Retinal vasculitis
Camillo Ribi
Médecin adjoint, PD-MER
Immunologie & AllergieCHUV Lausanne
SAoO 2020 Congress
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Diagnostic work-up and immunosuppressive treatment
Retinal vasculitis – Take home messages
1) Diverse pathomechanisms lead to vasculitis, which may be categorized by type and size of vessel affected
2) A minority of retinal vasculitis cases have underlying systemic disease (but for some 1st manifestation)
3) Systemic inflammatory diseases mostly responsible for retinal vasculitis are: Behçet’s, sarcoidosis, lupus…
4) Work-up should include urinalysis and chest imaging, as well as interferon-gamma releasing assay for Tbc
6) Monoclonal antibodies against TNF alpha are effective in treating severe retinal vasculitis
7) Maintenance is as important as induction treatment, as inflammatory disease tend to relapse frequently
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The case: 23-year old women, previously in good health
No history of health problems
January 2020: Admitted to Gyn ER
- Multiple very painful genital ulcers for on week, with alguria and hematuria
- Fever 39° for several days
- Blurry vision
- Headache
Caucasian
Smokes tobacco and sometimes weed; takes the pill; no drug abuse
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The case: 23-year old women, previously in good health
Suspected pyelonephritis (blurry vision / headache ‘scotomized’ in the wake of high fever)
Started on i/v antibiotics (ceftriaxone) and antiviral (acyclovir)
Urinary catheter
After 3 days:
No improvement of genital ulcers/fever
Persistent blurry vision and headaches
Lumbar puncture: normal
Sent to ophtalmologist for fundoscopy
Immunologist called to bedside
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23-year old women with genital ulcers, headaches, fever, and blurry vision
What is the MOST LIKELY diagnosis at this point ?
A Syphilis
B Crohn’s disease
C Behçet’s
D Herpes simplex
E Systemic lupus erythematosus
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Opthalmologist’s notes
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RE Examination LE
0.4 Distance VA 0.4
0.5 Near VA 0.8
Cells 0+ / Ty 0+
Slit-lamp Cells 0+ /Ty 0+
Multiple paramacular
lesions
Fundus exam
Multiple paramacular
lesions
Courtesy of Pr Y. Guex-Crosier, HJG Lausanne
Fundus examination
7Courtesy of Pr Y. Guex-Crosier, HJG Lausanne
Case presentation
Which of the following statements is TRUE regarding the possibility of Behçet’s disease in this case
A A definite diagnosis of Behçet cannot be made without HLA-B51 status
B Behçet’s disease is very unlikely in a patient without Mediterranean/Oriental/Asian Ancestry
C Behçet’s is very unlikely given the absence of concomitant oral ulcers, skin lesions and arthritis
D Retinal vasculitis need first to be confirmed by angiography before considering treatment
E High-dose corticosteroids should be started immediately
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Results from angiography (the day after starting methylprednisolone)
9Courtesy of Pr Y. Guex-Crosier, HJG Lausanne
The immunologist’s view of vasculitides (systemic)
Chapel-Hill Classification 2012 Categorized by vessel size
(adapted) Very distinct pathophysiology
Very diverse clinical courses
Most vasculitides of idiopathic origin will need to be treated aggressively and for a sustained period of time
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Retinal vasculitis - definitions
Inflammation of venous, arterial, or capillary retinal vasculature +/- extension to non-vascular structures
May be associated with infections, systemic inflammatory diseases, or no known systemic association
Systemic disease may suspected based on the type / size of retinal vessel involved (not always reliable)
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Veins Behçet’s disease; sarcoidosis; MS
Small arteries Systemic lupus erythematosus
Medium to small arteries Giant cell arteritis
Medium-sized arteries Polyarteritis nodosa
Arteries and veins Crohn’s; relapsing polychondritis, Behçet’s
