This series delves into complex OID cases in rheumatology. Clinical manifestations and inconclusive findings pose a challenging differential diagnosis. In a retrospective case series of 24 patients with biopsy-proven non-specific OID, involvement varied: Lacrimal gland (54.2%), extraocular muscles (50%), orbital fat (75%), sclera (4.2%), optic nerve (20.8%), and other structures (8.3%).[2] The histopathologic spectrum is often non-diagnostic, reflecting diverse presentations such as diffuse polymorphous infiltrate, lymphoid, granulomatous, sclerosing, eosinophilic, or vasculitic inflammation.[3] Biopsy is crucial for resolving those doubtful cases where diagnostic certainty is needed to promptly initiate therapy. Therefore, it is suggested to proceed with a biopsy of the area as soon as possible, even before the initiation of therapy, if possible. However, a delay in performing the biopsy should not delay the initiation of therapy, especially in the presence of strong clinical suspicion of a systemic and progressive disease. The biopsy should be performed at a specialized center, with a well-trained team for execution. It would be preferable for the team to also include a plastic surgeon, whose expertise could ensure the use of the least invasive and most skin-preserving technique possible. Rheumatologists, ophthalmologists, radiologists, and surgeons should hold pre-operative discussion meetings to pinpoint the area of greatest interest for biopsy based on imaging evidence, and efforts should be made to employ minimally invasive techniques. Indeed, the orbital area is a very delicate zone that can be adversely affected by poor scarring if not treated carefully. Typically, trajectory-guided procedures are the most commonly utilized and can be pre-planned for individual cases. Minimally invasive procedures are usually suitable for obtaining biopsies of the orbit in the majority of cases. However, for certain patients, a conventional, non-minimally invasive lateral orbitotomy may be necessary.

In an initial IgG4 disease diagnosis seemed likely based on clinical presentation, MRI, and slightly elevated IgG4. However, the biopsy excluded IgG4-positive cells, leading to an IOI diagnosis. IOI is characterized by histological findings such as lymphocytic, granulocytic, and sometimes histiocytic infiltrates, organized into lymph follicles with germinal centers, increased connective tissue with edema and fibrosis, and early destruction of lacrimal gland acini or muscle fibers. Typical symptoms include painful pseudoptosis, chemosis, exophthalmos, and impaired ocular motility. Comprehensive laboratory exams and serological diagnostics, including kidney and thyroid values, Anti-neutrophil cytoplasm antibodies (ANCA), Angiotensin converti enzyme (ACE), rheumatoid factors, and IgG4 serum level, are useful. The therapeutic approach includes NSAIDs, steroids, and immunosuppressants.[4]

Case 2, posed a diagnostic challenge with transient salivary gland manifestations. Histology supported Sjögren’s Syndrome. Orbital involvement, lacking specific features, is established in Sjögren’s syndrome,[5] with lymphoma as a severe complication.[6] In our case, essential histology confirmed a not otherwise specified lymphoma, verified by DNA analysis.

Case 3, suggestive of granulomatosis with polyangiitis, initially indistinguishable from IgG4 disease, underwent histology and revealed characteristic features. IgG4-RD is systemic, impacting various organs (pancreas, bile ducts, kidneys, lacrimal and salivary glands, and lymph nodes). Orbital manifestations involve painless lacrimal gland swelling, nerve-induced diplopia without pain, and enlarged lacrimal glands with orbital fatty tissue. Imaging depicts diffuse lacrimal gland enlargement, lateral muscle involvement, infraorbital nerve swelling, and often ipsilateral paranasal sinus involvement.[7] Histology showcases lymphoplasmacellular infiltration with obliterating phlebitis and eosinophilic inflammation. Criteria encompass >40% IgG4+ plasma cells, IgG4/IgG ratio >40%, or >50 IgG4+ cells/high-power field (×400). Laboratory findings show increased IgG4 serum levels but can be non-specific, especially in limited orbital involvement.[8] However, our patient did not meet IgG4 disease criteria due to normal serum IgG4 levels. The biopsy revealed granulomatosis with polyangiitis features, including vasculitis and inflamed necrotic tissue. In granulomatosis with polyangiitis, orbital involvement occurs in 15–20% of cases, either de novo or secondary to sinus disease, causing symptoms such as pain, diplopia, and decreased vision, with signs such as conjunctival injection, proptosis, and ophthalmoplegia. CT with contrast shows hyperintense lesions, obliteration of tissue planes, and bony erosion. On MRI, lesions are hypointense to orbital fat in T1 and T2, enhancing with gadolinium.[9]

Case 4 had a diagnosis of idiopathic orbital myositis from the first biopsy with a peculiar rate of remission and flare periods. Initial response to steroids is usual and has been already discussed in the first case as well as the need to use immunosuppressant agents for frequent or more severe flares.[10]

This short case series can be of potential clinical use and provide significance and contribution in a routine clinical setting. It offers an understanding of the diagnostic, histopathological, and therapeutic aspects of OID in the context of systemic diseases, with real-world cases providing valuable insights for both clinicians and researchers. The article highlights the diagnostic challenges associated with OID, emphasizing the complexity of differential diagnosis due to the varied clinical manifestations and overlapping imaging findings. This information is crucial for clinicians in rheumatology, providing insights into the intricacies of identifying OID in the context of systemic diseases. The focus on analyzing histopathological aspects and cell populations in OID contributes to a deeper understanding of the disease’s etiology, especially in the context of systemic diseases such as IgG4-RDs. It is important to stress the value of comprehensive evaluation, including orbital biopsy, to confirm diagnoses and address the lack of definitive diagnostic laboratory tests.

Case series diversity is also an important issue. The inclusion of a series of four diverse cases, each with distinct systemic diseases and OID manifestations, adds significant value. This diversity provides a comprehensive view of how OID can manifest in different systemic conditions, ranging from IOI to lymphoma, granulomatosis with polyangiitis, and idiopathic orbital myositis.

The article discusses therapeutic approaches for each case, detailing the treatments administered and their outcomes. The long-term follow-up information, such as remission, improvement, or flare-ups, contributes valuable insights into the effectiveness of different therapeutic strategies in managing OID associated with systemic diseases. Emphasizing the need for interdisciplinary collaboration, the article underscores the importance of collaborative efforts among specialists, particularly in rheumatology, to manage complex OID cases effectively. This highlights the necessity of a holistic approach involving various medical disciplines.

The article serves an educational purpose by providing a comprehensive review of the histopathological spectrum of OID, presenting it in a clinical context. It contributes to the existing literature by delving into the complexities of OID and its manifestations, offering a resource for researchers, clinicians, and educators. The detailed descriptions of cases and their outcomes have potential implications for both clinical practice and further research. Clinicians may find the presented cases relevant for improving their diagnostic and therapeutic approaches, whereas researchers may identify gaps in knowledge that warrant further investigation.