6/14/2013

Sjögren’s Syndrome

Alan Baer, MD Director, Jerome L. Greene Sjögren’s Syndrome Center Johns Hopkins University School of Medicine

Disclosures

• None

Scleroderma Vasculitis Arthritis Lupus Myositis

My Biases Outline of Talk

• The Sjögren’s phenotype • Sjögren’s syndrome is a – Heterogeneity systemic autoimmune disease. – Differentiation from other forms of Get the diagnosis right---it does Dry – • The diagnosis of Sjögren’s Dry eyes mouth matter! – Diagnostic methodology – Correct diagnosis is the prelude to – Classification criteria: evolution over the past 5 decades appropriate management. Auto- – Pitfalls in diagnosis immunity – The promise of biologic therapies will only be realized with • The treatment of Sjögren’s application to patients in whom – Multidisciplinary the symptoms are driven by an – Promise of new biologic therapies ongoing autoimmune process.

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Henrik Sjögren-1933 Lymphocytic infiltration of major and minor salivary glands • Described “keratoconjunctivitis sicca” as part of a systemic disease • Key features – Salivary and lacrimal gland dysfunction – Lymphocytic infiltration of exocrine glands, especially lacrimal and salivary – Association with chronic deforming arthritis (i.e. RA) – Remarkable female predisposition

Parotid gland Labial minor http://cms.revoptom.com/publish/images/2_1611_1.jpg

Key Features of Sjögren’s Syndrome

• Affects primarily peri- and postmenopausal women • Prevalence of 0.09-0.6% • Relatively stable disease course without treatment • 18-fold increased risk of lymphoma

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Sjögren’s is a systemic autoimmune SS stands out among autoimmune disease. diseases: Highest risk of lymphoma

• Characteristic SSA (Ro) and SSB (La) autoantibodies • 5% lifetime risk of (~60-80%) 35 lymphoma (relative 30 risk=18)

• Markers of B-cell overactivity 25 • Types – Rheumatoid factor (50-60%) 20 – Marginal-zone B cell – Polyclonal hyperglobulinemia (40%) 15 lymphomas, – Monoclonal proteins (15%) 10 arising from 5 diverse

• Extraglandular manifestations (<50%) 0 extranodal and nodal sites – Systemic: pain, fatigue – Diffuse large B – Organ-specific cell lymphomas • Strong association with other autoimmune diseases Blood 2008; 111:4029

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The Spectrum of Sjögren’s Syndrome Sjögren’s in the young and old

• Sjögren’s in the young and elderly • Young • Elderly – Higher frequency of – Sicca symptoms common • Seronegative Sjögren’s autoantibodies and in this age group • Overlap with other autoimmune diseases hypergammaglobulinemia – High prevalence of – More frequent medications that cause • High vs. low risk of lymphoma – Less frequent sicca sicca symptoms • Mikulicz syndrome – More frequent renal – Age-related histologic tubular acidosis changes of acinar atrophy, fibrosis, and ductal – Overlap with SLE dilatation – Schirmer’s test less reliable

Lupus 1998; 7:202 Arch Intern Med 1999; 159:1359 Scand J Rheumatol 1999; 28:227 Age Ageing 1984; 13:159 J Rheumatol 2008;35;278-284 Ann Rheum Dis 1994; 53:637

Seronegative Sjögren’s Overlap vs secondary Sjögren’s

• Defined by a positive biopsy and the • Common overlap of Sjögren’s with other autoimmune diseases absence of SSA and SSB antibodies – RA (polyarthritis with rheumatoid factor) • 20-40% of cohorts – SLE (leucopenia, hypocomplementemia, arthritis) – Primary biliary cirrhosis (SS-A antibodies) • Older age at diagnosis – Scleroderma (Raynaud’s, centromere antibodies) • Less systemic/hematologic involvement • Late manifestation of an established CTD – Genetic traits may differ from primary Sjögren’s • Greater pain severity • Shared serologic markers • Higher frequency of sensory neuropathy – SSA, SSB Arthritis Care and Research 2008;59:1780 – CCP, DNA, centromere antibodies, rheumatoid factor Arthritis Care and Research 2013 Jan 17 Clin Exp Rheumatol 2001;19:313 Primary vs secondary SS classification is not included in 2012 ACR criteria. Medicine 2011;90:133 Medicine 2008; 87:210

