IgG4-related orbital disease – An update

Abstract

IgG4-related orbital disease is an emerging systemic fibroinflammatory disease that has gained considerable recognition in the past 2 decades. The varied location and presentation of this indolent disease may often result in a diagnostic dilemma for clinicians. Early recognition, comprehensive systemic evaluation, and multidisciplinary approaches are essential for its management. Delayed diagnosis can cause irreversible organ damage, and this disease has shown to be associated with an increased risk of death. This article provides an update on the ophthalmic disease presentation, diagnostic criteria, and management.

IgG4-RD (IgG4-related disease) is a systemic inflammatory condition characterized by tumefactive lesions across multiple organs with infiltration of tissues with IgG4-positive plasma cells. This entity was first documented by Sarles et al.[1] in 1961 in patients who exhibited lymphoplasmacytic infiltration and fibrosis in the pancreas, accompanied by polyclonal hypergammaglobulinemia. IgG4-RD has emerged as a distinctive clinical entity with a broad range of clinical presentation that can involve nearly every organ throughout the body as either a single organ or several organs simultaneously or sequentially.[2,3] Typical sites of organ involvement in IgG4-RD include the pancreas, lacrimal glands (LGs), major salivary glands, retroperitoneum, orbit, bile duct, lungs, kidney, aorta, thyroid gland, and pachymeninges.

Wallace et al.[2] broadly categorized clinical manifestations of IgG4-RD into four broad categories: 1) hepato-pancreato-biliary disease, 2) retroperitoneal fibrosis, 3) head and neck limited disease, and 4) Mikulicz and systemic disease.

IgG4-related orbital disease (IgG4-ROD) falls under the ‘head and neck limited’ disease. It can affect LG, extra-ocular muscles (EOMs), trigeminal nerve, eyelid, orbital soft tissue, and optic nerve. LG is the most frequently involved site in IgG4-ROD and is commonly associated with extraorbital manifestation.[3,4,5] Allergic diseases are more commonly found to be associated with head and neck limited disease than the other categories.

Systemic immune disorders (SIDs) like sarcoidosis, Sjogren’s syndrome, multicentric Castleman disease, and granulomatosis with polyangiitis may affect eye and orbit and need to be differentiated from IgG4-ROD.[3] Additionally, numerous cases previously labeled as ‘idiopathic orbital inflammation’ (IOI) are increasingly being recognized as manifestations of IgG4-ROD. This recognition has been attributed to increasing awareness and high index of suspicion for IgG4-ROD.[6,7]

This review article aims to update the current understanding of IgG4-ROD, encompassing its pathogenesis, epidemiology, clinical features, diagnostic criteria, and therapeutic approaches.

Methods

This is a narrative review of IgG4 ROD. Literature search for this article was conducted using PubMed and Google Scholar databases. A comprehensive systematic literature search was performed using keywords such as “IgG4-related disease,” “IgG4-related orbital disease,” “ophthalmic IgG4,” “orbital IgG4,” “serum IgG4,” and “idiopathic orbital inflammation.” All relevant review articles, original articles, case series, and case reports published in the past 10 years were reviewed. Additionally, the references cited in those articles were also reviewed and included if they provided relevant information on the subject.

Pathogenesis

Immune dysregulation has been postulated to be the underlying mechanism of IgG4-RD. Currently, the most commonly proposed pathogenic mechanism is based on antigen-mediated interactions among B-cell and CD4 T-cell lineages – CD4 cytotoxic T lymphocytes (CD4 CTLs) and CD4 follicular T helper cells [Fig. 1]. B-cells target a wide range of self-antigens, which probably reflects the disease’s significant clinical heterogeneity in organ distribution.[8,9]

Figure 1.

Pathogenesis of IgG4-Related Disease

Presentation of autoantigens by plasmablasts or B cells to CD4 T-cells is the key inciting factor. Both cells express SLAMF7 (signaling lymphocytic activation molecule F7). Activation of CD4 CTLs leads to the expression of various cytotoxic molecules, like perforin and granzymes, and produces profibrotic proteins, such as IFN-γ, IL-1β, and TGF-β, which then activate fibroblasts and lead to excessive deposition of extracellular matrix proteins and fibrosis in the targeted tissue. Meanwhile, follicular T helper cells play a critical role in IgG4 production via B cells through IL-4 and IL-10 secretion, which is considered to be responsible for IgG4 isotype switching. Activated B cells may also exert a direct pro-fibrotic effect by expressing platelet-derived growth factor, a potent fibroblast activator.[8,9] The disease shows a biphasic progression course characterized by an initial inflammatory phase followed by a fibrotic phase.

