SJOGREN’S SYNDROME: Theory to Practice Robert I. Fox, M.D., Ph.D. Scripps Memorial Hospital...

SJOGREN’S SYNDROME:Theory to Practice

Robert I. Fox, M.D., Ph.D.

Scripps Memorial Hospital

Scripps/XiM Medical Center

La Jolla, California USA

robertfoxmd@mac.com

Goals-1:

1) There are no FDA approved drugs for the systemic manifestations of Sjogren’s syndrome

2) Therefore, expert opinion must be used to choose therapies based on literature

3) These recommendations are summarized in my new chapter in UpToDate

Goals-2

3. The existing treatment borrows from RA and SLE in the use of DMARDs, as well as interstitial pneumonitis and lymphoma

4. The most widely used biologic is rituximab, although not approved by FDA.

5. The question is when to use DMARD or Biologic Agent

Goals-3The most challenging issues for

therapy

6. Neurologic Manifestations—including peripheral neuropathy, ganglionopathy, and central nervous involvement

7. Fatigue and cognitive loss

8. Lympho-proliferative swelling and possible lymphoma

All slides are available and can be downloaded

from my websiteusing your desktop computer

robertfoxmd.com

(although these may not be accessed by iPhone due to

our web security)

5

“Old” Consensus Criteria, 2002 called the American-European

Consensus Group Criteria (AECG)

Evidence of a systemic autoimmune cause for the dryness--

– Positive anti-Ro (SS-A or SS-B antibody)

– Positive minor salivary gland biopsy (focus score >1)

A new consensus criteria is being developed with slightly different features

It will be called the SICCA-AECG criteria

ESSDAI- European SS Activity Index(to assess if therapy working)

• Weighted domains to give a total score— the Sjogren’s equivalent to ACR-50 for RA.

• The validated ESSDAI activity score has been the accepted outcome measure of FDA clinical trials.• Clinical significance is 3.5 units of change

Systemic Manifestations

• Steroids work but have side effects.

• DMARDs to taper or replace steroids.

• Hydroxychloroquine

• Methotrexate, Azathioprine

• Mycophenolic acid mofetil

• We are interested in Sirolimus (rapamycin)

Biologics Studied in SS

• Anti-CD20 (rituximab)* –most widely used in SS although FDA approved

• Belimumab (BAFF)-has been disappointing in SS• Abatacept (CD40 L)-Phase II safety good—

improved ESSDAI but no control arm

• TNF antagonists shown not useful

Rituximab

• Most widely used biologic in SS (ACR 2013 abstracts).

• Used in response to extraglandular manifestations such as persistent glandular swelling, pneumonitis, mixed cryoglobulinemia.

• Not approved by FDA.

EYE DRYNESS results in the clinical appearance of keratoconjunctivitis sicca (KCS)characteristic of Sjogren’s Syndrome

Artificial tearsPunctal occlusionOcular lubricants

Treat blepharitis first

Topical cyclosporinTopical “soft” steroids

oftenUsed if not able totolerate

Restsis alone

Systemic OcularOften need DMARDs

• Topical or intra-ocular steroids• Recurrent uveitis –may get by with azathioprine or cell cept

• Retinal vasculitis-may need rituxan or cyclophosphamide

• Watch out for ocular herpetic lesions

Rash distinct from SLE(erythema annulare)

the “old” subacute SLE which is negative for complement staining

Therapy of skin lesions

• Hydroxychloroquine for E. annulare

or methotrexate if psoriaform

• Vasculitis (usually small vessel) may need methotrexate

• Vasculitis of mixed cryoglobulinemia responds to rituximab (indication approved by FDA)

• Mono-neuritis multiplex (medium vessel) may also require cyclophosphamide

Arthritis distinct from RA(Jaccoud’s like or erosive OA)

Hydroxychloroquine, Methotrexate, Rituximab(less successful with azathioprine or leflunomide limited by leukopenia)