High risk of lymphoma Mikulicz Syndrome

• Chronic enlargement of salivary • Predictors at time of and lacrimal glands with histologic diagnosis evidence of chronic – Germinal center-like • Multiple etiologies for this structures in labial salivary gland biopsy 1 presentation – – Benign lymphoepithelial sialadenitis enlargement 2,3 • Sjögren’s syndrome – Palpable purpura 2,3 • Other systemic rheumatic diseases – MALT and other B-cell lymphomas – Cryoglobulinemia 2,3 – IgG4-related – Hypocomplementemia sialadenitis/dacryoadenitis – CD4+ T cell Diffuse infiltrative CD8 lymphocytosis lymphocytopenia 3,4 – – Leukemia, especially ALL Type I (high risk) vs type II • – Sarcoidosis (low risk) populations 2 1Ann Rheum Dis 2011; 70:1363 2Arthritis Rheum 2002; 46:741 – Tuberculosis 3Semin Arthritis Rheum 2011; 41:415 4Ann Rheum Dis 2006; 65:796

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Case 1 Case 2 • 81 year old man • 18 year old woman – Early 2011: onset cervical – Long history of adenopathy, xerostomia, dry eye symptoms – Recurrent parotid and – October 2011: • WBC 7800 (40% lymphs, 32% PMNs, atypical lymphs noted), hemoglobin swelling since age 8 12.8 g/dl, platelets 190K – White mucus plugs • SPEP: hypogammaglobulinemia, 0.3 extrude from her g/dl gamma spike; salivary glands • IgM lambda monoclonal gammopathy – November 2011: lip biopsy shows 2 – WBC 8600 with 29% foci in specimen with 6 lobules (c/w eosinophils Sjogren’s) – ANA 1:80, negative – ANA, anti-SSA, anti-SSB negative SSA/B antibodies – Treated with prednisone 15 mg qd and methotrexate 15 mg qwk Sialodochitis fibrinosa (allergic parotitis)

Case 2-cont’d Case 3 • 69 year old man • Left lacrimal gland biopsy: – January 2010: painless jaundice secondary to 2 cm – Monomorphic small bile duct stricture lymphocytic infiltrate – March 2010: Whipple – 85% of cells show monoclonal procedure expression of lambda light • Autoimmune pancreatitis chain colony with CD5, CD23, on path and relatively dim CD20 • Normal serum IgG4 – November 2011: – Findings indicative of B-cell CLL rheumatology referral • FISH • Dry eyes and mouth • Abnormal Schirmer’s – trisomy 12; 13q deletion; • Progressive enlargement of trisomy 14 vs translocation of submandibular > parotid IGH with another locus. glands since 1/2010 • Weak urinary stream

Case 3-cont’d Extraglandular Manifestations • Neurologic (20% of patients) – Central nervous system demyelination Often first • Evaluation at JHH-April 2012 – Sensory neuronopathies manifestation of – Induration and enlargement – Small fiber sensory neuropathy Sjogren’s – Multiple mononeuropathy of parotid and • Cutaneous submandibular glands – Palpable purpura – WBC 6200 (6% eosinophils) – Subacute cutaneous lupus overlap • Pulmonary – Alkaline phosphatase 254, – Obstructive bronchiolitis AST 48, ALT 57 – Lymphoid interstitial pneumonitis – IgG 2480, IgG4 36.9 mg/dl • Renal – Interstitial nephritis with RTA – ANA 1:40, negative SSA and – Glomerulonephritis SSB antibodies • Hepatic – Primary biliary cirrhosis – Negative rheumatoid factor – Autoimmune hepatitis • Systemic vasculitis • Lymphoma

