Treatment of Sjogren’s in 2010:Opportunities and Challenges

a) Treatment of Dry Eyes and Mouth

b) Treatment of Extraglandular Manifestations--

• Lupus-like symptoms-arthralgia, rash• Neuropathy (central and peripheral)• Cognitive and myalgia (fibromyalgia)• Lymphoproliferative

Take Home Points-1

1. Topical therapy of dry eyes and dry mouth: new targets include water transport, mucins, and topical small molecules such as jak 3.

2. Dry mouth symptoms may be “burning” mouth and require treatment as a local neuropathy.

Take Home Points-2

1. Poor correlation of symptoms and objective findings of both dryness and neuropathic symptoms.

2. This poor correlation is the greatest challenge, since it involves cortical perception of discomfort

3. The neuro-endocrine circuit in Sjogren’s may provide insight into “fibromyalgia.”

Take Home Points-3Systemic Manifestations for Lupus-like Symptoms

DMARDsHydroxychloroquineMethotrexateLeflunomide

Small molecules-Jak3 and Jak ½

Filomodulin (MS approved)

Biologic AgentsAnti-CD20 rituximab and new variants

Anti-BAFF (Benlysta)Anti-CD22 (Eprumazab)

Taci-Ig and ICOS

Homing receptors

New Approaches to Dryness

1. Topical Ocular Dryness“smart artificial

tears”MucinAndrogenMicro-iRNAAnti-IL-17*Jak 3 inhibitor*Metalloproteinase

inhibitor

* Currently cyclosporin is water insoluble and irritating

New Approaches to Dryness-2Oral Agents are better than pilocarpine or cevimeline

…since the gland is not destroyed but is paralyzed by cytokines and metalloproteinases

•Improved secretagogues (new muscarinic agents in trial)

•Anti-cytokine therapy has modest effect only in patients with early disease

Novel methods of water conservationNew Approaches to Dryness-3

1. Transport water across the conjunctiva (diquafasol)

p2Y2 purine receptor agonist

2. Decrease evaporative loss (muc 3, muc 5A, lipid)

3. Decrease water reabsorption through membranes of eye by blocking trans-epithelial salt(and water) channels that drain orbit(compound P552-02)

p2Y2 receptor directly transports water across conjunctiva

Tear film

Membranes at the base of the orbit are a major site of ‘water exit” (in addition to the puncta)

Systemic Therapies

Traditional DMARDs- alone and combination• Hydroxychloroquine• Methotrexate• Leflunomide and mycophenolic acid

Steroids• Traditional steroids (prednisolone,

methylprednisolone)—work-- but side effects• Soft steroids—novel I inhibitors

Biologics and Cytotoxics

Biologic Agents—the new “holy target” based on success in RA.

Cytotoxics—although we worry about cyclophosphamide, we need to ask how much is actually justified if we use carefully . We worry about marrow depletion yet use it to generate “stem cells.”

Mycophenolic Acid—now generic so unclear why so expensive in US.

Available biologic therapy

TNF antagonists- disappointing results despite one initial report with infliximab*

Repeat infliximab study*

Etanercept*

*Refs 43-47

Rituximab (anti-CD20 antibody)-numerous reports in Sjogren’s

• B-cell depletion efficient

• Surprisingly, little change in serum BAFF or IgG levels

Rituximab Most Consistent RoleFor

Hematologic Features in SS

*lymphadenopathy, *pseudolymphoma, *thrombocytopenia

* mixed cryoglobulin*low grade lymphoma

As it will not have “FDA label,” it will be an off-label use.

Rituximab Treatment

1. Only small changes in tear/saliva flow and only in patients with early disease.

2. Changes in salivary gland biopsy with improvement in foci score.

3. B-cell depletion as expected.

4. Change in T-cell repertoire (CD25+ T-reg) in some patients.

Important lesson about biologicsfrom rituximab

When you deplete B-cells (rituximab):

1. Create an excess of circulating BAFF in comparison to the number of B-cells that bear BAFF-Receptor.

2. This excess of ligand stimulates a round of cell division not only of B-cells but of B-cells.

3. Any round of cell division leads to activation induced cell death (AICD) and opportunity to re-shape the repertoire.

The “cure” of autoimmune disease

Will depend on changing the repertoirea) T-regs to modulate auto-immune cells

b) Alteration of homing receptors

c) Regeneration of damaged target organs

Humanized anti-CD20(ocrelizumab)

Higher Affinity for B-cells;

Had Fc receptor for complement and B-cell depletion;

Clinical trials halted due to increased infection (although mostly at non-US sites).

Other Biologics-1

Anti-BAFF (Benlysta) antibody:• Likely to be approved for SLE by FDA.• The SS subset of SLE did not show significant

improvement compared to entire SLE subset.• Although the Benlysta subset did better than no

treatment, the patient and physician global assessment was not significant.

