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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