Nicholas H Andrew

IgG4-related orbital disease: a meta-analysis and review

IgG4‐related orbital disease (IgG4‐ROD) is a recently described condition that may account for a significant proportion of idiopathic lymphoplasmacytic or sclerotic orbital lesions. This study is the first meta‐analysis of published cases and reveals several differences between IgG4‐related disease affecting the orbit and that affecting the pancreas. IgG4‐ROD affects a slightly younger group of patients, affects men and women approximately equally, is commonly associated with salivary gland lesions, is associated with a relatively higher serum IgG4 and may confer an increased risk of non‐Hodgkin Lymphoma. Its pathogenesis may involve an immune response to antigen exposure in the upper aerodigestive tract.

An analysis of IgG4-related disease (IgG4-RD) among idiopathic orbital inflammations and benign lymphoid hyperplasias using two consensus-based diagnostic criteria for IgG4-RD

Aim To determine the proportion of idiopathic orbital inflammation (IOI) and orbital benign lymphoid hyperplasia (OBLH) accounted for by immunoglobulin (Ig)G4-related orbital disease (IgG4-ROD) using the comprehensive diagnostic criteria for IgG4-related disease published by Umehara et al and the consensus diagnostic criteria published by Deshpande et al. Secondary aims were to compare the histological and clinical features of IgG4-ROD and non-IgG4-ROD cases, and to compare IgG4-ROD cases diagnosed using the comprehensive diagnostic criteria with those diagnosed using the consensus diagnostic criteria. Methods A retrospective histopathological review and clinical case series. 55 cases of biopsy-confirmed non-granulomatous IOI and 10 cases of biopsy-confirmed OBLH were included. The intensity of sclerosis, lymphoplasmacytic infiltration and eosinophilic infiltration was graded from 0 to 3+ using a standardised and validated scoring system. Results IgG4-ROD accounted for 50% and 40% of cases originally diagnosed as OBLH and 23.6% and 5.4% of cases originally diagnosed as IOI, using the comprehensive diagnostic criteria and the consensus diagnostic criteria, respectively. IgG4-ROD cases had numerous significant histological differences, but relatively few significant clinical differences, from non-IgG4-ROD cases. Compared with the comprehensive diagnostic criteria, the consensus diagnostic criteria identified a group of IgG4-ROD cases with a slightly higher ratio of IgG4+ to IgG+ (p=0.01) and a slightly longer duration of symptoms (p=0.02). Conclusions This is the largest review of IgG4 staining among biopsy-confirmed IOI and OBLH. IgG4-ROD accounted for a substantial proportion of OBLH. The prevalence among cases of IOI was considerably reduced when the consensus diagnostic criteria were used in place of the comprehensive diagnostic criteria.

Rituximab for the treatment of IgG4-related orbital disease: experience from five cases

PurposeTo review the clinical efficacy and safety of rituximab for treatment of IgG4-related orbital disease (IgG4-ROD).DesignRetrospective multicentre interventional case series.MethodsChart review for five cases of biopsy-confirmed IgG4-ROD (IgG4+>10/HPF, ratio of IgG4+/IgG+>40%) treated with rituximab. Information retrieved included the dosing schedule, adverse events and the magnitude, temporality, and duration of the clinical response.ResultsAll cases of IgG4-ROD were either steroid dependent or steroid resistant. Rituximab doses for induction therapy included two doses of 1000 mg at 2-weekly intervals, and four doses at 375 mg/m2 at weekly intervals. Two months after starting rituximab, three cases achieved complete clinical resolution and two cases achieved partial clinical resolution. Complete radiological resolution occurred in one case, and partial radiological resolution in three cases. Three cases received rituximab maintenance therapy and one case was commenced on mycophenolate. No relapse occurred during a mean follow-up of 33 months (range: 7–65 months). One disease relapse occurred when the dosing interval of rituximab maintenance therapy was extended to 6–monthly intervals; remission was swiftly achieved with rituximab reinduction therapy. The only adverse effects reported were one episode of fatigue lasting 1 week and two episodes of orbital discomfort.ConclusionRituximab may be an effective treatment option for IgG4-ROD that is steroid dependent or steroid intolerant. Rituximab therapy resulted in swift clinical and radiological improvement, many months free of relapse, and few side effects.

IgG4-Related Ophthalmic Disease: Pooling of Published Cases and Literature Review

In recent years, IgG4-related ophthalmic disease (IgG4-ROD) has emerged as a common cause of orbital inflammation, accounting for a substantial proportion of idiopathic orbital inflammation and lymphoid hyperplasia. The last pooled analysis of published cases was conducted in 2012, but a large number of new cases have been added to the literature since then. In this review, we present the demographic, clinical, histological, and treatment data for 172 published cases of biopsy-confirmed IgG4-ROD. Results are accompanied by a review of the relevant literature.

Review of 268 lacrimal gland biopsies in an Australian cohort.

To review the distribution of pathology in lacrimal gland biopsies performed in an Australian cohort.

Immunoglobulin G4-related disease of the hard palate.

A 71-year-old woman presented with erythematous, nontender, bilateral hard palate nodules of 6-month duration. Biopsy showed collagenous sclerosis and a follicular lymphoplasmacytic infiltrate among the minor salivary glands. Immunoglobulin G (IgG) and IgG4 staining showed 280 IgG4(+) cells per high-power field and a ratio of IgG4(+) to IgG(+) cells of 0.8. The patient subsequently developed bilateral lacrimal gland and parotid gland enlargement associated with an increased serum IgG4 level of 3,031 mg/dL (≤ 135 mg/dL). Left lacrimal gland biopsy confirmed IgG4-related dacryoadenitis. The patient declined corticosteroid treatment for IgG4-related disease (IgG4-RD) and remained stable at 15 months after the first presentation. Spontaneous, partial resolution of the palatal lesion was observed during follow-up. IgG4-RD should be considered in the differential diagnosis of lymphoplasmacytic lesions of the hard palate.

