Orbital IgG4-Related Disease

Raed Behbehani , MD FRCSC

Case• A 36 year old Philippino : acute painful loss of vision and

droopy lid in the right eye.

• H/O right 6th nerve palsy 2 years ago , MRI showed right cavernous sinus and sphenoid sinus lesion.

• He was referred to ENT later by ENT and then was lost to follow up by me.

• Recent contact with ENT : biopsy was “non-specific inflammatory” and was treated with oral steroids only.

• PMH : no TB

• Social history : Smoker for 15 years

Case• VA : HM recognition OD , 20/20 OS.

• TA : 14 mm/Hg OU.

• Pupils : large right RAPD

• Complete ptosis and severe limitation of eye movement in all gaze direction OD.

• Anterior and posterior segment normal OU.

• Humphrey automated visual field testing was normal OS.

MRI

MRI

Investigations• PPD : negative

• Serum ACE : 20 U/L (range 8-52 U/L)

• C-ANCA : 4 U/ml (normal < 23 U/ml)

• (P-ANCA) : 1 U/ml (normal < 22 U/ml).

• Chest x-ray was normal

• Gallium 67 scan : no uptake in the lacrimal gland, parotid gland or mediastinum.

Management

• Rx : IV methylprednisolone 1 gram/day for 5 days followed by oral steroids 1 mg/Kg.

• Improvement in his ptosis and ocular motility.

• Visual acuity deteriorated to LP OD

• Neurosurgical consultation to obtain a dural biopsy.

• Dura Histology : “Patchy lymphocytic infiltration” few plasma cells.

Follow up

• Presented 2 months later with sudden decrease in vision OS !

• VA was light perception OD and hand motion recognition OS !

• Pupils : bilaterally sluggish.

• Normal lids and full ocular motility and intact corneal reflexes and facial sensation.

• Fundoscopy : optic nerve pallor OD , normal optic nerve OS.

Follow up MRI

Follow up MRI

Follow up

• VDRL , TPHA, and HIV serology : negatives.

• Lumbar puncture : normal CSF analysis (cells , glucose , protein) and negative staining for AFB , no fungus and negative bacterial culture growth.

• IV steroids

• Review initial specimen of the paranasal polyp biopsy.

Pathology

H&E stain x400 Masson’s Trichrome Stain x 100

Pathology

IgG4 positive plasma cells 80/hpf (x 400).

Follow Up

• Dx : Orbital and intracranial IgG4-related disease

• He received two infusion of 1000 mg IV Rituximab.

• Two months following Rituximab infusion, his serum IgG 4 was elevated at 1440 mg/L (normal 39.2-864 mg/L).

• 6/12 later (2nd infusion Rituximab) : VA NLP OD VA 20/40 OS.

Follow up MRI

May 2014 October 2014

Case

• A 32 with recurrent bilateral painless orbital swelling and puffiness for 3 years.

• Severe asthma for 3 years and with that he noticed resolution of eye swelling with oral steroids.

• Significant peripheral esinophilia and high IgE level necessitating treatment with anti IgE therapy.

Case

Both lacrimal glands were palpable and firm

No other palpable masses or lymphadenopathy or any skin lesions

CT

2014

CT

2010

Case

• IgG 24.1 g/L (6-16g/L) , IgG4 >1440 mg/L ( 39.2- 864 mg/L).

• ANA, p-ANCA ,c-ANCA - negative

• Bilateral lacrimal gland biopsy performed.

• Biopsy - high IgG4 plasma cell infiltrate.

Case

Oral steroids (Recurrence)IV Rituximab

IgG4-RD• An inflammatory condition of unknown etiology.• Autoimmune pancreatitis (AIP) with elevated serum

IgG4 levels and later systemic lesions found (Hamano H et al. NEJM 2001)

• Tumefactive lesions in a number of tissues and organs.

• Diagnosis is established by IgG4-bearing plasma cells in addition to characteristic morphologic features, with or without elevated serum IgG4.

2,

Mikulicz

Johann von Milulicz-Radecki , 1888

IgG4-RD

Mickulicz disease, Kuttner tumor (sclerosing sialadenitis)Riedel thyroiditismultifocal fibrosclerosisOrmond disease (idiopathic retroperitoneal fibrosis)Aortitis, periaortitis Retroperitoneal fibrosis, Eosinophilic angiocentric fibrosis (EAF)

Diagnosis

Orbital IgG4-RD and AIP

• 50% of patients with Orbital IgG4-RD will have systemic lesions (salivary gland, liver , pituitary , pancreas, retroperitoneeum) .