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Peripheral Neuropathies in Sjögren’s Peripheral neuropathies have varied pathogenesis Sensory ataxic neuronopathy • Absent vibratory sense • Axonal sensorimotor polyneuropathy • Impaired proprioception – Frequent extraglandular disease, associated low C4, • Positive Romberg 1 • Absent DTR’s cryoglobulinemia, monoclonal protein, lymphoma risk Vasculitis evident on nerve biopsies 2 Axonal sensory or – sensorimotor neuropathy • Sensory ataxic neuronopathy • Stocking-glove paresthesias – Histopathologic evidence of dorsal root ganglionitis • Normal or decreased strength • Decreased or absent DTRs – Lower frequency of women, SSA/B antibody positivity, and • Abnormal nerve conduction studies extraglandular disease Small fiber sensory • Small fiber sensory neuropathy neuropathy – Non-length dependent pattern suggests dorsal root 3 • Mild or no reduction in ganglionitis (confirmed in autopsy of one patient) temperature or pinprick sensation 1 • Normal proprioception and – Lower frequency of B-cell activation markers vibration • Normal electrodiagnostic studies 1 2 3 • Reduced intraepidermal nerve fiber Medicine 2011; 90:133; Neurology 1989;39:390; J Neurol Sci 2012; 319:139; density

What defines Sjögren’s syndrome? The Mosaic of Different Classification Criteria Sets

included not included

Ocular symptoms Ocular dryness Oral dryness Oral symptoms Schirmer’s test • Symptoms • Symptoms Rose Bengal test • Surface staining •Sialometry Lissamine green staining • Schirmer’s • Imaging Break up time Fluorescein test Unstimulated salivary flow Autoimmunity Stimulated salivary flow • SSA/B antibodies Parotid •Lip biopsy Salivary scintigraphy •ANA and RF Minor gland biopsy •Underlying rheumatic Rheumatoid factor disease Antinuclear antibodies Anti-SSA/SSB antibodies Obligatory criterion

Adapted from C. Vitali

The International Sjögren’s Syndrome Registry Classic Dry Eye Evaluation Rose Bengal staining Schirmer strip testing • The Sjögren’s International Collaborative Clinical Alliance (http://sicca.ucsf.edu) – NIH-funded 2003-2013, based at UCSF, 9 global sites-including JHU • Goals – Develop standardized classification criteria for SS – Collect, store, and disseminate uniform clinical data and biospecimens for future studies of Sjögren’s syndrome (SS) • Genome wide association studies • Schirmer’s test strips: filter • SICCA cohort includes >3000 individuals with possible paper with mm ruling early SS to well-established disease • Schirmer’s test measures tear production >700 underwent a repeat evaluation with second lip biopsy two – • ≤ 5 mm wetting /5 min is years after baseline visit abnormal

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Grade 1 SICCA Grade 1 Salivary Gland Hypofunction: Oral ocular Exam surface staining Grade 2 Grade 2 Either eye

Grade 3 Grade 3

Total score Am J Ophthal 2010;149:405-415

Measurement of Salivary Function Imaging of sialadenitis: Not specific for Sjögren’s Whole unstimulated sialometry Salivary gland scintigraphy

Contrast CT MR imaging Ultrasound sialography • Involves • No radiation • No radiation • Involves radiation • Parenchymal • Parenchymal radiation • Identifies changes heterogeneity, cysts, • Best correlate of oral • Not widely available • Difficult to sialoliths, areas – T2-hyperintense sialoliths perform of punctate foci (dilated • Can guide needle health calcification ducts) aspiration or core • High sensitivity but • May incite – T1-hyperintense biopsy inflammation foci (fatty • Normal >0.1 ml/min low specificity atrophy) • Declines with age

Minor salivary gland pathology: a key Reading lip biopsies must to that of the major salivary glands be protocol-driven.

