FP1751 : Orbital Immunoglobulin G4- Related Inflammation, an Emerging Disease : a Case Series

Dr. Amrita Sawhney, S17593, Dr.Shaloo Bageja, Dr. Ashok Kumar Grover, Dr. Harsh Rathod

Dr. Amrita Sawhney, Dr. A.K. Grover, Dr. Shaloo Bageja, Dr.Harsh

 Purpose :

a)To show the wide spectrum of clinical manifestations in nine cases of orbital    IgG4 –related disease (IgG4-RD) along with their epidemiological, radiological, laboratory and histological data.  b) To evaluate the clinical outcomes of the disease with the targeted  therapies like immunosuppressants and rituximab.

Immunoglobulin G4-related disease is a relatively newly defined emerging entity which is characterized by mass forming lesion, lymphoplasmacytic infiltration rich in IgG4 positive plasma cells and raised IgG4 levels in 60-70 % cases.¹ It  was first  identified in a group of patients  with autoimmune pancreatitis with raised serum IgG4 levels² and  was recognized as a systemic condition in 2003.³

IgG4 –RD  can involve  several organs of the body including the orbit, lymph nodes, skin, lungs, salivary glands, thyroid, aorta, biliary tract, breast, kidneys, retroperitoneum, and CNS. ^The orbit is the most common extrapancreatic site to be involved by this disease entity.⁴ The most frequently involved site in IgG4 –related orbital disease is the lacrimal gland (IgG4 –related dacryoadenitis).  Other  sites in the orbit that can be involved  are  the extraocular muscles (IgG4 –related orbital myositis), the orbital soft tissue (IgG4 related orbital inflammation), the eyelids and the orbital nerves. Orbital IgG4 –related disease is predominantly seen in adults with no gender predilection.⁵

Microscopic features which are characteristic of IgG4–RD are lymphoplasmacytic infiltrate (predominantly T-lymphocytes), a storiform/cartwheel pattern of fibrosis and obliterative  phlebitis. However, in lacrimal gland involvement both storiform fibrosis and obliterative phlebitis  may not be present.

Diagnostic criteria include : 1)Clinical presentation – diffuse or localized mass in single or multiple organs, 2) Serum IgG4 concentration >135mg/dl  and 3) Histopathological features consisting of – a) fibrosis and lymphoplasmacytic infiltration b) IgG4/ IgG ratio  >40 %   and  > 10 IgG4 cells/HPF . According to these criteria IgG4-RD can be labeled as – Definite disease : 1+2+3, possible disease : 1+2, probable disease : 1+3.

Long term followup is required as there is a risk of recurrence and development of lymphoma.

 Materials and method

Nine patients were diagnosed  from 2012-2016 on the basis of published diagnostic criteria for  IgG4 related  disease. Their epidemiological profile (including age and sex), presenting complaints, laboratory results(CRP, ESR and serum IgG4), orbital imaging and histopathological findings were recorded.

All the patients were started on oral steroids to begin with. Azathioprine was used as a steroid sparing agent. Two patients with resistant disease were given rituximab.

 

Results

We diagnosed nine cases of IgG4 related orbital disease from 2012-2016.

The average age at presentation in our study was 50 years (20-68years) with a male:female ratio of 1.2:1 (5 males and 4 females).

Clinical presentations included swelling of upper lid due to dacryoadenitis in  5/9 cases (Figure 1)(unilateral-3, bilateral-2),  proptosis with  extraocular muscles or intraconal fat involvement  in 2/9 cases (Figure 2), proptosis with lid swelling due to both lacrimal gland and extraocular muscle involvement in 2/9cases (Figure 3).

Serum IgG4 level was  raised in 7 /9 cases.

The histopathological diagnosis was based on IgG4 positive plasma cells with fibrosis. (Figure 4)

Systemic involvement including mediastinal lymphadenopathy  and hepatosplenomegaly  was seen in 1/ 9  cases.

The number of cases diagnosed as definite, probable and possible IgG4 related orbital disease were  3,2 and 4 respectively.

In our study, 7/9 patients had good and stable clinical outcomes with steroids and azathioprine. However,  2/9 patients were given rituximab (1gm iv to be repeated after 15 days, total two doses) as there was resistance to steroids. Both the patients had better clinical outcomes after rituximab  therapy.

Table 1: Shows epidemiology, presenting complaints and laboratory results .

S.NO	AGE/SEX	IgG4-RD TYPE	PRESENTING COMPLAINTS	CRP (mg/l)	ESR (mm/hr)	Serum IgG4 LEVELS
1.	55/female	Bilateral dacryoadenitis	Bilateral upper eyelid swelling	15	28	425 (<135mg/dl normal )
2.	20/male	Bilateral dacryoadenitis with mediastinal LAP and hepatosplenomegaly	Bilateral upper eyelid swelling	14	30	13 (0.03-2.01)
3.	30/female	Left dacryoadenitis	Left eye upper lid swelling	4	20	2.97( <2.01)
4.	55/male	Left dacryoadenitis	Left eye upper lid swelling	11	18	123(<135mg/dl)
5.	50/female	Right dacryoadenitis	Right eye  upper lid swelling	19	34	131(4-86)
6.	60/male	Left orbital pseudotumour	Left eye proptosis	8	16	153.3 (4-86)
7.	50/male	Right orbital pseudotumour	Right eye proptosis	5	19	43.4(4-86)
8.	60/male	Left orbital pseudotumor+dacryoadenitis	Left eye swelling upper lid+proptosis	10	12	4.54( 0.03-2.01)
9.	68/female	Left  orbital pseudotumor+proptosis	Left eye swelling upper lid+proptosis	5	23	155(>135mg/dl)

