Oral communication at the EADV 2018, Paris. Update version 02.2020. A survey of the cutaneous and mucosal manifestations associated with Sjögren syndrome.

1. Sjögren [ɧøːɡreːn]
syndrome
Nicolas Kluger
Dermatology
Helsinki University Central Hospital

2. 17/09/2020 Sjögren’s syndrome 2
J. Mikulicz
•1892
•Parotid and
salivary gland
swelling
H. Gougerot
•1926
•3 women with
dry eyes and
mouth +/- larynx
H. Sjögren
•1933
•19 patients with
dry eyes and
mouth

3. Sjögren syndrome
• Key epidemiologic data
• New diagnostic criteria (2016/2017 – ACR EULAR)
• How to make a biopsy of minor salivary glands?
• Systemic manifestations
• Cutaneous and mucous manifestations
• Lymphoma risk
• Management
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4. Key datas
• Common systemic autoimmune disease
– « SLE affecting the mucosa »
– Type I interferon, B-cells (plasmablasts; plasma cells)
• Exocrinopathy
• Female predominance 9:1
• Peak of incidence: (20-30s and) mid-50s
• 0,3 – 1/1000 individuals
Sjögren’s syndrome17/09/2020 4

5. 17/09/2020 Sjögren’s syndrome 5
Sjögren
Primary
Isolated
Thyroiditis
Biliary cirrhosis
Cholangitis
Secondary
Rheumatoid arthritis
Lupus
Scleroderma
Dermatomyositis
Sjögren +
SSc/CREST + PBC =
Reynolds
syndrome

6. 17/09/2020 Sjögren’s syndrome 6
> 80%
of
patients
Dry eyes
and
mouth
Fatigue
Joint pain 30-40%
have systemic
manifestations
Mariette X et al, N Engl J Med 2018

7. 2016 ACR – EULAR criteria
Item Description Score
Focus score of 1 Minor labial salivary gland biopsy
Nr of mononuclear cell infiltrated containing >
50/4mm2
3
SSA/Ro antibodies + Serum, anti-Ro60 3
SSB/La antibodies positive alone: no longer a criteria
SICCA ocular staining score ≥ 5 Ophthalmologist score from 0 to 12
Fluoresceine/Green lissamine
1
Schirmer test of 5mm per 5 min Ophthalmologist test 1
Unstimulated whole salivary
flow ≤ 0.1 mL/min
Salivary flow for at least 5 min 1
Total score 9
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Sjögren
if > 3
Shiboski et al: Ann Rheum Dis 2017

8. 2016 ACR – EULAR criteria
Exclusion criteria
• Active hepatitis C (PCR +)
• Radiotherapy of cervical spine
• Sarcoidosis
• Graft-versus-host disease
• Prescription of anticholinergic drugs
• IgG4 disease
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9. How to make a minor salivary gland biopsy?
• Antiseptic
• Scalpel
• Pince, scissors
• Resorbable 4.0
• Pathology
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10. • Inferior lip,
LATERALLY
• Angle 35 deg /
orbicularis oris
muscle
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Slide by Pr M Samimi (Tours)

11. Salivary glands biopsy
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12. 17/09/2020 Sjögren’s syndrome 12
1580 patients
92.9% W, 55 y at diag
13% severe disease
Lymphoma, Nervous
system, Lungs, Kidney
20% mortality
Mariette X et al, N Engl J Med 2018
Flores-Chavez et al, Clin Exp Rheumatol 2018
• Man
• Anemia
• Lymphopenia
• RF +
• Low C3
• Low C4*
• Cryoglobulinemia*

13. Exocrine glands manifestations
Dryness Frequency
Dry mouth 98%
Dry eyes 93%
Dry skin 31%
Genital dryness 19%
Parotidomegalia 18%
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Garcia-Carrasco M et al. Medicine 2002

14. Dry mouth
1 out of the 3 following criterias
Sensation of dry mouth every day for at least 3 months
Recurrent swelling of salivary glands
Necessity to drink water to swallow dry food
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Fox RI. Lancet 2005; Lee YC et al. J Oral Facial Pain Headache 2018
• BMS +++ (5%)
• Difficulties to eat
• Dysgueusia
• Dysphagia
• Difficulties to talk
(« clicking »)
• Sleeping problems
• Dry and sensitive
mucosa
• Red fissurated and
sticky tongue
• Angular cheilitis
• Dental problems
• Caries
• Periodontopathies
• Pb with prothesis
• Expenses

15. Management
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Stimulation of saliva secretion with muscarinic agonists
• Pilocarpine (Salagen) 5 mg 3-4 times a day
•Cevimeline (Evoxac), not available in the EU
• If you are vintage Jaborandi’s tincture: XXX drops x 3 times a day
Oral hygiene and dental examination
• Chewing gum with xylitol or sorbitol; dental floss etc.
• Saliva substitutes (gel, spray)
• Cheilitis and oral candidosis: fungal treatment
No systemic treatment has really shown efficacy

16. Small tips
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Lemon juice 5 mL + glycerin 45
mL + water 50 mL between meals
! anticholinergic drugs

17. Dry skin
• Underestimated by patients themselves
– 15-67% of the patients
– Primary SS > secondary SS
• Itch, tingling, burning sensations
• Thin, red, scaly skin, rough to the touch
• Less perspiration (heat stroke)
• Crusts and scales in the ear canal
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• Moisturizers
• Avoid warm
showers/baths
• No irritant soap