• Assess adequacy of specimen – 4-7 glands • Assess histopathologic pattern • If focal lymphocytic sialadenitis: – Calculate total surface area – Count number of foci adjacent to normal acini – Calculate focus score • Number of lymphocytic foci per 4 mm 2 of glandular tissue – Assess for germinal centers

Protocol available at: http://sicca.ucsf.edu/Labial_Salivary_Gland_Assessment.doc Photos courtesy of Troy Daniels, UCSF Daniels TE et al, Arthritis Rheum, 63:2021, 2011

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Correlates of Labial Gland SICCA Cohort (1156 participants)

Histopathology in the SICCA Cohort 24 27 Positive SSA Phenotypic feature FLS FLS NS/SCS P (chi 2) Focus score ≥1 36 or SSB FS≥1 FS<1 No FS N=730 N=328 N=668 N (%) N (%) N (%) 325 79 Positive anti-SS-A/-B 487 (76) 63 (10) 91 (14) <.0001 106 Rheumatoid factor 458 (72) 64 (10) 113 (18) <.0001 Ocular surface staining ≥ 3 630 (50) 206 (16) 415 (33) <.0001 ANA ≥ 1:320 477 (72) 68 (10) 115 (17) <.0001 IgG >1445 mg/dl 424 (73) 54 (9) 104 (18) .0001 UWS flow <0.1 ml/min 502 (53) 148 (15) 306 (32) <.0001 Ocular surface Dry mouth symptoms 669 (43) 292 (19) 595 (38) 0.3 323 staining score Dry eye symptoms 624 (43) 292 (20) 549 (37) 0.01 ≥3 FLS=focal lymphocytic sialadenitis; NS/SCS-non-specific/sclerosing chronic sialadenitis; UWS=unstimulated whole saliva Daniels TE et al, Arthritis Rheum, 63:2021, 2011 Arthritis Care and Research 61:711, 2009

ACR Preliminary Classification Criteria Diagnostic Steps for Sjögren’s Syndrome

Eye exam • The classification of Sjögren’s syndrome will be met in • Ocular surface patients who have at least two of the following three staining score Rheumatologic • Schirmer’s objective features: if: Suspicion exam, plus Lip biopsy, of • Seronegative • Oral exam • Weak positive – [Positive serum anti-SSA and/or anti-SSB] or [positive Sjögren’s • Salivary gland exam Serologic anti- SSA/B rheumatoid factor and ANA ≥ 1:320] testing • Anti-SSA, anti-SSB – Labial salivary gland exhibiting focal lymphocytic • ANA sialoadenitis ≥ 1 focus/4 mm 2 • Rheumatoid factor – Keratoconjunctivitis sicca with SICCA staining score ≥ 3 Salivary gland • The same criteria apply to patients with other autoimmune tests connective tissue diseases, such as rheumatoid arthritis, systemic • Imaging ± biopsy • Sialometry lupus, etc. Parotid gland Arthritis Care Res 2012; 64:475 swelling

Lip Biopsies: Pros and Cons Pitfalls in Sjögren’s Diagnosis

Pros • • Overinterpretation of sicca symptoms – Important criterion for disease classification • Ocular component – Provides prognostic – Failure to perform/score ocular surface staining information regarding the risk – Age-related decline in tear production of lymphoma • Oral component – May reveal an alternative – Failure to account for anti-cholinergic drug effects diagnosis – Poor specificity of abnormal testing • Cons • Labial gland biopsy – Need for invasive procedure – Inadequate tissue – Risk of persistent lip numbness averages 3-5% in reported – Failure to interpret according to established protocols series 1,2 • Serologies 1 – Inadequate tissue sampling Arthritis Rheum 2008; 59:714 – Low titer SSA or SSB antibodies 2Eur Arch Otorhinolaryngol 2006; 263: – Misinterpretation of biopsies is • 2012 ACR criteria are not clinician-friendly! common. 3 233 3J Rheumatol 2002; 29:938

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Three Common Types of Labial Gland Histopathology: SICCA Cohort (n=1787)

Focal Non-specific chronic Sclerosing chronic lymphocytic sialoadenitis sialoadenitis sialoadenitis 21% 17% 61%