• 20-45% of patients with AIP will have orbital IgG4-RD.

Orbital IgG4-RD• Clinically can be confused with idiopathic

orbital inflammatory (IOI) , infectious and neoplastic conditions.

• Many patients with IOI do not undergo biopsy and even if done biopsy is no stained routinely for IgG4.

• Many cases of IOI represent misdiagnosed IgG-RD. (Geyer et al. 2010).

Patterns or Orbital IgR4-RD

1) IgG-4 Dacryoadenitis (62%-88) (Sogabe et al. Wallace et al. Sato et al. )

2) Enlargement of orbital nerves (V2) associated with orbital

myositis and lacrimal gland disease, +_ with paranasal sinus

disease, eosinophilia, and systemic involvement; and

3) Sclerosing orbital inflammation

4) Optic nerve involvement

5) Ocular adnexal involvement

IgG4-RD Darcyoadenitis

• The most common maniesfation of orbital Ig4-RD (62%-88) (Sogabe et al. Wallace et al)

• Unilateral , Bilateral • History of allergy with an elevated IgE

levels (50%) .

Enlargement of the Infra-orbital Nerve

• In 39% of cases (Sogabe et al.) usually with EOM and Sinus involvement.

• In 20 of 68 patients with “Miculikz IgG-4 RD”. (Takano K at al. 2014)

• In 20 of the 28 eyes with either RLH or IgG4-RD. (Hardy et al. Ophthalmology 2014)

• Incidence higher in IgG4-ROD patient group than non-IgG4-ROD (p < 0.0001). (Ohshima et al. 2012)

• No sensory disturbance.

IgG4-RD vs IOIIgR4-RD

Idiopathic Orbital

InflammationMode of Onset Chronic Acute-Subacute

Pain - + severe

Laterality Bilateral Unialteral

Infra-orbital nerve

enlargement+ pathognomonic -

Associated systemic diseases

Allergic rhinitis, asthma rare

Other organ involvement

AIP, sclerosing cholangitis,

retoperitoneal fibrosis -

Optic Neuropathy

• Usually compressive (enlarged V2, enlarged EOM, fat, mass)

• Infiltrative or inflammatory.

Ocular Adnexal IgG4-RD

• Orbital Myositis• Lacrimal Sac• Conjunctiva and sclera

Orbital IgG4-RD Mimickers

Andrew NH, BJO 2015

Pathology

lymphocytic infiltrates are usually composed ofreactive lymphoid follicles with germinal centers + plasma cells ( +- Arteritis +_ Eosinophlis)Storiform fibrosis

Pathology (IgG4 Stain)

• No of IgG4-positive cells is variable (>= 10 cells/hpf).

• In lacrimal glands (100/hpf).

• Depends on fibrosis (sclerosing IOI) , amount of systemic lesions, and serum IgG4.

• IgG4+/IgG+ plasma cell ratio (>40%)

Orbital IgG4-RD and Lymphoma

• 44 of 448 (9.8%) cases of extranodal marginal B-cell lymphoma of (MALT) type had IgG4+ plasma cell infiltrates. (Japanese Study Group of IgG4-Related Ophthalmic Disease. . Jpn J Ophthalmol. 2013)

Pathogenesis• Abnormal immune response to food

and environmental agents (microbes or tissue damage) .

• Humoral auto-immunity (B-cells) : response to Rituximab.

• Increased mRNA levels of cytokines IL-4,IL-5, and IL-13, suggestive of Th2 cell response (atopy).

• Low levels of C3,C4.

Treatment• Steroids have been the mainstay

of treatment.• Relapses common (50%).• Serum IgG4 fall with steroid

therapy.• Steroid-spraing (azathioprine,

methotrexate, and mycophenolate)

Anti-CD 20 (Rituximab)

• Many series shown dramatic response.

• Relapses occurred when B-cells recovered after 6 months, and responded well to a repeat dose.

• Single-dose Rituximab can be effective sometimes.

Summary• Orbital IgG4-RD can present with

inflammtion of the orbit and ocular adnexa.• Clinical should keep high-index of suspicion. • Orbital IgG4-RD has distinctive pathologic

features.• Good communication with a pathologist is

essential.• Steroids and anti-CD 20 can be useful in

treatment.