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SJÖGREN’S SYNDROME: A CLINICAL UPDATE

ARIZONA UNITED RHEUMATOLOGY ALLIANCE ANNUAL

MEETING DECEMBER 6,2020

FREDERICK B. VIVINO, MD, MS, FACR Chief, Division of Rheumatology

Penn Presbyterian Medical Center Director, Penn Sjögren’s Syndrome Center

University of Pennsylvania Perelman School of Medicine

DISCLOSURES

• Consultant and/or participant in clinical trials for: • Trinity Biotech, Inc. • Biogen-Idec, Inc. • Novartis, Inc.

• Discussion of medication use for unapproved indications

• Editor, Sjögren’s Syndrome: A Clinical Handbook, Elsevier, Inc, 2020.

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OBJECTIVES

• Heterogeneity of presentations • Changing epidemiology & demographics

• Evaluation • Current classification criteria • Management

HISTORY OF SJOGREN’S SYNDROME

• 1933 monograph- 19 women with dry eyes, dry mouth and (66%) chronic arthritis.

• Interrelationship of dry eyes, dry mouth, arthritis.

• Systemic nature of disease.

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SJOGREN’S SYNDROME CHANGING EPIDEMIOLOGY

• Rare (NORD) →2nd most common autoimmune rheumatic disease 1

• SS may affect 3-4% of British pop’n.2

• 20 million Americans affected by dry eyes.3,4

• 4.5 million Americans over 50 have “clinically significant” dry eye4 (Women’s Health Study, Physicians Health study).

1. Helmick G et al. Arthritis Rheum, 2008.

2. Thomas et al. Brit J Rheum, 1998. 3. Schaumberg D et al. In.: The Cornea: Scientific Foundations and Clinical Practice, 2004, 205. 4. Market Scope, Report on the Global Dry Eye Market, 2004.

STUDY OF ARTHRITIS PREVALENCE

HELMICK C. ARTHRITIS RHEUM, 2008.

Disease* Estimates (# affected) RA 1.3 million Sjogren’s 0.4 to 3.1 million JRA 0.294 million SLE 0.161 – 0.322 million Scleroderma 0.049 million

*Autoimmune Rheumatic Diseases

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WHO GETS SJOGREN’S SYNDROME?

• 80 % of Sjogren’s patients present with sicca symptoms

• Sicca from siccus (Latin for “dry or thirsty“)

• Dry eyes most frequent presentation

HETEROGENEOUS DISEASE WITH VARIED CLINICAL PRESENTATION

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ATYPICAL PRESENTATIONS OF SJÖGREN’S SYNDROME (20%)1,2

• Seropositive polyarthritis

• Polymyalgia rheumatica

• Leukocytoclastic

vasculitis

• Demyelinating disease

• Peripheral neuropathy

• Inflammatory myositis

• Salivary gland swelling

• Accelerated caries

• Renal tubular acidosis

• Fever of unknown origin

• Chronic fatigue syndrome

• Interstitial lung disease

• Corneal melt or

perforation

• Elevated ESR

• Positive ANA or RF in an

asymptomatic patient

1. Vivino F, Clin Immunol, 2017.

2. Vivino F, Sjogren’s Syndrome: A Clinical Handbook, Elsevier, 2020.

SICCA SYMPTOMS MAY BE MINIMAL OR NIL !!!!

DIAGNOSTIC CAVEAT

• Poor correlation between symptoms of dry eyes1,2 and dry mouth3, and results of objective tests.

• Sjögren’s can be diagnosed in the absence of sicca symptoms!!!!

• People with severe xerostomia don’t always have Sjögren’s.

1. Bartlett J et al. Clin Ophthalmol, 2015. 2. Vehof J et al. Ophthlmology, 2017. 3. Shiboski S et al. Arthritis Care Res, 64, 475, 2012.