Variable vessel type / no vessel involvement Bechterew and other HLA-B27-associated
Epidemiology of retinal vasculitis associated with systemic disease
Proportion of subjects presenting with retinal vasculitis disclosing a systemic disease varies greatly
Middle East (Israel / Iran / Saudi-Arabia): ¼ - ⅔ of cases with systemic disease (Behçet >> other)
Western Europe / USA: ¼ of retinal vasculitis patients have systemic disease:
most frequent disorders: Behet, sarcoidosis, lupus erythematosus and related conditions
more rarely: Vogt-Koyanagi-Harada, multiple sclerosis, IBD, psoriasis
less than 2% of cases with retinal vasculitis have systemic vasculitis
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Behçet’s disease
More common (and often more severe) along the ancient silk road (Eastern Asia to the Mediterranean)
Most common in Turkey (80-370:100,000 cases), followed by Korea, China, Iran, Iraq, and Saudi Arabia
Europe: 1:15’000
Sporadic, with some familial clustering
Affects predominantly young adults 20-40 years, male ~ female
Tends to be more severe in men
Genetic background (HLA-B51+ increases OR to >5, among other factors); aberrant response to microbes…
Hulusi Behçet
Behçet – clinical presentation
- recurrent oral +/- genital aphthae
- ocular disease (up to 70% of cases)
- skin lesions
- gastrointestinal involvement
- neurologic disease
- vascular disease
- arthritis
Most clinical manifestations believed to be due to vasculitis
May involve blood vessels of all sizes (small, medium, and large) on both arterial and venous circulation
Driven by Th1 and Th17 lymphocytes, with neutrophil and endothelial activation
Behçet’s disease - diagnosis
By CLINICAL findings
NO pathognomonic laboratory tests
HLA-B51+ may help, but present in minority of cases
Diagnostic criteria (International Study Group for Behçet’s disesase criteria; Lancet 1990)
Recurrent oral aphthae (at least three times in one year) + 2 of the following clinical features:
- Recurrent genital ulceration (aphthous ulceration or scarring, observed by clinician or patient)
- Eye lesions (anterior or posterior uveitis cells in vitreous in slit-lamp examination; or retinal vasculitis)
- Skin lesions (erythema-nodosum-like lesions papulopustular skin lesions or pseudofolliculitis)
- Pathergy test (interpreted at 24 to 48 hours by clinician; in our practice obsolete…)
Sarcoidosis
The many clinical features of sarcoidosis:
25-54% of patients with sarcoidosis have eye involvement
Most frequent presentation are uveitis and conjunctival nodules
Retinal involvement in up to 27%, with typical periphlebitis – candle wax drippings
Epidemiology of Sarcoidosis
Prevalence in Switzerland (active, diagnosed sarcoidosis): ~ 44/100'000
- worldwide: 3 x more frequent in patients of African descent (and more severe)
- 2/3 of cases in young adults (25-45 years)
increased in areas with
- metallurgy
- water supply
- potato farming
- grasslands…
CH 2000-2005
Deubelbeiss U, et al. Eur Respir J 2010
Causes of sarcoidosis
Genetic predisposition (polygenic)
- familial clustering possible : OR 5.8 for 1st degree relative with sarcoidosis
- sarcoid-like manifestations in common variable immunodeficiency
- association with other conditions such as celiac disease
Arguments for environnemental factors:
- Reports of small epidemics confined in space and time
- Kweim-Siltzbach reaction
- Cases of transplanted sarcoidosis
- Dust from WTC bombing (incidence x 8 in NYC after 2001)
- Various microbial candidates (incomplete forms of mycobacteria, other…)
Injection of sarcoidosis spleen
extract into skin (obsolete)
Proprionibacterium (Cutibacterium acnes)
Gram-positive rod colonizing skin and mucosa
Only microorganism to grow in cultures from sarcoid tissue
Recently reported in epi-retinal granulomas
In situ hybridization using catalyzed reporter deposition for signal amplification withdigoxigenin-labeled oligonucleotide probes that complement 16S rRNA of P. acnes
Hamazaki-Wesenberg bodies
Phagolysosomally-degraded P. acnes or intact forms of intracellular bacteria ?