Epidemiology and systemic association of IgG4-ROD

While middle-aged to older patients (5^th–7^th decade) with a definitive male preponderance (male-to-female ratio = 4:1 to 3:1) are typically affected by systemic IgG4-RD, studies have reported either no difference in sex predisposition or a slight male preponderance in IgG4-ROD (male-to-female ratio = 2.2:1).[5,10]

Wallace et al.[11] reported that the lesions associated with IgG4-RD are often confined to the head and neck area in women. Further, authors noticed that a higher number of females were reported to present with ocular lesions, especially LG lesions. Goto et al.[10] hypothesized that this may be because females are more sensitive to the esthetic change caused by the same.

In systemic IgG4-RD, the overall frequency of ophthalmic involvement is 3.9–17%.[10,12,13] Conversely, systemic manifestations are seen in 48.1–100% of IgG4-ROD cases, and they are strongly related to bilateral presentation (79% systemic disease in bilateral cases vs. 14% in unilateral cases).[3,10,13,14] Furthermore, the likelihood of systemic involvement increases with LG involvement.[13] Pancreas, lymph nodes, and salivary glands are the most commonly affected extraocular sites in IgG4-ROD.[7,15,16]

In a study by Wallace et al.,[17] evaluating incidence, prevalence, and mortality of IgG4-related disease in the USA, the authors reported a mortality rate of 3.42 and 1.46/100 person-years, among patients with IgG4-RD and non-IgG4-RD population, respectively. The authors concluded that patients with IgG4-RD face an excess risk of death. This could be due to a combination of irreversible organ damage caused by the disease, and complications from treatment.

Clinical features of IgG4-ROD

In the first systematic review on IgG4-RD presentation in the head and neck region, containing 484 patients, the authors reported the most common site of presentation as the orbit, followed by the submandibular gland.[18]

In the study by Goto et al.,[10] evaluating clinical features and symptoms in 378 patients of IgG4-ROD, authors reported pathologic lesions involving the LG in 86%, EOM in 21%, trigeminal nerve in 20%, and eyelids in 12% cases. Eleven percent presented with isolated orbital mass and 8% with diffuse orbital lesion, 8% with the peri-optic nerve, and 1% with scleral involvement. Dry eye was the most common symptom (22%), followed by diplopia in 20%, decreased vision in 8%, and visual field defects in 5% patients.

LG involvement in IgG4-ROD may present as a unilateral or bilateral dacryoadenitis, typically presenting with superolateral eyelid swelling with/without proptosis or S-shaped ptosis [Fig. 2].[19,20] All patients should be evaluated for associated dry eye disease.[10] Unlike IOI, pain and acute inflammatory signs are uncommon in IgG4-ROD.

Figure 2.

(a) Clinical picture showing proptosis of left eye in a 30-year-old male; (b and c) MRI head and orbit (coronal cuts) showing a soft tissue mass in superolateral orbit which is isointense on T1W1 and hypointense on T2W1 imaging; (d and e) Microphotographs of an incision biopsy specimen from the same patient showing areas of fibrosis and hyalinized blood vessels (arrows), plasma lymphocytic infiltrate along with eosinophils (H and E stain, 100x); (f) Positive immunohistochemistry for IgG4 plasma cells (100x)

Eyelid swelling in IgG4-ROD occurs due to LG enlargement, or infiltration of the eyelid soft tissue, conjunctiva, or tarsal plate involvement.[21] On examination, nontender diffuse swelling without erythema is typical, ruling out preseptal cellulitis or IOI.

Orbital soft tissue involvement in IgG4-ROD can be diffuse infiltrative or may occur in isolation as discrete orbital mass.[20,22] The patient may present with proptosis, globe dystopia, cellulitis, or periocular mass [Fig. 3].

Figure 3.