Applying the consensus statement on the pathology of IgG4-related disease to lacrimal gland lesions.

Applying the consensus statement on the pathology of IgG4-related disease to lacrimal gland lesions

Review of paediatric retinal microvascular changes as a predictor of cardiovascular disease.

Recent studies have supported the hypothesis that exposure to established cardiovascular risk factors in early life predisposes to the development of adult cardiovascular disease. Retinal imaging is an emerging technique which facilitates non‐invasive, accurate and reproducible assessment of the retinal microvasculature. The assessment may be in the form of static vascular calibre measurements and assessment of the vascular geometry or dynamic structural and functional assessments. Paediatric retinal microvascular changes are reported in response to elevated blood pressure, type 1 diabetes, increasing adiposity, diet, physical activity, systemic inflammation, metabolic peptides, family history and prenatal factors. The resultant microvascular changes have been linked to sub‐clinical and overt cardiovascular, cerebrovascular and metabolic disease states in the adult population. Still missing however is longitudinal evidence showing the persistence of retinal microvascular alterations into adulthood. Future studies will enable retinal microvascular assessment to further evaluate the pathogenesis of disease states and response to intervention. The data obtained will also aid in expanding the clinical utility of retinal imaging as a cardiovascular risk prediction and monitoring tool and supplement existing recommendations to reduce cardiovascular morbidity and mortality.

Bilateral IgG4-related ophthalmic disease: a strong indication for systemic imaging

Background/aims To investigate whether bilateral or unilateral IgG4-related ophthalmic disease (IgG4-ROD) is associated with extra-ophthalmic IgG4-related disease (IgG4-RD). Methods Twin-centre retrospective observational case series of biopsy-confirmed IgG4-ROD. Clinical and radiology data were reviewed for laterality of IgG4-ROD and presence of extra-ophthalmic disease. The literature was reviewed for case series of IgG4-ROD. Results 40 IgG4-ROD cases were identified, with median follow-up of 36 months. At diagnosis of IgG4-ROD, all cases were screened for extra-ophthalmic disease with physical examination and blood testing. Systemic imaging was performed in 20 (50%) cases due to clinical suspicion of extra-ophthalmic disease. Of the 21 unilateral IgG4-ROD cases, 3 (14%) had extra-ophthalmic involvement. Of the 19 bilateral cases, 15 (79%) had extra-ophthalmic involvement. Extra-ophthalmic involvement was strongly associated with bilateral IgG4-ROD (p<0.001). On pooling our data (n=40) with previously published cases (n=142), the association remained strong (p<0.001). Conclusions Bilateral IgG4-ROD is strongly associated with extra-ophthalmic IgG4-RD. We recommend that imaging of the neck, chest, abdomen and pelvis be performed for all bilateral cases. Systemic imaging should also be considered in unilateral cases as a significant proportion of these patients will also have extra-ophthalmic disease.

Periocular Squamous Cell Carcinoma: TNM Staging and Recurrence

PURPOSE To analyze the TNM stage, management, and recurrence rates of patients with histologically confirmed squamous cell carcinoma (SCC) of the eyelid. DESIGN Retrospective case series from 3 Australian centers. PARTICIPANTS A total of 254 cases of eyelid SCC from 254 patients (median age, 73 years; range, 28-102 years; 159 were male). METHODS Tumors were staged according to The American Joint Committee on Cancer 7th edition TNM criteria for eyelid carcinoma. MAIN OUTCOME MEASURES Outcomes and recurrence rates according to TNM stage at presentation. RESULTS A total of 25 cases (9.8%) were recurrent tumors. TNM classifications were as follows: T1N0M0, 74 patients (29.1%); T2aN0M0, 92 patients (36.2%); T2bN0M0, 50 patients (19.7%); T3aN0M0, 31 patients (12.2%); T3bN0M0, 5 patients (2.0%); T2bN0M1, 1 patient (0.4%); and T3bN1M1, 1 patient (0.4%). Perineural invasion (PNI) was present histologically in 8.3% of cases. Treatment modalities included Mohs microsurgery (31.1%), wide local excision (WLE) with paraffin section control (21.7%), WLE with frozen-section control (19.3%), and excision without margin control (24.4%). Three cases did not receive treatment. Median follow-up was 40 months (range, <1-132 months). Local recurrence occurred in 17 treated patients (6.8%). The recurrence rate was 5.3% (12/226 patients) for primary tumors and 20% (5/25 patients) for recurrent tumors (P = 0.019). Four patients (1.6%) died of their disease during follow-up. Higher T stage was significantly associated with both PNI (P = 0.035) and local recurrence (P < 0.001). We could not identify a T-stage threshold below which there was no risk of recurrence, as evidenced by 3 T1 primary tumors that recurred. CONCLUSIONS Higher T stage was significantly associated with local recurrence, and recurrent tumors had a 4-fold increased risk of further recurrence compared with primary tumors. Therefore, it may be reasonable to consider sentinel lymph node biopsy or close nodal surveillance and follow-up for patients with recurrent or high T-stage tumors. Of note, we could not identify a T-stage threshold below which there was no risk of recurrences; therefore, clinicians should be aware of the potential for low T-stage tumors to recur.