Goto H, et al. Br J Ophthalmol 2017
Diagnostic work-up for sarcoidosis
other clues:
- BAL/vitreal fluid: CD4/CD8 ratio >3.5
- increased lysozyme
- hypercalciuria
- hypergammaglobulinemia
Jamilloux Y, et al. Autoimmun Rev 2014
+
-
-
-
ACE
Sensitivity 29-59%
(60-max 90% if highly active)
Limited specificity (Tb, HIV…)
Similar for lysozyme
Systemic lupus erythematosus
Easy to exclude:
ANA negative =
lupus very unlikely
check for anti-phospholipid Ab !
Chronic inflammatory disease
Affects predominantly young women
Multi-systemic involvement:
– skin, joints, blood, general signs
– kidneys, brain, hearth, lungs...
Profound immune disturbances:
- vast array of auto-antibodies
- alteration of the complement system (immune complexes)
Retinal involvement:
- classic cotton wool spots with/without hemorrhage or
- occlusion of retinal vascular tree
Anti-phospholipid antibodies
E. Svenungsson and A. Antovic J Intern Med 2020
Increased awareness of morbidity related to anti-phospholipid antibodies (APL)
APL screening consists of 3 types of tests: anti-β2-GPI + anti-cardiolipin antibodies + lupus anticoagulant (LA)
LA = functional test (anticoagulant therapy may interfere)
High risk profiles (for thrombosis and other complications): triple APL positivity (all 3+) or presence of LA
APL test+ needs to be confirmed by 2nd assessment at 12 weeks (high suspicion: anticoagulate without delay)
Retinal vasculitis work-up: ① Exclude infectious cause
Exclude active infection / screen for persistent / latent infection that would complicate immunosuppression
Minimal screen* we perform before immunosuppression:
HIV, HBV, HCV, Syphilis, interferon-release assay for Tb (IGRA)
IGRA are sensitive to immunosuppressants
(may be false negative if done after high-dose corticosteroids)
In migrants/with blood eosinophilia: exclude Strongyloïdes stercoralis infestation
(risk of hyperinfestation when treated with high-dose glucocorticoids, in doubt: ivermectin)
*other infections that are part of the work-up of retinal vasculitis include:
Toxoplasmosis, HSV, VZV, Lyme, Bartonella, Tropheryma whipplei…
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Retinal vasculitis work-up: ② Screen for systemic inflammatory disease
History: Known inflammatory disease and if yes, is it treated/are there any signs of activity?
n.b. some patient present with retinal vasculitis as inaugural symptom of systemic disease
(e.g. Tel Aviv University: 43% present with RV as 1st manifestation – mostly Behçet’s)
Physical exam: Pay particular attention to oral and genital ulcers (scarring) and skin lesions
Routine lab: Erythrocyte sedimentation rate, complete blood count
Renal function, including urinalysis – liver enzymes
ANA, ANCA (+ antiphospholipid antibodies if vascular occlusions)
Chest X-ray: Hilar enlargement (sarcoidosis – Behçet’s: pulmonary aneurysm); nodules (sarcoidosis);
interstitial lung disease; signs of Tbc…
If extra-ocular findings suggestive for systemic disease consider referral to imunologist/rheumatologist
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Optimal immunosuppressive strategy in this 23-year old women with Behçet’s and severe retinal vasculitis ?