(a) Clinical picture showing severe proptosis and lateral displacement of left eye; (b-d) CECT orbit and PNS (sagittal, axial, and coronal cuts) showing contrast enhancing sino-orbital mass with erosion of the left orbital floor and medial wall causing proptosis in this case with definite IgG4-ROD

Many studies have reported the involvement of EOM in IgG4-ROD; however, most are case reports or review articles.[20,23,24] Imaging plays an important role in identifying EOM in IgG4-ROD, which typically shows tendon sparing pattern, although tendon involvement may occur less commonly. There is preferential involvement of lateral rectus, contrary to inferior rectus involvement in thyroid eye disease (TED).[25] Although detailed clinical aspects with respect to ocular motility have been scarcely reported, it appears that ocular motility is usually preserved in most cases, with few patients experiencing diplopia and eye movement abnormality.[20,24] Kim et al. described EOM involvement in four cases of IgG4-ROD. All four patients with IgG4-ROD showed marked enlargement of the EOM; however, no squint was observed, and both ductions and versions were full in two patients. The authors concluded that the key distinguishing feature of IgG4-ROD from other orbital inflammatory diseases is that there is usually normal ocular motility despite EOM enlargement.[24]

Uveitis may be the presenting symptom of IgG4-RD, and it should be considered in the diagnostic workup of uveitis. In a cohort study of 16 patients by Stuchfield-Denby et al., uveitis accounted for 3% of IgG4-RD cases. Uveitis occurred before any other IgG4-related symptoms in 4/16 (25%) cases, concurrently in 9/16 cases (56%), and during follow-up in 3/16 patients (19%). 50% cases had bilateral uveitis, and 50% had granulomatous uveitis. The majority (62%) had anterior uveitis, while 23% had intermediate and 31% had panuveitis.[26]

IgG4-ROD may also present as a highly steroid-sensitive anterior or posterior scleritis. In rare instances, posterior scleritis may progress to multifocal orbital involvement, as reported by Reynolds et al.[27] A similar unpublished case, a 25-year-old male, presented to our center with right eye decreased vision and proptosis. Imaging revealed an intraocular mass with extraocular extension with associated retinal detachment and deterioration of vision. A biopsy from the orbital lesion was suggestive of IgG4-ROD and showed complete resolution with oral steroids. The patient presented with a similar picture in the other eye a year later. At this time, the patient was started on oral steroids and there was a complete resolution of disease. Such cases may be confused for an ocular malignancy.

Trigeminal nerve enlargement may occur in lymphoproliferative disorders of orbit. However, several studies have shown that it is a specific sign of IgG4-ROD and has diagnostic value for IgG4-ROD.[20,28,29] In a study by Goto et al.,[30] enlargement of the trigeminal nerve was observed in 35/149 (23.5%) cases of IgG4-ROD as compared to 7/218 (3.2%) non-IgG4 ROD cases (P < .0001). They reported 23.5% sensitivity and 96.8% specificity of trigeminal nerve enlargement for diagnosis of IgG4-ROD. However, details regarding the presence and severity of associated sensory disturbances are lacking.

Optic nerve involvement in IgG4-ROD may result in loss of vision. Several case reports have reported peri-optic nerve infiltrative lesions, compressive effect from EOM enlargement or orbital mass, and more recently inflammatory optic neuropathy secondary to hypertrophic pachymeningitis as the cause of vision loss.[31,32,33,34] In a previously published case report, we documented the delayed diagnosis in a case of bilateral IgG4-ROD with severe bilateral proptosis and vision loss secondary to compressive optic neuropathy that responded promptly to steroid treatment.[35]

Imaging findings of IgG4-ROD

Imaging has a central role in the diagnosis and initial evaluation of disease burden and also evaluating treatment response in IgG4-ROD. Whole body 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) imaging is especially useful in the early stages to delineate systemic involvement.

Zhang et al.,[36] in a prospective cohort study, evaluated 35 patients of IgG4-RD with baseline and follow-up 18F-FDG PET/CT after 2–4 weeks of steroid therapy. More organ involvement was found in 71.4% (25/35) patients on 18F-FDG PET/CT than conventional evaluations comprising physical examination, ultrasonography (USG), and computed tomography (CT). There was complete remission in 72.4% (21/29) of the patients, whereas >81.8% decrease in 18F-FDG uptake was noted in rest after treatment. Lai et al.,[37] in a retrospective review, found 86/91 (95%) patients had extraorbital involvement radiologically. Lymph node was the most common reported site, followed by salivary gland, lung, kidney, hepatobiliary tree, and pancreas.