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DIFFERENTIAL DIAGNOSIS OF THE SICCA SYNDROME

• Amyloidosis

• Chronic sialadenitis (SOX syndrome)

• Diabetes mellitus

• Dysautonomia

• Eosinophilia-myalgia syndrome

• Fibromyalgia syndrome

• Graft-versus-host disease

• Hepatitis C

• IgG4 Syndrome

• Medication-related dryness

• Mouth breathing

• Multiple sclerosis

• Organ specific autoimmune

disease

• Radiation injury

• Sarcoidosis

• Sialadenosis

• HIV- DILS (Diffuse infiltrative

lymphocytosis syndrome)

• Silicone breast implant disease

• Sjogren’s syndrome (1° or 2°)

• Type V hyperlipidemia

SJOGREN’S SYNDROME DIAGNOSTIC GOALS

• Comprehensive evaluation

• Objective evidence of dry eyes

• Objective evidence of salivary gland involvement

• Proof of autoimmunity

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HOW TO SCREEN FOR DRY EYES

Schirmer’s test (unanesthetized)

Normal >10mm/5min and/or Vital dye staining Normal = no staining

Fluorescein Lissamine green

HOW TO SCREEN FOR DRY MOUTH

Sialometry Unstimulated whole mouth

salivary flow rate Normal > 0.3-5 cc/min.

Saliva 1 g = 1cc

.

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HOW TO PROVE INVOLVEMENT OF THE SALIVARY GLANDS

Abnormal salivary gland scan Defects in saliva formation/ excretion

Abnormal parotid sialography Narrowing or widening of the ducts Abnormal ultrasound Parenchymal inhomogeneity or increased echogenicity

Normal Sjogren’s

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HOW TO PROVE AUTOIMMUNITY

• Test serum for Anti-SSA a.k.a. Anti-Ro

• Lip Biopsy

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AUTOANTIBODIES IN SJOGREN’S

• ANA (70-90%) • RF (60-90%) • Anti-SSA (Ro) (40-

60%)* • Anti-SSB (La) (20-

40%)* • Anti-CCP (7-19%) • Anti-centromere (4-

13%)

• Anti-M3R (62-90%) • Anti-α fodrin (1-50%) • Anti-CA-6 (?)1,2

• Anti-SP-1 (?)1,2

• Anti-PSP (?)1,2

1. Shen L et al, Clin Immunol, 2012. 2. Available commercially as “Sjo Kit” or “Early Sjogren’s Profile”

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SJOGREN’S SYNDROME : LABIAL MINOR SALIVARY GLAND BIOPSY

Adequate tissue sampling = 5 minor salivary glands (8 mm2)

SJOGREN’S SYNDROME SALIVARY GLAND BIOPSY (EARLY STAGE) SHOWS

LYMPHOEPITHELIAL LESION

• Mononuclear infiltrates • T lymphs CD4 > CD8 • B lymphocytes (20%) • plasma cells, dendritic

cells, macrophages.

• Cluster around acinar & ductal epithelium

FOCUS = 50 OR MORE MONONUCLEAR CELLS

Acini

Duct

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BIOPSY FOCUS SCORE REFLECTS DENSITY OF INFLAMMATION

Normal Salivary Gland Salivary Gland in SS

Positive biopsy = Focal Lymphocytic Sialadenitis Focus Score ≥ 1 per 4 mm2

FOCUS

ANOTHER CAVEAT OF DIAGNOSIS BIOPSY INTERPRETATION

• Frequent errors made (53% of 60 accessions) • Failure to calculate a focus score • Failure to cite QNS/sampling error • Misinterpretation of a focus • Failure to measure tissue surface area • Failure to describe chronic sialadenitis

Ref: Vivino F et al., J Rheumatol 29;5: 938-44, 2002.

