Infliximab Therapy for a Severe Case of IgG4-related Ocular Adnexal Disorder Recalcitrant to Corticosteroid Treatment

Since the recognition of inflammatory disorders associated with elevated serum concentrations or tissue deposition of IgG4 immunoglobulin, the list of tissues targeted by IgG4-related sclerosing disease has not ceased to expand. Involvement of periorbital tissues and ocular adnexa has previously been reported.¹ Histopathological landmark for identification of the disorder is the presence of tissue infiltration by plasma cells that bear IgG4.² The rarity of the condition prevents the identification of an optimal treatment approach.³

We report here a case of orbital IgG4-related sclerosing disease associated with bilateral recalcitrant panuveitis leading to unilateral pthisis bulbi. Response to corticosteroid and immunosuppressive treatment was suboptimal and only the introduction of infliximab therapy allowed the containment of inflammatory activity.

The case of this 40-year-old patient constituted a real diagnostic challenge. In 2004 the patient suffered from an episode of postinfectious reactive poly-arthritis secondary to Yersinia enterocolitica infection. Serological investigations at the time had identified circulating immune complexes (IgG, IgA) against the microorganism. Antibiotic treatment with ciprofloxacin and corticosteroids had yielded limited benefit. In June 2007 he developed severe right diffuse scleritis and panuveitis treated with perfusions of methylprednisolone followed by oral corticosteroids. Extensive serological investigations excluded potential causes of infectious and autoimmune conditions. In September 2007, while still under treatment, he exhibited right sudden complete visual loss prompting administration of a cycle of intravenous cyclophosphamide, with minimal improvement. A few weeks later the patient presented inflammatory protrusion of the right superior–temporal orbit. MRI revealed a space-occupying lesion of the lacrimal gland with infiltration of the ocular globe and diffusion of the contrast agent at the level of the retina, raising the suspicion of orbital lymphoma.

In October 2007 orbital decompression surgery was performed and samples were obtained for histology. The latter excluded a lymphoma and revealed extensive chronic lympho-histiocytic infiltration with sclerosing elements, consistent with the diagnosis of inflammatory pseudotumor (Figure 1A). In view of the dramatic clinical aspect with right phthisis bulbi and anterior chamber inflammation in the contralateral eye (tyndall +, cells +), the introduction of infliximab treatment was considered, in analogy with similar practices in the context of uveitis resistant to classical immunosuppressive treatment. Three biweekly injections of infliximab 5 mg/kg were performed with concomitant continuation of oral corticosteroids. Clear improvement of the inflammatory aspect was achieved. All treatment was discontinued in March 2008 and 4 months later a new inflammatory lesion appeared in the left mastoid process.

FIGURE 1  (A) Histology of the orbital biopsy showing a dense inflammatory infiltrate and fibrous tissue obliterating the orbital fat (hematoxylin and eosin, ×100). (B, C) The orbital inflammatory infiltrate comprises many IgG-positive plasma cells (B, immunoperoxidase, ×200) of which a minority are positive for IgG4 (C, immunoperoxidase, ×200).

A reassessment of the orbital tissue biopsied in 2007 for plasma cell typing showed numerous IgG-positive plasma cells, with a minority staining positively for IgG4. In terms of absolute counts, more than 10 IgG4⁺ plasmocytes per high-power field were occasionally seen in plasma cell-rich foci (Figure 1B, C). Serum IgG4 concentration was, however, at the superior limit of the normal range (127 mg/dL). Biopsy of the lesion of the left mastoid revealed some IgG4⁺ plasmocytes, though fewer than those observed in the earlier orbital sample. Infliximab therapy was resumed with resolution of the inflammatory process of the mastoid.

The diagnosis of IgG4-related sclerosing disease remains challenging in view of the lack of universal agreement on diagnostic criteria. Infiltration by IgG4⁺ plasma cells is considered essential for histological diagnosis of the condition. Increased serum IgG4 levels, although strongly suggestive of the disease, are not considered indispensable, as they tend to decline under treatment, as was the case also here.^3,4 Diagnostic criteria for the disease have recently been suggested by Umehara et al.⁵ and should include two of the following: (a) diffuse or focal enlargement of mass lesions in one or more organs, (b) elevated serum levels of IgG4 (>135 mg/dL), and (c) compatible histopathological findings, such as prominent infiltration of lymphocytes and plasmacytes with fibrosis, infiltration of IgG4-positive plasmacytes (more than 10 per high-power field), storiform/swirling fibrosis, and obliterative phlebitis. In the present case, mass lesions of the orbital content and mastoid were present and orbital tissue biopsy revealed more than 10 IgG4-bearing plasmocytes per high-power field, reiterating the diagnosis of IgG4-related ocular adnexal disorder.

Immunopathogenesis of the disease remains largely unknown and although infiltration of various organs by IgG4-postive plasma cells has been identified, the triggering mechanism for this phenomenon has not been clearly established. Interestingly, inflammatory infiltrate consists of both IgG4-positive plasma cells and numerous CD4⁻ or CD8⁺ T lymphocytes. IgG4 production is controlled primarily by type 2 helper T (Th2) cells. This finding is consistent with the theory that production of IgG4 in vivo is induced preferentially in the setting of a Th2-cell–dominant immune reaction, characterized by the activation of regulatory T cells that produce interleukin-10; thus, interfering with the T-cell-mediated immune reaction would have a blunting effect on the production of IgG4.⁶

The condition has been reported to be refractory to classical immunosuppressive therapy with a high degree of relapse, even under maintenance corticosteroid treatment.^7,8 For patients with recurrent or refractory disease, B-cell depletion with rituximab appears to be a useful approach, causing rapid decline of IgG4 concentration in the serum. Rituximab is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of B cells, hence the rationale of its use in the context of this condition. In the study by Khosroshahi et al., rituximab appeared to be a viable treatment option for IgG4-related sclerosing disease.³ Infliximab is a monoclonal antibody against tumor necrosis factor alpha (TNFα). Infliximab causes programmed cell death of TNFα-expressing activated T lymphocytes, an important cell type mediating inflammation.⁹ Its use in the presented case was empirical as salvage therapy in a sight-threatening and unrelenting inflammation of the orbit in accordance with similar practices in other cases of severe ocular inflammation recalcitrant to conventional immunosuppressive treatment. Accounting for its effectiveness in the presented case would be speculative, though the fact that it targets T lymphocytes may play a role in interrupting IgG4 production mediated by Th2 cells. The use of infliximab in this particular clinical context is for the first time described in the present report. This case re-ascertains the role of anti-TNFα agents as salvage therapy in cases of severe orbital and ocular inflammation recalcitrant to classical immunosuppressive treatment. Further observations would serve to accrue experience on the use of infliximab in IgG4-related disease.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.