Scripps TSRI)V. Ramachandran, MD (Salk Neurology)P. Rosenthal (Harvard Corneal Pain Unit)

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 receptorsTRPM8, TRPA1, and CGRP in trigeminal ganglion neuronsTrigeminal ganglion neurons- MCP-1, MIP-2,CCR and CCL at the blood brain barrierCCR and Blood Brain Barrier

EmotionalPhysiologicalSimilar pattern ofFos-ir in PVH neurons in response to distinct stressorsWe need to examine microglial pathwaysUpon 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/AKTIn absence of thrombospondin, constitutive activation of Th17 and IFN-g activates microglial cellsNociceptive (pain) pathway occurs through smad3 and non-smad pathways that involve mTor/AKT pathways in cranial nerve V