Total surface area=22.5 mm 2 Daniels TE et al, Arthritis Rheum, 63:2021, 2011

Sclerosing Chronic Sialadenitis Reference laboratory for labial • Glandular fibrosis, acinar atrophy, and ductal gland biopsies dilatation/hyperplasia increase with age. 1,2

• Sclerosing chronic http://dentistry.ucsf.edu/oralpath sialadenitis correlated with increased age in SICCA. 3 • Does not correlate with the autoimmune abnormalities of primary SS. 3

1J Clin Pathol 1986;39:406 2Age Ageing 1984;13:159 3Arthritis Rheum, 63:2021, 2011

Correlates of SSA and SSB Reactivity in Treatment of Dry Eyes the SICCA Cohort • Artificial tear Positive SSA & SSB Positive SSA only Positive SSB only Negative SSA & SSB substitutes/gel/ointments Phenotypic feature (N= 447) (N= 357) (N=61) (N=1612) – Preservative-free if >4/day (18.1%) (14.4%) (2.5%) (65.1%) • Anti-inflammatory therapy ANA≥1:320 (%) 311 (77) 127 (43) 3 (9) 207 (16) Rheumatoid factor ≥44 IU/ml 353 (79) 132 (37) 9 (15) 282 (18) – Topical corticosteroids for flares only IgG>1445 mg/dl 319 (72) 135 (38) 5 (8) 196 (12) – Topical cyclosporine C4<16 mg/dl 105 (24) 69 (19) 5 (8) 164 (10) – Systemic: tetracycline WBC ≤ 4000 117 (27) 69 (20) 2 (3) 96 (6) • Dietary omega-3 fatty acids ( fish or Anemia 120 (27) 57 (16) 9 (15) 192 (12) flaxseed oil) Ocular surface stain ≥ 3 427 (96) 292 (82) 37 (61) 1093 (68) • Punctal occlusion Schirmer’s ≤5 mm/5 min 216 (48) 122 (34) 10 (16) 387 (24) • Secretagogues UWS ≤0.1 ml/min 304 (68) 192 (54) 22 (37) 755 (47) Focus score ≥ 1 343 (79) 169 (49) 15 (25) 307 (19) • Autologous serum tears Germinal centers 125 (28%) 39 (11%) 4 (7%) 72 (4%) • Bandage contact lenses, ocular surface prosthesis Punctal plug Baer et al, manuscript in preparation

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Scleral Prosthesis Treatment of Dry Mouth

• Discontinue medications with anti- cholinergic effects • Moisture replacement • Small sips of water, ice chips • Saliva substitutes, gels, patches, lozenges • Stimulation of glandular secretions – Gustatory and mechanical (sugarless chewing gum and hard candies containing xylitol, fruits rich in malic acid) – Systemic (pilocarpine and cevimeline) http://www.bostonsight.org/PROSE- treatment/Conditions-PROSE-Treats/Dry-Eye- Syndrome

Prevention of Dental Caries Chronic Erythematous Candidiasis • Targeted dental care: early detection of caries, prevention measures • In setting of poor saliva • Diet assessment: sugar, fermentable production, topical carbohydrates, exogenous acid treatment required. • Promote remineralization • Topical oral anti-fungal – Supplemental fluoride agents typically have – Calcium/phosphate products high sugar content. • Anti-bacterial rinses • Choices: • Compounded troches with • Secretagogues nystatin and artificial Erythematous candidiasis : before (left) and after 4 sweetener weeks treatment. Note restoration of filiform papillae • Treat oral mucosal infections and resolution of angular • Vaginal nystatin tablets • Miconazole buccal tablets Photos courtesy of Troy Daniels, UCSF