Most radiological features of IgG4-ROD are nonspecific and may be confused with other clinical entities like SIDs, TED, and lymphoproliferative disorders. Contrast-enhanced computed tomography (CECT) of the orbit usually demonstrates soft-tissue attenuation lesions. In one unpublished case of definitive IgG4-ROD diagnosed at our center, the orbital lesion showed peripheral enhancement on CECT scan. USG orbit however was suggestive of a solid lesion. This is an unusual imaging finding and may be explained by possible central fibrosis.

Magnetic resonance imaging (MRI) orbit may show lesions that are isointense on T1-weighted images and characteristically hypointense on T2-weighted images reflecting the fibrosis, with a homogeneous/heterogenous contrast enhancement.[38] Signs such as enlargement of infraorbital nerve [Fig. 4], infiltration of the orbital fat, hypertrophic pachymeningeal involvement, and surrounding sinus mucosal thickening provide cues to the diagnosis of IgG4-RD.[34,39,40]

Figure 4.

(a) Clinical picture showing congestion and proptosis of left eye; (b) CT scan orbit (coronal cut) showing inferior orbital mass with dilatation of infraorbital nerve canal (arrow); (c and d) CEMRI (sagittal cuts) showing a contrast-enhancing mass in inferior orbit which is hypointense on T2W images

There is scarcity of data on USG in IgG4-ROD. In a study by Shimizu et al.,[41] authors studied the effectiveness of different imaging modalities for screening of IgG4-related dacryoadenitis and sialadenitis (IgG4-DS) in 39 patients. On sonography, primarily reticular and nodal patterns were observed in patients with IgG4-DS. Sonography showed the highest values among MRI/PETCT/CT/USG for sensitivity, specificity, and accuracy. The authors recommend sonography as a modality for the screening of IgG4-DS.

Role of laboratory biomarkers

Elevated serum IgG4 levels (≥135 mg/dl) aid in the diagnosis of IgG4-RD and can serve as an adjunctive marker for treatment response.[11] However, it is neither highly sensitive nor specific to IgG4-RD. Serum IgG4 may be raised in various other conditions like pancreatic adenocarcinoma, eosinophilic granulomatosis with polyangiitis, atopic dermatitis, pemphigus, asthma, and Castleman disease.[40,42,43,44] Studies report variable sensitivity ranging from 51% to 80% and a specificity of only 60% for IgG4-RD.[45,46,47,48,49,50,51,52]

Although specificity increases with increasing baseline serum IgG4 levels, it is still imperative to consider a broad differential when evaluating patients with raised serum IgG4 levels. Furthermore, a higher baseline serum IgG4 level is associated with an increased risk of multiorgan involvement and a higher likelihood of relapse in IgG4-RD.[49] Goto et al.[30] reported a significantly higher serum IgG4 in patients with enlargement of the trigeminal nerve in their study. Authors suggested that IgG4-ROD in male patients with associated enlargement of the trigeminal nerve and high serum IgG4 levels should be monitored carefully for systemic involvement. Woo et al.[53] in retrospective study on 24 patients of IgG4-ROD reported higher serum IgG4 levels in patients with systemic involvement (P = 0.046) with a decrease in serum IgG4 levels noted after steroid treatment (P = 0.005) and normalization in nine patients.

While nonspecific inflammatory laboratory tests such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) may be mildly elevated in IgG4-RD, significantly higher levels may indicate an alternate diagnosis. Laboratory parameters like peripheral eosinophilia, elevated serum IgE level, raised plasmablast count, and hypocomplementaemia provide initial clues to the diagnosis and can additionally identify patients at high risk of relapse [Table 1].[11,54,55]

Table 1.

Prognostic laboratory parameters in IgG4-RD

1. Serum IgG4 2. Serum IgE 3. Peripheral eosinophilia 4. Hypocomplementaemia (C3 and C4) 5. Plasmablast count 6. ESR, CRP

Histological findings of IgG4-ROD

Histological findings, though central to diagnosis of IgG4-ROD, remain the most variably reported parameter in various case reports and series. Tissue biopsy plays a crucial role in establishing the diagnosis of IgG4-RD. Presence of dense lymphoplasmacytic infiltrate, storiform fibrosis, obliterative phlebitis, and positive immunostaining of IgG4 cells are important hallmarks of IgG4-RD. Storiform fibrosis refers to the whorled arrangement of spindle-shaped cells, inflammatory cells, and fine collagen fibers, while obliterative phlebitis is defined as fibrous venous obliteration with inflammatory cells.[56]

