Patients and methods
All the patients provided informed written consent for the use of their data and the possible outcomes were explained to them.
Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research.
This was a retrospective cohort study that included subgroup analyses. We investigated the clinical records of all the patients seen in the Ophthalmology Department of Nagoya Medical Center from 1 April 2003 to 30 June 2020, and enrolled 195 patients diagnosed with IOI. Previously published reports on IOI and orbital myositis described some of these patients.11–13 However, the clinical follow-up data were updated for this study. We recorded the patient’s age, sex, signs and symptoms, bilaterality, duration of symptoms from onset to the initial visit, past and present illnesses, and the anatomical location of the lesions. Periocular findings were recorded by pictures.
In order to compare the differences in the degree of the periocular symptoms between the two groups, we scored them based on three cardinal signs/symptoms of periocular inflammation, namely, pain, redness (including conjunctival hyperaemia), and swelling (including conjunctival chemosis). Heat was excluded from the score since the objective evaluation was challenging. In addition, mass effects, such as tumour-like lesions, were not considered swellings in our study. Based on these items, the periocular inflammation score ranged from 0 to 3 points. A score of 2 points was given to a patient presenting redness and pain. In addition, functional disturbances were scored with a maximum of 3 and a minimum of 0 points based on the presence or absence of ocular motility restrictions, ptosis, and visual acuity disturbances, including visual field defects in our study.
Based on the criteria of IOI, we defined unique onset as an acute or subacute onset in which periocular inflammatory symptoms emerge suddenly but progress slowly.1 Patients reported either the day or week of onset (eg, the third week of March). Patients also reported either these symptoms were slightly progressive before initial visits (acute onset) or they had increasing symptoms for 2 weeks after onset (subacute onset). For example, a patient who noticed eyelid swelling and then would have periocular pain 1 week after onset was classified as a subacute onset. To determine the optimal cut-off for the speed of symptom onset, our study followed the proposed criteria (cutoff >14 days).7 We also investigated the laboratory data for disease-related autoantibodies such as thyroid-associated ophthalmopathy, Sjogren syndrome and diseases with positive antineutrophil cytoplasmic antibodies, serum levels of IgG4 and other laboratory data.1 2
To determine the presence of ocular adnexal lesions for all patients, CT scan and MRI (figure 1) were carried out before and after treatment, and classified as diffuse IOI, dacryoadenitis, myositis, optic perineuritis, and scleritis.14 Furthermore, we subclassified the diffuse type into three subcategories: adjacent lesions of the eye (figure 1), extraconal and intraconal lesions (figure 2).
Figure 1Idiopathic orbital inflammation in the typical group top: orbital myositis in the typical group. CT scan coronal view (left) shows lateral rectus muscle enlargement in the left eye and adjacent fuzzy shadows (arrowhead) and fat-suppressed T2-weighted MRI a coronal view (right) shows high signal intensity of lateral rectus muscle fascia in the left eye. Bottom: diffuse type adjacent lesion around the eye.
Figure 2Idiopathic orbital inflammation in the atypical type top: CT scan (left) showing diffuse intraconal lesion in the left eye and inflammatory cells infiltrating extraocular muscle. (Right, H&E staining, original magnification ×200) bottom: Patient subsequently diagnosed with sarcoidosis. CT scan (left) showing enlargement of the right inferior oblique left and medial rectus muscles, and histopathology showing non-caseating granulomatous tissue with lymphoid cell infiltration (right, H&E staining, original magnification ×100).
To determine whether a histological confirmation for diagnosis of IOI was required, our study followed the proposed criteria.15 Thus, patients with typical myositis, scleritis and acute dacryoadenitis, which were cured within several days following corticosteroid treatment or cured within several months after observation,15 and had higher surgical risks than benefits and did not undergo open biopsy. In contrast, we performed open biopsies on 23/130 (18%) patients in the typical group and 59/65 (91%) patients in the atypical group. Histological findings were classified according to the proposed classification system, which includes classic (non-specific and polymorphous inflammatory cells infiltrations), granulomatous and sclerosing.14
We excluded the following orbital inflammatory diseases: IgG4-related ophthalmic disease,5 16–18 reactive lymphoid hyperplasia,18 19 marginal zone B-cell and other lymphomas,20 21 xanthogranuloma,22 vasculitis syndrome, thyroid-associated ophthalmopathy,23 Sjogren’s syndrome, parasitic infections,24 amyloidosis, primary and metastatic carcinomatous lesions in the other ocular adnexa,13 25 orbital cellulitis and other orbital inflammatory diseases.13 Regarding sarcoidosis, seven patients with histological granulomatous epithelioma and later confirmation of systemic sarcoidosis were excluded, and two patients with histological granulomatous inflammation and later confirmation of systemic sarcoidosis were included in the study (figure 2).
Treatments
The flow chart of the patient allocation to investigate the treatment outcomes is shown in figure 3. Systemic corticosteroid treatment was initiated only after informed consent was obtained from the patients. High dosage of corticosteroid treatment was either prednisolone at 1 mg/kg/day with a slow taper or 1000 mg intravenous methylprednisolone once per day for 3 days with prednisolone at 5–10 mg for a few weeks. Medium dosage was prednisolone at a minimum of 0.2 mg/kg/day to a maximum of 0.6 mg/kg/day with a slow taper. Patients who received prior immunosuppressive treatments due to IMIDs or other treatments, except corticosteroid treatment, were excluded from treatment outcomes. Patients in the typical group who reported less inflammatory symptoms (pain, redness and swelling) at the initial visit than those at the onset of disease and patients in the atypical group who refused treatment due to mild symptoms were observed as the natural course of IOI. Overall, we analysed 159 patients who received high-dose or middle-dose corticosteroids and 22 who were not treated.
Figure 3Flow chart of patient allocation. IOI, idiopathic orbital inflammation; IMIDs, immune-mediated inflammatory diseases; NSAIDs, non-steroidal anti-inflammatory drugs.
To assess the treatment response, we evaluated physical findings and CT scans. In addition, we followed the patients’ conditions during tapering of the corticosteroids, and determined steroid-refractory IOI, namely, incomplete treatment response, recalcitrant, and recurrent.26 When a novel ocular adnexal lesion emerged, it was considered a novel lesion. Further, we considered recurrence more than 5 years following complete remission as unpredictive recurrence and did not include it in the risk factor analysis.
Statistical analyses
To determine the differences between the two subgroups, we compared sex, a presence or absence of ocular adnexa-specific lesions, bilaterality and immune-mediated inflammatory diseases using the χ2 test. We also compared the age, number of inflammatory symptoms and functional disturbances using the Mann-Whitney U test.
To identify risk factors for steroid-refractory IOI, patients in both groups were analysed using the univariate analysis using the χ2 test and multivariate analysis using the logistic regression model.
All the statistical analyses were performed with the statistical package SPSS for Windows (V.12.0), and the statistical software EZR.27 A p<0.03 was considered statistically significant.