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2016 ACR- EULAR SJOGREN’S CLASSIFICATION CRITERIA

Derived from 2002 AECG criteria (Vitali C et al. Ann Rheum Dis, 2002) 2012 ACR-SICCA criteria (Shiboski S et al. Arthritis Care Res, 2012)

CLASSIFICATION CRITERIA

• Designed for research purposes

• Define homogeneous population of patients for clinical trials and other studies

• Not intended for diagnosis

• Sometimes sacrifice sensitivity for specificity

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2016 ACR- EULAR SJOGREN’S CLASSIFICATION CRITERIA

SHIBOSKI C ET AL. ARTHRITIS & RHEUM, 2017

Inclusion • 1 sx oral and/or ocular dryness (AECG) or • 1 extraglandular manifestation (ESSDAI)

Item Weight

+ biopsy (FS > 1 / 4mm2) 3

Anti-SSA (Ro)+ 3

OSS > 5 (van Bijsterfeld > 4) 1 eye 1

Schirmer (unanesth.) < 5mm/5 min. 1 eye 1

Unstimulated salivary flow < 0.1 ml/min 1_

POSITIVE SCORE FOR SS = 4 9

PHYSICIAN GOLD STANDARD FOR DIAGNOSIS OF SJOGREN’S

• Objective evidence of dry eyes • Objective evidence of salivary gland involvement • Anti- SSA positivity • Focal lymphocytic sialadenitis

• Focus score > 1 / 4 mm2

*After exclusion of other causes

(any 3 of 4)*

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TREATMENT CONSIDERATIONS

• No remittive agent or cure exists

• Goals • palliate symptoms • prevent complications • assess need for immunosuppressants

• Triage- eyes, mouth, internal organs

SURVEY ON QUALITY OF LIFE IMPACT OF SJÖGREN’S SYNDROME

0 10 20 30 40 50 60 70 80

Vaginal dryness

Sleep difficulties

GI symptoms

Difficulty swallowing

Dry skin

Dry nose

Joint pain

Fatigue

Dry mouth

Dry eyes

Reprinted with permission from the Sjögren’s Syndrome Foundation. The

Moisture Seekers. 2006;24:1-3.

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DRY EYE GUIDELINES FOULKS G ET AL. OCULAR SURFACE, 2015.

• Determine mechanism of dryness • production- aqueous tear deficiency and/or • evaporation- meibomian gland dysfunction

• Treat in stepwise fashion based on severity (1-4)

MEIBOMIAN GLAND DYSFUNCTION AKA BLEPHARITIS

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• Tear replacement • PRN preserved tears to qid • Preservative-free tears up to q 1hr • Ocular gels & ointments qhs • Blepharitis- lipid containing tears, lid hygiene

• Anti-inflammatory drops • Autologous serum tears • Secretagogues • Physical measures

• Punctal plugs or cautery • Bandage contact lens

Bunya V et al. Sjogren’s Syndrome: A Clinical Handbook, 2020 pp 57-70.

DRY EYE TREATMENTS

CORNEAL NEUROPATHY IN SJÖGREN’S

Normal Sjögren’s

A B

Figure A. In vivo confocal microscopy demonstrates normal corneal (subbasal) nerve plexus. B. Sjögren’s patient with corneal nerve dropout (solid arrow), abnormal branching (open arrow) and presence of dendritic cells (diamond arrow).

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TREATMENT OF DRY MOUTH

• Mild symptoms → gustatory/masticatory stimuli • Sugar-free (not sugarless) gums, lozenges • Sugar-free hard candies • Xylitol preferred 1

• Mild-moderate symptoms → secretogogues 2

• Pilocarpine • Cevimeline

• Severe symptoms (no flow) → replacement therapy • Artificial salivas • Moisturizing gels

1. Maguire A, Rugg-Gunn A., Brit Dent J, 2003 2. Noaiseh G et al, Clin Exp Rheumatol, 2014.

TIPS ON SECRETOGOGUE USE

• Start low and go slow (e.g. pilocarpine 5 mg or cevimeline 30 mg pc dinner then advance weekly as tolerated).