Although IgG4-positive plasma cell infiltrates are important for IgG4-RD diagnosis, they are not specific and may also be seen in some malignancies, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, and multicentric Castleman’s disease. Therefore, IgG4⁺/IgG⁺ plasma cell ratio is considered more diagnostically reliable than the absolute IgG4⁺ cell count.[56]

However, IgG4-ROD, unlike systemic IgG4-RD, may not always show the typical features of storiform fibrosis and/or obliterative fibrosis. Instead, IgG4-ROD may show increased germinal centers and a dense infiltrate of IgG4-positive plasma cells (>50 IgG4+ cells per high-power field).[4]

Ebbo et al.[13] evaluated ophthalmic manifestations in a nationwide French case series and highlighted the problems with the histopathological diagnosis of IgG4-ROD. The biopsy for diagnosis of IgG4-ROD was often performed on extraorbital tissues, and although “modified” comprehensive diagnostic criteria were fulfilled in all cases, the pathological consensus criteria for LG were not fulfilled for all. They reported a frequent lack of the IgG4/IgG ratio measure owing to high background for IgG staining reported by the pathologists. In many cases, IgG4 plasma cells count per high power field was not reported, despite an increased IgG4/IgG ratio >40%.

Diagnostic criteria

Comprehensive diagnostic criteria for IgG4-RD

The first diagnostic criteria for IgG4-RD were the 2011 comprehensive diagnostic criteria published by the Japanese team organized by the Ministry of Health, Labor and Welfare of Japan.[40] However, numerous issues were identified with this criterion, including challenges in acquiring biopsy samples, sensitivity/specificity of serum IgG4 cutoff level, and highly variable immunostaining of IgG4 in histopathology samples. Consequently, diagnostic criteria were amended in 2020. Revised comprehensive diagnostic criteria consist of three domains: 1) Clinical and radiological features, 2) Serological diagnosis, and 3) Pathological diagnosis [Table 2].[56]

Table 2.

The 2020 Revised Comprehensive Diagnostic (RCD) Criteria for IgG4-RD

1. Clinical and radiological features		One or more organs show diffuse or localized swelling or a mass or nodule characteristic of IgG4-RD. In single organ involvement, lymph node swelling is omitted.
2. Serological diagnosis		Serum IgG4 levels greater than 135 mg/dl.
3. Pathological diagnosis		Positivity for two of the following three criteria: 1. Dense lymphocyte and plasma cell infiltration with fibrosis. 2. Ratio of IgG4+ plasma cells/IgG+ cells greater than 40% and the number of IgG4+ plasma cells greater than 10/hpf. 3. Typical tissue fibrosis, particularly storiform fibrosis, or obliterative phlebitis.
DIAGNOSIS: Definite: 1 + 2 + 3 Probable: 1 + 3 Possible: 1 + 2

ACR/EULAR classification criteria for IgG4-RD

American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) have also provided diagnostic criteria for IgG4-RD. These criteria are not intended for clinical diagnosis; they serve as a valuable framework for evaluating patients and facilitate identification of more homogeneous cohorts for inclusion in clinical trials and observational studies. Notably, it defines exclusion criteria for eliminating other diseases such as malignancies, infections, and hematological and immunological diseases; these include lack of an objective response to glucocorticoids, presence of fever, and primarily granulomatous inflammation on histopathology.[57]

Organ-specific diagnostic criteria for IgG4-ROD

Due to varied systemic involvement, diagnostic criteria unique to each affected organ have also been established. The Japanese Study Group for IgG4-ROD has published the diagnostic criteria for ophthalmic involvement [Table 3].[4] While systemic IgG4-RD necessitates >10 IgG4+ cells per high-power field, IgG4-ROD requires >50 IgG4+ cells per high-power field.

Table 3.