18. Skin biopsy of the axillae
• Small series of 12 patients
• 66% of the patients
• T CD4+ and B CD27+ IgD- lymphocytic
infiltration of the sweat glands
• 6 mm punch skin biopsy
– in normal appearing skin of the axillae
• May be of interest in case of normal
salivary gland biopsy
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Tobon GJ, et al. Int J Clin Rheumatol 2011.
With the courtesy of AM Roguedas (Brest)

19. Vaginal dryness
• Serie of 169 patients: 26%
Al-Hashimi I et al. J Oral Pathol Med 2001
• Irritation, itch
• Dyspareunia
• Fertility and pregnancies: not affected
• Vaginal atrophy correlated to age and menopause
Skopouli FN et al. Ann Rheum Dis 1994
• Impaired sexuality in women: desire, arousal, orgasm, lubrication,
pain, sexual distress and less sexually active
van Nimwegen JF et al. Rheumatology 2015
Priori R, et al. J Rheumatol 2015
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20. Erythema annulare
• Rings, patches, papules
• Photosensitivity
• Face, neck, upper extremities
• Anti-Ro/SSa +
• Asian patients +++, also white caucasians
• Sub-acute lupus - like
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Katayama I et al. Dermatology 1994;189:14-7

21. «Systemic » cutaneous manifestations
Joints 37%
Raynaud 16%
Thyroiditis 15%
Cutaneous vasculitis 12%
Lung 9%
Peripheral nerves 7%
Lymph nodes 7%
Kidney 6%
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Garcia-Carrasco M et al. Medicine 2002;81:270-80

22. Raynaud
• 13-30% of the patients
• Can precede dry symptoms in 45% of cases
• Association with: joint, cutaneous vasculitis
• ANA (13%), RF (21%), Ro/Ssa (26%), CryoGb (33%)
• Treatment necessary for 40% of the patients
• Tobacco/Protection from the cold/Calcium inhitors/CS
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Garcia-Carrasco M et al. J Rheumatol 2002;29:726-30

23. 17/09/2020 Sjögren’s syndrome 23
• Women
• 1 episode in half of the cases
Cutaneous vasculitis
• Purpura (73%) > macules (30%) > papules (4%) and
ulcerations (4%)
• Lower limbs (92%)
Skin
• Joint (50%)>Raynaud (40%)>PNS (31%)>kidney (10%)
• ANA (88%), anti-Ro (70%), cryoGb
• Anemia; ESR; hypergammaGb
Systemic
• Hospitalization
• Oral corticosteroids
• Others: CYP, AZA
Treatment
Ramos-Casals M et al. Medicine 2004

24. 17/09/2020 Sjögren’s syndrome 24
CryoGb
during SS
Extra-
glandular
symptoms
Lymphoma
Severe
cutaneous
vasculitis

25. Miscellaneous
• Blepharitis, meibomian gland dysfunction
Katayama I et al. Int J Dermatol 1994; Sullivan, et al. Ophtalmic Res 2018; Kang et al. Int Ophthalmol 2018
• Livedo
• Erythema nodosum
• Vitiligo
• Alopecia areata
• Cutaneous B cell lymphoma
• Non specific: contact eczema, toxiderma
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26. B-cell non-Hodgkin lymphoma
• Salivary glands
• Mucosa associated lymphoid tissue (MALT) Lymphoma
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x 15-20
• Reccurent swelling of parotid glands
• SMG, LN, or both
• Purpura
• EULAR Sjögren Syndrome DAI > 5
• RF +
• CryoGb +
• Low C4 level
• CD4 Lymphocytopenia
• Focus score > 3
• Presence of etopic germinal centers
• Germinal mutations in TNFAIP3
Lympho, EPP,
C3, C4, RF,
Cryo
Every 1-2 y
(6 mo)

27. Treatment is overall disappointing
• No treatmentFatigue
• Acetaminophen; NSAID (joint)
• Gabapentin, pregabaline, duloxetine
• Avoid amitriptyline (dryness)
Pain
• HCQ (joint and skin)
• CS, Aza, MTX, MFM, CyA
Systemic
involvement
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Do not work:
Anti-TNF
Tocilizmab (anti-IL6)
Baminercept (LTbR-Ig)
Need more proofs :
Belimumab (BAFF inhibitor)
Epralizumab (humanized IgG1 anti-
CD22)

28. 17/09/2020 Sjögren’s syndrome 28
Rituximab
Cryoglobulinemia
(vasculitis)
Parotid swelling
Lymphoma
prevention in at
risk patients ?
Mariette X, et al. N Engl J Med 2018
Letaief H, et al. J Bone Spine 2018
Rituximab fails vs:
fatigue; oral and eye
dryness

29. What’s in the pipelines according to Clinicaltrials.gov
UCB5857/Seletasilib
Completed, EU
Randomized vs PCB, proof of
concept, 12 weeks study
PI3Kd inhibitor
CFZ533/
On going
Randomized, double-blind, vs
PCB, safety and tolerance
Fully human mAb anti-CD40
(B and T cell)
INCB050465
Going to start, USA
Open-label phase 2 study PI3Kd inhibitor
VAY736
On going, International
Randomized, phase 2 study vs
PCB
IgG1 mAb anti-BAFF-R
(receptor for B cell activating
Factor of the TNF family)
Filgotinib, GS-9876, GS-4059
On going
Randomized, double blind
phase 2; randomized
Filgotinib: JAK1 inh
GS-9876: oral SYK inh
GS-4059: Bruton TK inh
Abatacept
On going, International
Randomized double-blind vs
PCB Phase 3 study
Fusion protein blocking CD80-
CD28
T-cell inhibitor
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