• May help other oral symptoms as well as extraoral sicca symptoms (higher doses)1

• Failure to respond to one drug doesn’t necessarily predict failure with the other2.

• Side effects with one drug don’t always predict side effects of the other2.

1. Vivino F, Scand J Rheum, 2001. 2. Noaiseh G et al, Clin Exp Rheumatol, 2014.

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DENTAL GUIDELINES FOR CARIES PROPHYLAXIS

ZERO D ET AL. JADA, 2016.

• Topical fluoride for all SS patients with dry mouth (strong)

• Remineralizing solutions (moderate)

• Chlorhexidine antimicrobial rinses (weak)

• Stimulation of salivary flow (secretogogues etc.) (weak)

USE OF 1.1% NEUTRAL SODIUM FLUORIDE

• Brush on qhs after tooth brushing, floss, leave on for 30 minutes, then rinse/expectorate.

This Photo by Unknown Author is licensed under CC BY-NC-ND

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Recommendation

Strength of the Recommendation

1)

A first line of treatment

should be

hydroxychloroquine.

Moderate

Recommendation Strength of

Rec

Recommendation Strength of

Rec

2)

methotrexate alone

Moderate

OR 3)

hydroxychloroquine

plus methotrexate

Moderate

*Carsons S et al. Athritis Care Res, 2017.

RHEUMATOLOGY PRACTICE GUIDELINES* Musculoskeletal Pain

Recommendation

Strength of Rec 4a) short-term (≤1mo.) corticosteroids <=15mg a day

Strong

4b) Long-term (> 1 mo.) ≥15mg/d corticosteroids with efforts to begin a steroid-sparing agent as soon as possible.

Moderate

Recommend- ation

Strength of

Rec

Recommend-

ation

Strength

of Rec

Recomm

endation

Strength

of Rec

5)

leflunomide

Weak

OR

6)

SSZ

Weak

OR 7)

AZA

Weak

*Carsons S et al. Athritis Care Res, 2016.

RHEUMATOLOGY PRACTICE GUIDELINES* Musculoskeletal Pain

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Recommendation

Strength of the Recommendation

8) cyclosporine Weak

Recommendation Strength of Rec

7b) If major organ

involvement occurs in the

primary Sjögren’s patient, AZA

may be preferred over

leflunomide or SSZ for the

treatment of all systemic

manifestations including

inflammatory musculoskeletal

pain.

Moderate

*Carsons S et al. Athritis Care Res, 2016.

RHEUMATOLOGY RACTICE GUIDELINES* Musculoskeletal Pain

RHEUMATOLOGY CLINICAL PRACTICE

GUIDELINES- FATIGUE CARSONS S ET AL. ARTHRITIS CARE RES, 2017.

Education about self care measures & exercise to reduce fatigue in Sjögren's – Strong

Hydroxychloroquine may be considered in selected situations to treat fatigue in Sjögren's – Weak

DHEA is not recommended for the treatment of fatigue in Sjögren's – Strong

Neither etanercept or infliximab is recommended for treatment of fatigue in Sjögren's - Strong

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SJÖGREN’S SYNDROME TREATMENT OF INTERSTITIAL LUNG

DISEASE

• Variable presentations • NSIP & other patterns • Decreased QOL & cause of

mortality • Treatable • Steroids, azathioprine,

mycophenolate mofitil, IV rituximab, cyclophosphamide.

• Pulmonary guidelines on the way

Refs: 1. Johr C, Extraglandular abnormalities in Sjögren’s syndrome in Sjögren’s Syndrome: A Clinical Handbook, 2020 pp 93-115. 2. Mongroo R et al. Sjögren’s Syndrome: A Clinical Handbook 2020, pp211-233.