Other Biologics-2

Anti-CD22 (Epratuzumab)—another B-cell marker--

• Initial clinical trials in SS (and SLE) plagued by production of a uniform product (problems in glycosylation), so 6 different lots needed with interruption of protocol;

• New Drug Manufacturer and preliminary studies indicate safety;

• Any FDA approval for SS will require increased saliva and tears. Expect at best, results similar to rituximab.

Other therapies in trial (biologic)

1. Anti-CD22 antibody: initial results inconclusive and repeat trials in progress*

2. Antibody to IL-6 (Medi 545) in SLE*

(including subset with SS features)

3. Antibody to type I IFN (MRA)*• Antibody to BAFF, BAFF-R or TACI-Ig*

*Refs 60-61 and clinicaltrials.gov

Fingolimod- a novel approach

The molecular biology of phospho-fingolimod is thought to lie in its activity at one of the five sphingosine-1-phosphate receptorsStromal cell has sphingosine receptor

Lymphocyte is retained in the lymph node until the sphingosine ligand is “removed”

Fingolimod-2(recently approved for multiple sclerosis)

• It can sequester lymphocytes in lymph nodes, preventing them from moving to the central nervous system for auto-immune responses in multiple sclerosis and was originally proposed as a anti-rejection medication indicated post-transplantation.

• It has been reported to stimulate the repair process of glial cells and precursor cells after injury.

• Fingolimod has also been reported to be a

Fingolimod provides rationale for new therapies that interfere with homing

1. T- and B-cells have surface “homing receptors” when generated in node or marrow.

CD4+CD4+

B cellB cell

BloodBlood

3. When the homing receptor encountersvascular adhesive molecules,the lymphocyte enters tissue.

4. Pearl:Failure to bind to homing

receptor in 72 hoursleads to obligate apoptosis

of the lymphocyte. This is why we do not become

one large lymph node.

2. Lymphs migrate through blood

to tissues.

Caution—PML (progressive multifocal leukoencephalopathy)

Due to reactivation of polyoma virus (JC) in CNS

We have seen with agents: that alter homing: • Natalazumab (Tsabri)

• Efalizumab (Raptiva)

and

B-cell depleting agents (rituximab);

SS and SLE patients already handle polyoma poorly, as evidenced by higher frequency pap smear abnormalities

Our most difficult problems

1. Neuropathy—peripheral and central

2. Chronic fatigue and vague cognitive

3. Lymphoproliferation

4. Accelerated cardiovascular complications

Neuropathy

Poor correlation between symptoms and objective findings:

• Eye pain- does not correlate with tear flow.

• Mouth pain- does not correlate with saliva.

• Peripheral neuropathy- does not correlate with nerve biopsy.

• Cognitive- does not correlate with acute phase reactants.

Fibromyalgia: The elephant in the Room

FatigueCognitive

Nervepain

Dry eyes and dry mouth

As rheumatologists…

We will need to learn a new vocabulary about the perception of pain and how it is modulated by cytokines.

The key term is the “plasticity” of the nervous system. How the perception of pain is modulated by cytokines of the “stress axis.”

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

Pai

n S

ensa

tio

n

Cytokines alter pain perception

The Pain Roadmap: Peripheral and Central Nervous System Landmarks

Brain image courtesy of ATI

Peripheral Nervous System

Central Nervous System

• The neural processing of pain involves the:

– peripheral nervous system

– spinal cord (central nervous system)

– brain (central nervous system)

Brain Regions that May Modulate Pain and Emotion1-4

Prefrontal Cortex

Hippocampus

Insular Cortex

Thalamus

Somatosensory Cortex

Both

Pain

Central Amplification of Pain from Eyes and Mouth: Regions Found on Functional MRI

Take Home Lesson 1

1. Topical therapy and ability to stimulate saliva or tears remains inadequate.2. Treatment of extraglandular manifestations

such as arthritis, rashes, hemolytic anemia, or lymphomas is rapidly improving.

3. The treatment of the neuro-endocrine manifestations (cognitive impairment and fatigue) remains inadequate.

Thank you

for your time and attention

I would be happy to entertain any questions

now or later.

The slides are available to you for your use.

RobertFoxMD@mac.com

Pearl: Rituxan does more than deplete B-cells

a) Alteration of T-cell subsets (especially appearance of CD25+/FoxP3 T-regs) after treatment

indicates a role in “rebooting the computer.”

b) Lymphocytes remain present in the SG

biopsy, probably due to BAFF secreted by

dendritic cells.

*Refs 57-59

Rituximab (anti-CD20)*

1. Multiple studies of small number of patients and single center trials

2. General Conclusion--

a) useful in extra glandular manifestations including: -- mixed cryoglobulinemia -- pseudolymphoma (glands or lung)

-- hemolytic anemia and thrombocytopenia

b) results in tear/saliva flow not significant except in group of patients with early SS, where increase saliva was statistically increased but still modest improvement and biopsies showed improvement;

3. Among SLE patients treated with anti-CD20, SS-A subset responded less frequently and had shorter remissions;

4. After an NIH multi-center trial, company is not pursuing indication.

*Refs 47-59