Parotid swelling

(after rule out infection and lymphoma, steroids and rituximab)

Lymphocytic Interstitial Pneumonitis

Bi-basilar on CXRProminent Cystic on CATLymphocytes on biopsy

Lung involvement(after rule out TBC, MAI,

Lymphoma)• Interstitial pneumonitis—steroid and

Mycophenolic acid; have avoided MTX due to MTX lung

• Rituximab

DeVic’s Syndrome: Transverse Myelitis Neuromyelitis Optica

After rule out infection, treatments with cytoxan and or rituximab.Maintenance with azathioprineMay need to treat like multiple sclerosis—new options approved

Lymphocytic Interstitial Nephritis(steroids, mycophenolic acid, rituximab)

SUMMARY-1

The American European Consensus criteria:

•Subjective symptoms of dryness

•Objective evidence of autoimmune process such as a positive antibody to SS-A or RF

•Positive minor salivary gland biopsy

Additional Differential Diagnosis include:

• Celiac disease

•Hepatitis C and HIV

•Sarcoidosis, IgG4-related disease

•Tuberculosis, Syphilis, and Leprosy

•Fibromyalgia with incidental autoantibodies

SUMMARY-3

SUMMARY-5

Recognize systemic (extraglandular) sites

–Rule out infections and begin treatment with DMARDs to spare steroids.–DMARDs similar to use in SLE.–Hydroxychloroquine–Methotrexate, Azathioprine, mycophenolic acid

SUMMARY-7

• Our treatment of fatigue in SS remains unsatisfactory, and represents a great therapeutic challenge for the next decade.

• Later, we can discuss our approach to this problem in collaboration with Salk Institute and our research institute.

Thank you for your time and attention

We are still missing key targets in the

pathogenesis of fatigue and the

adrenal-hypothalmic axis.

• In both SS and SLE, we can lower the cytokine with biologics, but the patient still feels little improvement.

• This will be the focus of future direction for therapy.

Information on website

Benign manifestations include:

• Dry and painful eyes• Dry and painful mouth• Myalgias, arthralgia, fatigue • Impaired cognition (executive function)— trying to distinguish “fibromyalgia” from “depression”

Differential Diagnosis of SS-3

• The antibody to Ro (SS-A) or La (SS-B) do not fulfill criteria for SLE.

• Many older patients labeled with mild SLE actually have SS.

• Many patients in Hematology clinic with mixed cryoglobulinemia, hemolytic anemia or ITP actually have SS.

Is Sjogren’s just SLE with 4/5 SLE Criteria?

• Different antibody profile (anti-SSA/B)

are not criteria for SLE;

• SS is more organ specific –

(salivary/lacrimal gland)

and more lymphoproliferative.

Why is Sjogren’s not just SLE with 4/5 Criteria?

1. Interstitial pneumonitis (not pleurisy), interstitial nephritis (not glomerulonephritis)

2. Higher frequency of lymphoma

3. Genome Screens support this with Homing receptors found in SS but not SLE (CXCR5)

Summary-1

1. Functional circuit needs to be considered when assessing “benign” symptoms of corneal or oral pain.

2. 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.

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.

Dry and Painful Mouth-1

• If you thought that Dentists did not care about SS, then wait until you see their Dental Care Plans --

The answer to all problems is a $25,000 tooth implant.

Dry and Painful Mouth-2

• Must treat underlying oral candida (which is erythematous spots on roof of mouth) before anything will work.

• Candida often lurks under dentures–

• Patients would rather run naked through clinic than remove a denture.

Dry and Painful Mouth-3

• Angular cheilitis the most obvious hint.

• Treatment of oral candida is a slow process involving multiple steps.

• Use website for education.

We are also looking atadditional targets of interest

• 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 siRNA• Neural 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

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

Thank you for inviting us.

Robert I. Fox, M.D., Ph.D.

http://www.robertfoxmd.com

RobertFoxMD@mac.com