Diagnostic criteria for IgG4-ROD, 2014

Imaging studies		Enlargement of the lacrimal gland, trigeminal nerve, or extraocular muscle as well as masses, enlargement, or hypertrophic lesions in various ophthalmic tissues
Histopathological examination		Marked lymphocyte and plasmacyte infiltration, and sometimes fibrosis. A germinal center is frequently observed. IgG4+ plasmacytes are found and satisfy the following criteria: ratio of IgG4+ cells to IgG+ cells of 40% or above, or more than 50 IgG4+ cells per high-power field (×400)
Blood test		Elevated serum IgG4 (≥135 mg/dl)
DIAGNOSIS: Definite: 1 + 2 + 3 Probable: 1 + 2 Possible: 1 + 3

More recently, a revision in the diagnostic criteria for IgG4-ROD (2023) has been made to highlight vision loss as the most severe symptom. While the three main diagnostic criteria remained unchanged, attention has been brought to hypertrophic pachymeningitis as a cause of optic neuropathy. Further emphasis has also been given to the possibility of development of IgG4-positive lymphomas besides MALT lymphoma in IgG4-ROD.[34]

IgG4-related disease: Malignancy

Various studies have reported an association between lymphoma and IgG4-RD.[58,59] Low-grade extra nodal marginal zone B-cell lymphoma originating from mucosa-associated lymphoid tissue (MALT) is the most frequently observed lymphoma in association with IgG4-RD.[60]

IgG4-related MALT lymphomas of ocular adnexa exhibit distinct histological features when compared to other MALT lymphomas. Notably, these are devoid of lymphoepithelial lesions, a feature commonly observed in other MALT lymphomas.[61] Additionally, there is frequent background fibrosis, which is otherwise rarely observed in other MALT lymphomas. Furthermore, MALT lymphomas typically have a low presence of IgG4+ cells, as reported by Cheuk et al.[58] However, lymphomas other than MALT lymphomas such as follicular lymphoma and diffuse large B-cell lymphoma related to IgG4-ROD have also been reported.[62] Yamamoto et al. reported an increased incidence of lymphoma and nonlymphoid tumors, in IgG4-RD, although further analysis is required to establish a definite relationship.[63]

Differential diagnosis

Diseases like Sjogren syndrome, IOI, TED, and lymphoma may mimic IgG4-ROD.

Inflammatory orbital disease usually presents with pain, along with features such as proptosis, lid swelling, or decreased vision. In contrast, IgG4-ROD is usually not associated with pain. Additional serological tests including c-ANCA, p-ANCA, anti-Ro/La antibodies, and serum ACE can aid in differentiating IgG4-ROD from other SIDs. Further, any association with fever or markedly raised ESR/CRP may be helpful in ruling out IgG4-ROD.[11]

Although tendon-sparing EOM involvement may be seen in both IgG4-ROD and TED, absence of other features of TED including lid retraction, lateral flare, and associated underlying thyroid dysfunction in addition to previously discussed imaging features may help in establishing the diagnosis.[24,64]

Ocular adnexal lymphoma primarily affects the conjunctiva and orbital soft tissue, though LG involvement is also common. Histopathological features are central to differentiation from IgG4-ROD.[58,59,60]

Management

The primary objective of managing IgG4-RD is to alleviate inflammation, sustain disease remission, and preserve organ functionality, while reducing the cumulative toxicity of prolonged treatment. Treatment response depends on the organ(s) involved as well as the duration of disease as both determine the degree of fibrosis.[65] Patients displaying signs of disease advancement in crucial organs, despite being asymptomatic, also warrant treatment. Since a large percentage of IgG4-ROD may have systemic involvement, whole body PET-CT scan is recommended. Before commencing treatment, it is essential to pursue tissue diagnosis and rule out malignancy. The treatment strategy usually consists of an initial induction phase, aimed at reducing disease activity and inducing remission, followed by maintenance phase, aimed at maintaining remission and preventing disease flares.

Induction phase

High rate of response to prednisone is a common feature of IgG4-RD. Hence, glucocorticoids are the mainstay treatment for IgG4-ROD. Ebbo et al.[13] reported response in all 19 cases with glucocorticoids, but 68.4% relapsed. Wallace et al.[57] in their paper on EULAR classification have advised a reconsideration of the diagnosis in the absence of response to steroid treatment.

Currently, there are no universally accepted guidelines for the treatment of IgG4-ROD. However, some studies recommend a course of prednisone (0.6–1 mg/kg/day) for at least 4 weeks followed by gradual tapering by 5 mg/day every 1–2 weeks to induce remission. Glucocorticoids should be continued for at least 3–6 months.[66,67] Treatment with intravenous methylprednisolone is also reported as a safe and effective alternative.[68] Change in serum biomarker, follow-up imaging studies, and degree of clinical response influence dose titration.