SJÖGREN’S SYNDROME TREATMENT OF RENAL DISEASE

• Prevalence 5-50% • Tubulointerstitial nephritis (TIN) most

common • Slowly progressive and leads to

azotemia, low range proteinuria and RTA (distal >> proximal)

• Treated with steroids, bicarbonate and potassium replacement

• Mycophenolate mofitil (MMF), azathioprine (AZA), IV rituximab (RTX) for refractory cases

• Glomerulonephritis ~ 2% • Membranoproliferative GN • Associated with cryoglobulinemia • Coexists with TIN • Tx with IV RTX and steroids • Can use plasmapheresis, MMF,

AZA, CYC in refractory cases

Refs: 1. Johr C, Sjögren’s Syndrome: A Clinical Handbook 2020. pp 93-115. 2. Mongroo R et al. Sjögren’s Syndrome: A Clinical Handbook 2020 pp 211-233,

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SJÖGREN’S SYNDROME TREATMENT OF NEUROPATHIES

• Prevalence up to 20%

• Need to r/o other causes

• Variable course • Multiple neuropathies

can coexist

• Various types • Small fiber PN • Axonal sensory or

sensorimotor • Autonomic • Vascultic • Sensory ataxic

neuronopathy • Cranial neuropathies • Multiple cranial

neuropathies • CIDP,

Radiculoneuropathy, Motor neuron disease

Ref: Younger D, in Sjögren’s Syndrome: A Clinical Handbook 2020 pp 153-188.

SJÖGREN’S SYNDROME TREATMENT OF CNS INVOLVEMENT

• Prevalence 2-5% • Need to r/o other causes • Difficult to diagnose because can

precede sicca symptoms • Various clinical syndromes

• Asymptomatic white matter lesions • Focal/multifocal disease • Demyelinating disease • NMO • Diffuse disease • Optic neuropathy • ALS-like syndrome • Cerebellar ataxia

• Treatments vary by cause • Clinical Practice Guidelines to be

developed • Algorithm parallels SLE • IV pulse steroids • PO 1 mg/kg steroids • Azathioprine • Cyclophosphamide (IV or PO) • Mycophenolate mofitil • IV Rituximab • Plasma exchange • Physical therapy

Ref: Pavlakis P et al. Sjögren’s Syndrome: A Clinical Handbook 2020 pp 189-209.

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SSF RHEUMATOLOGY GUIDELINES FOR USE OF BIOLOGICS

CARSONS S ET AL. ARTHRITIS CARE RES, 2016.

FUTURE TREATMENTS • Iscalimab (CFZ533)

• Monoclonal antibody that inhibits CD40-CD-154-mediated signaling pathway (Fisher B et al. Lancet Rheumatology, 2020).

• Ianalumab (VAY-736) • Monoclonal antibody that

causes B cell depletion through ADCC and BAFF receptor blockade (Dorner T et al. Ann Rheum Dis, 2019)

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SJÖGREN’S SYNDROME CONCLUSIONS

• Variety of presentations.

• Dx requires documentation of objective evidence of dry eyes, salivary gland involvement.

• Dx requires proof of autoimmunity (+SSA or +lip biopsy).

• Not curable but certainly treatable.

• Clinical practice guidelines published.

SJÖGREN’S SYNDROME

The End. Time for a drink !

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1. Vivino F et al. an update of disease pathogenesis, clinical manifestations and treat, Clin Immunol 203:81-121, 2019. 2. Shiboski C et al. 2016 Classification Criteria for primary Sjögren’s Syndrome: A Consensus and Data-Driven Methodology Involving Three International Patient Cohorts, Arthritis & Rheumatology 69:35-45, 2017. 3. Baer A et al. The SSB positive/SSA–negative antibody profile is not associated with key phenotypic features of Sjogren’s syndrome. Ann Rheum Dis 74: 1557–1561, 2015. 4.Sjögren’s Syndrome: A Clinical Handbook (F Vivino Ed.). Elsevier. Amsterdam, Netherlands, 2019.

KEY REFERENCES