Photo from http://emedicine.medscape.com/article/1008536-overview

Vaginal Dryness Case 4

• Over-the-counter vaginal lubricants and • 33 year old woman, school teacher moisturizers – 2 year history of parotid gland • Vitamin E oil swelling – Dryness of mouth and eyes • Local vaginal estrogen: cream, tablets, – Evaluation • Schirmer’s 3 mm OD and 4 mm OS hormone-releasing rings (wetting over 5 min; nl > 10 mm) • Ocular surface staining score 11 OU • Hormone replacement therapy (normal <3) • Whole unstimulated saliva flow 0.259 cc/5 min (normal >0.5 ml/5 min) • IgG 1901 mg/dl • Rheumatoid factor 78 IU • High titer SSA and SSB antibodies Menopause 2012; 19:109

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How should I monitor for lymphoma? Case 4-cont’d

• No established guidelines. • 10% monoclonal B cell population • Causes for concern: • Admixture of T and B cells – Persistent or new onset salivary/lacrimal gland • Benign lymphoepithelial swelling or masses sialadenitis – Lymphadenopathy – Splenomegaly – Several autoimmune diseases in same patient What therapy would you offer this – B symptoms patient? – New onset serious extraglandular disease

Controlled Trials of Systemic Placebo-controlled Trials of Rituximab Immunomodulatory Therapy in SS for Sjögren’s Syndrome

Study No. of Duration 1° outcome 1° Significant Agent Subjective Objective pts of F/U measure outcome effect seen improvement improvement met? Alternate-day prednisone Yes No Meijer et al, 20 RTX 48 weeks Increase in No ↑ stimulated Hydroxychloroquine No No 2010 10 stimulated whole saliva @ 5, Placebo saliva at week 48 12 wks Cyclosporine Yes No Dass et al, 8 RTX 6 months >20% No ↓ fatigue Azathioprine No No 2008 9 improvement in VAS relative Thalidomide Intolerable SEs placebo fatigue VAS at 6 to baseline months Infliximab No No Mariette et 60 RTX 24 weeks ≥30 mm No ∆ salivary Etanercept No No al 2012 60 improvement in 2 flow, ∆ sicca Interferon-gamma (lozenges) No No placebo of 4 VAS and fatigue VAS Anakinra Primary outcome not met: reduced fatigue at 4 weeks Open label experience: benefit for extraglandular disease, parotid gland swelling, cryoglobulinemia

Clinical and histologic evidence of salivary Effect of Belimumab on Parotid Gland gland restoration supports the efficacy of Swelling in Sjögren’s Syndrome rituximab treatment in Sjögren's syndrome • Glandular domain activity: 15/30 at baseline, 7/29 at wk 28 • In 13 pts with parotid swelling (non- malignant): – Glandular domain improved in 10 (77%) at wk 28 – Persistent disappearance of swelling in 4/5 at wk 52 – Relapse of swelling in 2/5 after cessation of belimumab

Pijpe J, Meijer JM , Bootsma H, et al Arthritis & Rheumatism , 2009; 60:3251-3256 Arthritis Rheum 2012; 34:S926

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Therapeutic choices for patient Summary

• Hydroxychloroquine • It does matter….. • Low-dose prednisone • Only a minority of patients with dry eyes • A decision to do more is controversial. and/or mouth have Sjögren’s syndrome. – Rituximab • Diagnostic testing for Sjögren’s must now be – Belimumab protocol-driven. – Low-dose irradiation • SS is a heterogeneous disorder and definition • Participate in a clinical trial of phenotypic subsets is crucial for elucidating – Baminercept diverse pathogenetic pathways.

The Jerome L. Greene Sjögren’s Syndrome Center

• Rheumatology • Medical Office Coordinators – Alan Baer, MD; Julius Birnbaum, – Caitlin Bishop, Kelly Dudek MD, MHS; Thomas Grader-Beck, MD, PhD • Research Coordinators • Ophthalmology – Anthony Keyes – Esen Akpek, MD; Monica – Rebecca Ozl Schaeffer, OD • Administrative Assistant • Otolaryngology – Jill Stephenson – Jean Kim, MD, PhD; Roni Dinkes, Au.D Funding support • Gynecology Jerome L. Greene – Anne Burke, MD • • Neurology Foundation – Julius Birnbaum, MD, MHS; Michael Polydefkis, MD • NIDCR • NIAMS

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