Treatment with conventional DMARDs, such as methotrexate, cyclophosphamide, and tacrolimus, or biological DMARDS, such as rituximab, abatacept, and dupilumab, may be required in cases of steroid dependence, significant adverse effects of corticosteroids, or resistance to steroid treatment. Risk of recurrence is reported to be higher with increasing number of organ involvement at baseline and a higher serum IgG4 level at baseline.[66,69,70,71]

Rituximab is the most studied biological DMARDS in IgG4-RD. Being an anti-CD20 monoclonal antibody, it targets peripheral B cells and has shown good clinical response with significant improvement in disease activity.[72,73] It is administered in two doses of 1000 mg at 2 weeks interval. Newer drugs like Obinutuzumab, a humanized anti-CD20 monoclonal antibody, has shown promising therapeutic results.[74] Dupilumab, a monoclonal anti-IL-4 receptor-α antibody, has also been reported to show good results, though its efficacy remains untested in prospective trials. Meanwhile, T-cell targeted therapy with abatacept, an inhibitor of T cell co-stimulation and activation, has shown variable treatment results.[75]

Maintenance phase

High risk of disease relapse is found in individuals with multiorgan disease, organ-threatening severity (vision-threatening in IgG4-ROD), highly elevated serum IgG4, and peripheral eosinophilia. Therefore, such patients should be considered for maintenance treatment with either low-dose glucocorticoids (<10 mg/day of prednisone) or steroid-sparing agents for 6–36 months depending on patient-specific factors.[66,76]

According to a meta-analysis of reported IgG4-ROD cases, about 50% of patients treated with corticosteroids showed disease relapse during dose tapering or immediately after discontinuing medication.[77] In a systemic review by Detiger et al.,[78] 89% of IgG4-ROD patients responded well to primary glucocorticoid treatment, but 14% relapsed while tapering and 36% relapsed after discontinuation. This study also evaluated the use of both conventional and biological DMARDs and found rituximab to be more effective than conventional DMARD (93% vs 36–75%). For refractory disease, surgical debulking combined with low-dose steroid/DMARDs is also considered a viable treatment option. Ominato et al.,[79] in a retrospective study on IgG4-ROD, reported a relapse rate of 13.3% with debulking surgery alone.

Response assessment

Treatment response is assessed by serial clinical, serological, and radiological examinations. While symptoms due to damage/fibrosis remain stable, those due to active disease will improve with treatment. Serial changes in the laboratory test values of serum IgG4 and IgE concentrations, complement levels, and circulating plasmablast levels may be helpful.

A comprehensive evaluation system, IgG4-RD Responder Index (IgG4-RD RI), has been developed and found to be a reliable and valid method for assessing both disease activity and organ damage.[80,81] However, no studies have evaluated its use in IgG4-ROD.

Conclusion

Clinicians need to be aware of this emerging disease entity and its diverse presentation. Vision loss is the most serious organ-threatening complication of IgG4-ROD. Additionally, multisystem involvement and long duration of treatment can potentially increase the risk of death in these cases. Therefore, a high index of suspicion, early identification, and timely and optimal treatment are imperative to ensure good patient outcomes in terms of preservation of both eye and life.

Abbreviations

IgG4 ROD: IgG4-related orbital disease

IgG4 RD: IgG4-related disease

LG: Lacrimal gland

EOM: Extraocular muscles

SIDs: Systemic immune disorders

IOI: Idiopathic Orbital Inflammation

CD4 CTL: CD4 cytotoxic T lymphocyte

SLAMF7: Signaling lymphocytic activation molecule F7

FDG PET/CT: Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography

USG: Ultrasonography

CT: Computed tomography

CECT: Contrast Enhanced Computed Tomography

MRI: Magnetic Resonance Imaging

IgG4-DS: IgG4-related dacryoadenitis and sialadenitis

ESR: Erythrocyte sedimentation rate

CRP: C-reactive protein

ACR: American College of Rheumatology

EULAR: European League Against Rheumatism

MALT: Mucosa-Associated Lymphoid Tissue

DMARD: Disease-modifying anti-rheumatic drugs

IgG4-RD RI: IgG4-RD Responder Index

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.