SJOGREN ’ S SYNDROME: Theory to Practice in San Diego

SJOGREN’S SYNDROME:Theory to Practice in San Diego Robert I. Fox, M.D., Ph.D. Scripps Memorial Hospital Scripps/XiM Medical Center La Jolla, California USA robertfoxmd@mac.com

Thank you for inviting us to your beautiful city • Tack för inbjudan

Take home lesson 1: • There are no FDA approved drugs for the systemic manifestations of Sjogren’s syndrome • Therefore, expert opinion must be used to choose therapies based on literature • These recommendations are summarized in my new chapters with Alan Baer in UpToDate

Take home lesson-2Therapy of SS 1. The treatment for SS uses steroids and NSAIDS in same manner as SLE and RA 2. Lymphoproliferation and demyelininating disorders distinguish therapy 3. The role of rheumatologist in SS is how to taper steroids

Take home lesson-3 • 3. Immunosuppressants including mycophenolic acid, cyclosporin A and rapamycin are useful and not fully utilized • 4. Attention to co-morbid conditions such as anti-coagulants and accelerated atherosclerosis

Take home lesson-3 • Coordinate therapy for dry eyes and dry mouth • Determine if patient is using medications with anti-cholinergic side effects • Evaluate the causes of fatigue--depression, sleep disorders, or whether we just do not understand the process

Take home lesson-3The most challenging issues for SS therapy 1. Neurologic Manifestations—including peripheral neuropathy, ganglionopathy, and central nervous involvement 2. Fatigue and cognitive loss 3. Lympho-proliferative swelling and possible lymphoma

Current issue in the patient with intractable eye symptoms The dissociation between ocular symptoms and objective findings: The patient with severe discomfort or complaints but relatively mild objective ocular surface a) meibomian gland dysfunction and irritant or allergic effects (tear breakup and osmolality) b) Central pain syndrome: a loss of corneal nerve density and up-regulation of central pain processing (conforcal microscopy and fMRI)

To estimate the role of "central pain", we use the method of Rosenthal et al at Harvard Cornea Clinic1. We score the pain level (1-10) and then use opthaine to anesthesitize the eye--then rescore the pain2. Early in disease, the ophthaine completely reverses pain but later in course a much lower decrease

The concept of pain plasticity is well known to psychologists (we collaborate with V. Ramachandran at Salk Institute)The concept of phantom pain will be important later as we deal with "brain fog" or "neuropathy"

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.

Emotional stressors potential the role of cytokines in pain pathways Emotional Physiological Similar pattern of Fos-ir in cortical neurons in response to distinct stressors

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

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

Don-t miss other causes of ocular pain • Topical or intra-ocular steroids in uveitis • Recurrent uveitis –may need azathioprine or mycophenolic acid • Retinal vasculitis-may need rituximab or cyclophosphamide • Watch out for ocular herpetic lesions • Make sure not a fungal or embolic lesion

Systemic Extraglandular Manifestations • Steroids work • The definition of a rheumatologist is how to taper steroids • Anti-malarials • DMARDs-MTX, Leflunomide, Mycophenolic Acid • Biologics

Hydroxychloroquine • Current debate about "efficacy" --we use it when we are dealing with increased ESR, rash, or arthritis. Current debate is about "fatigue" only. • Efficacy in SLE was convincingly shown in "withdrawal studies" and those need to be done in SS patients • Issue of cost/benefit of OCR monitor and total dose vs. daily dose

Biologics Studied in SS(that show some promise) • Anti-CD20 (rituximab)* –most widely used in SS and Europe for SS although FDA approved • Belimumab (BAFF)-has been disappointing in SS • Abatacept (CD40 L)-Phase II safety good—improved ESSDAI but no control arm

Rituximab* • Most widely used biologic in SS (ACR 2013 abstracts) in French and Scandanavian registries. • Used in response to extraglandular manifestations such as persistent glandular swelling, pneumonitis, mixed cryoglobulinemia. • New "black box" to rule out hepatitis B • *Not approved by FDA.

Other challenging problems • Lymphoma--MALT or diffuse lymphoma, or just an atypical lymphoid reaction • Interstitial pneumonitis and nephritis--huge issues in sample variation during biopsy

Persistent Parotid swelling(after rule out infection and lymphoma, steroids and rituximab)

Lymphocytic Interstitial Pneumonitis (LIP) Bi-basilar on CXR Prominent Cystic on CAT Lymphocytes on biopsy

Thank you for your time and attention • We can stop for questions or • We can tell some of the history of how we came to use rituximab and mycophenolic acid--the actual history had less to do with science than luck

Lymphocytic Interstitial Nephritis(steroids, mycophenolic acid, rituximab)

Lung involvement • rule out TBC, Infections including MAI, and Lymphoma • Interstitial pneumonitis—steroid and Mycophenolic acid; have avoided MTX due to MTX lung • Rituximab useful but rarely will exacerbate

Lung and Renal Involvement:(Basis for treatment) • We like initial steroids and tapered steroids with mycophenolic acid or perhaps rituximab • We saw many UIP/DIP and interstitial nephritis biopsy samples at Stanford (Carrington and Dorfman in our Path Dep't) • At the same time, mycophenolate was developed there for our transplant program

Lymphoma or Pseudolymphoma • Stanford was a lymphoma center • We also developed rituximab at Stanford (Levy Lab) and it had low toxicity • A lot of Levy post-docs founded IDEC across street from Scripps • One of first uses of rituxan was a member of the Scripps family • Ask me how we arrived at 375mg/m2 dosing?

SUMMARY-1 1. Symptoms of ocular and oral symptoms are often greatly out of proportion to objective findings 2. This may be due to augmentation of "central pain" pathways

SUMMARY-3 Additional Differential Diagnosis include: • Celiac disease • Hepatitis C and HIV • Sarcoidosis, IgG4-related disease • Tuberculosis, Syphilis, and Leprosy • Fibromyalgia with incidental autoantibodies

SUMMARY-4 • Our treatment of fatigue in SS remains unsatisfactory, and represents a great therapeutic challenge for the next decade. • The pathways may be similar to PTSD and animal models indicate new pathways such as prostaglandins--the mouse viral model

All slides are available and can be downloaded from my websiteusing your desktop computerrobertfoxmd.com(although these may not be accessed by iPhone due to our web security) 32

SJOGREN ’ S SYNDROME: Theory to Practice in San Diego