A. TNF alpha inhibitor + corticosteroid tapering
B. Azathioprine 2mg/kg p/os + corticosteroid tapering
C. Corticosteroid only, slow tapering
D. Anti-IL-6 receptor antibody (tocilizumab) i/v + corticosteroid tapering
E. Cyclosporine A 5mg/kg/day p/os + corticosteroid tapering
Back to the case: treatment of severe retinal vasculitis
Treatment of vision-treatening retinal vasculitis
Limited published evidence regarding optimal managment in retinal vasculitis
High-dose glucocorticoids (1mg/kg/day of Prednisone equivalent, if severe RV methylprednisolone pulses
+ 2nd line agent (to enhance anti-inflammatory effect / facilitate corticosteroid withdrawal)
In severe RV due to Behçet’s (or sarcoidosis): most authors recommend to use TNF blockers
Once flare under control: need to maintain remission (may be achieved with other drugs)
Regarding our case:
She was started on methylprednisolone 250mg (before angiography), for 3 days, then Prednisone 1mg/kg
Infliximab 5mg/kg i/v started within 5 days (insurance approval needed), repeated at 2, 6 and 8 weeks
Rapid tapering of corticosteroids to < 20mg/day
Introduction of azathioprine up to 2mg/kg/day (good option for Behçet’s, compatible with pregnancy wish)
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Visible glucocorticoid side effects
+ osteoporosis, metabolic disturbances…
Risk of corticosteroids and alternate targeting of T-cell activation in RV
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T-cellanti-IL-2R
basiliximab
Cytokine-R
TCR CD3TNFR
IL-2
anti-TNF-mAb
everolimus
sirolimus
JAK
STAT
tofacitinib
e.g. IL-2R
IL-2
TNFα
PI-3K
mTOR
G1
S
G2
M
azathioprine
mycophenolate
NFκBcorticoids
IL-1
IL-6
IL-17
anakinra
anti-IL1 / anti-IL-1R
anti-IL6 / anti-IL6R
anti-IL17
etanercept
Ineffective in Behçet’s
Ineffective in Behçet’s
Ineffective in uveitis/RV
e.g. infliximab, adalimumab
Other:
- methotrexate
- cyclophosphamide
- calcineuine inhibitors
effective
effective
Which of the following sentences regarding TNF inhibitors is FALSE ?
A. It is good practice to perform cerebral MRI prior to starting TNF inhibitors, particularly in retinal vasculitis
B. It is good practice to perform an interferon gamma release assay before starting TNF inhibitors
C. There is a risk of rapid loss of efficacy due to neutralizing anti-drug antibodies
D. There is convincing evidence that adalimumab is superior to infliximab in severe retinal vasculitis
E. The risk of adverse reactions is lower with subcutaneous formulations compared to i/v TNF inhibitors
TNF-inhibitors
Advantages: Parenteral administration (…compliance)
Act quickly
No head to head comparison regarding efficacy in RV
Longest experience with infliximab and adalimumab
Disadvantages: Risk of hypersensitivity (i/v > s/c)
Enhance risk of opportunistic infections (in combination with corticosteroid), especially Tbc
TNF blockade may induce demyelinating disease (rare)
also: potential association of RV and (subclinical) CNS involvement of sytemic disease / MS
-> Recommended to do a cerebral MRI before starting TNF inhibitors in uveitis / RV
Administration of mAbs may generate anti-drug antibodies, with loss of efficacy
TNF-inhibitors
MHC TCR
CD28CD80/8
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APC
TNF-α
infliximab, adalimumab, golimumabcertolizumab pegol
Conclusions
Retinal vasculitis warrants search for underlying infection and systemic inflammatory disease
Systemic disease may present first with severe retinal vasculitis
Work-up should include (among other): Urine sediment
Chest X-ray
IGRA for Tbc
Inflammatory diseases that lead to retinal vasculitis are: Behçet’s, sarcoidosis, lupus, HLA-B27+, Crohn’s…
In contrast, retinal vasculitis only rarely discloses systemic vasculitis
Corticosteroids remain mainstay therapy
TNF blocker very effective in Behçet’s / sarcoidosis - should be used as 1st line in severe retinal vasculitis
Consider cerebral MRI before using TNF blockers (to exclude CNS involvement and as baseline exam)
Distinguish between induction and maintenance treatment and avoid long-term systemic corticosteroids
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