Table 2: shows radiology and biopsy findings along with final diagnosis

S.NO.	AGE/SEX	RADIOLOGY	BIOPSY	DIAGNOSIS
1.	55/F	Bilateral soft tissue swelling in extraconal superotemporal quadrant with enhancement of lacrimal gland area	Fibrosis with IgG4 positive plasma cells >10perHPF	Definite IgG4
2.	20/M	Bilateral lacrimal gland swelling and mediastinal LAP on CT chest	Lymphoplasmacytic infiltration with 5-8% IgG4 positive cells	Possible IgG4
3.	30/F	Left lacrimal gland swelling	Fibrosis with IgG4 positive plasma cells <10 per HPF	Possible IgG4
4.	55/M	Left lacrimal gland swelling	Fibrosis with IgG4 positive plasma cells >30 per HPF	Probable IgG4
5.	50/F	Right lacrimal gland swelling	Lymphoplasmacytic infiltration with 30% IgG4 positive cells	Definite IgG4
6.	60/M	Left intraconal soft tissue with inferior rectus involvement	Fibrosis with IgG4 positive plasma cells <10 per HPF	Possible IgG4
7.	50/M	Intraconal+extraconal mass involving medial rectus	Dense fibrosis with IgG4 positive plasma cells and raised eosinophils	probable IgG4
8.	60/M	Left orbital soft tissue mass  involving lacrimal gland	Fibrocollagenous stroma with lymphoplasmacytic infiltrate 25% positive IgG4 plasma cells.	Definite IgG4
9.	68/F	Left orbital soft tissue mass  involving lacrimal gland	Fibrosis with few IgG4 positive cells	possible IgG4

TABLE 3:  Treatment and clinical outcome

S.NO.	AGE/SEX	TREATMENT	OUTCOME AND FOLLOWUP
1.	55/F	Steroids and azathioprine	Stable (1year )
2.	20/M	Steroids and azathioprine	Stable ( 5months)
3.	30/F	Steroids and azathioprine	Stable and  off steroids since April 2016
4.	55/M	Steroids and azathioprine	Stable (2years)
5.	50/F	Steroids , azathioprine,rituximab (resistant)	After rituximab stable On tapering steroids with azathioprine 25mg/day
6.	60/M	Steroids, azathioprine for 4 years. On stopping steroids proptosis recurred. On steroids 5mg and azathioprine	Low dose steroids with azathioprine (4 years)
7.	50/M	Steroids, azathioprine	Steroids tapered off,on azathioprine (3years)
8.	60/M	Steroids,azathioprine,rituximab	After rituximab stable On tapering steroids with azathioprine
9.	68/F	Steroids,azathioprine	Steroids,azathioprine( reacted to azathioprine, stable on low dose steroids) 1 year

Figure 1: a) 55 year old female presenting with bilateral upper lid swelling (bilateral dacryoadenitis)b) CTscan showing soft tissue swelling in superotemporal quadrants on both sides.
Figure 2: a) 50year old male presenting with right eye non-axial proptosis
b) CT scan shows intraconal and extraconal mass involving medial rectus muscle.

Figure 3: a) 60year old male presenting with left eye proptosis with upper lid swelling
b) MRI shows left orbital soft tissue mass involving lacrimal gland

Figure 4: a) H & E staining under 10X showing extensive fibrosis ( storiform pattern)
b) H&E staining under 40X showing plasma cells
c) IHC under 40X showing CD-138 positive plasma cells
d) IHC under 40X showing IgG4 positive plasma cells

Discussion
This study depicts the spectrum of manifestations in orbital IgG4 related disease along with their epidemiological, radiological , laboratory and histological data. Standard treatment for this disease remains oral steroids with immunosuppressants as maintenance therapy. However, in our study 2/9 patients had to be given rituximab due to resistance to steroid therapy and it proved to be beneficial as patients had better clinical outcome.

The diagnosis of IgG4 related disease,often missed earlier, is critical as it has led to targeted therapies with immunosuppressive agents and rituximab with better clinical outcomes.

Rituximab is a monoclonal antibody which acts against CD-20 positive B lymphocytes. These B lymphocytes differentiate into short acting plasma cells that produce IgG4 antibodies. This therapy has shown promising results in inducing clinical remission and is also associated with fall in serum IgG4 levels, especially in resistant and recurrent cases.^6,7

We plan to conduct more studies in future with more number of patients to look into the role of rituximab in management of IgG4 related disease.

References
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2.Hamano H, Kawa S, Horiuchi A ,et al. High serum IgG concentrations in patients with sclerosing pancreatitis. N Engl J Med. 2001;344:732-738.
3.Stone JH. IgG4- related disease:nomenclature,clinical features, and treatment. Semin Diagn Pathol. 2012;29:177-190.
4.Divatia M, Kim SA, Ro JY. IgG4 –related sclerosing disease, an emerging entity: a review of a multi-system disease. Yonsei Med J. 2012;53:15-34.
5. Kubota T, Moritani S, Katayama M, et al. . Ocular adnexal IgG4-related lymphoplasmacytic infiltrative disorder. Arch Ophthalmol. 2010;128:577-584.
6.Khosroshahi A, Bloch DB, Deshpande V,et al.Rituximab therapy leads to rapid decline of serum IgG4 levels and prompt clinical improvement in IgG4 –related systemic disease. Arthritis Rheum 2010;62:1755-62.
7. Wu A, Andrew NH, Tsirbas A, et al. Rituximab for the treatment of IgG4-related orbital disease:experience from five cases. Eye(Lond) 2015;29:122-8.