Tacrolimus for Treating Orbital and Cranial Form of Idiopathic Inflammatory Pseudotumors

Idiopathic inflammatory pseudotumor (IIP) is a nonneoplastic inflammatory lesion with histological features of polymorphous inflammatory cell infiltration, fibrosis, necrosis, and a granulomatous reaction.1 Such lesions commonly involve the orbit and so are often called orbital IIP, but the lesion may also spread through the superior orbital fissure to the intracranial structures. IIP can also develop solely within the cranium, and Tolosa-Hunt syndrome (THS)—which is an idiopathic granulomatous inflammation mostly involving the cavernous sinus and the superior orbital fissure—can be considered as cranial IIP because THS shares histological, radiological, and clinical features with orbital IIPs.1 Both orbital and cranial IIPs are known to respond favorably to short-term systemic corticosteroids.1, 2 In refractory or relapsing forms of these disorders, treatment with long-term corticosteroids and second-line immunosuppressants may be attempted like they are in other autoimmune disorders.1, 2, 3, 4

Tacrolimus forms a complex with the immunophilin-FK-binding protein that inhibits calcineurin, which is essential for activating NF-AT, the T-cell-specific transcription factor.5 Therefore, tacrolimus exerts selective inhibitory effects on T-cell activation and T-cell-dependent B-cell activation, which becomes an immunological basis for immunosuppressive treatment. Tacrolimus is currently commonly administered to patients with organ transplantation, rheumatoid arthritis, and myasthenia gravis.5 However, the effectiveness of tacrolimus has not been documented in orbital and cranial IIPs.

Here we report three patients with orbital or cranial IIP who showed favorable outcomes with the administration of tacrolimus as an adjuvant treatment.

This study is a case series of three patients who were diagnosed with orbital or cranial IIP and treated with tacrolimus. The clinical course of each patient is depicted in Figs. 1A, 2A, and 3A. The details of each patient are reported in the Results and summarized in Table 1. The Institutional Review Board of Seoul National University Bundang Hospital approved the protocol applied in this study and did not require consent to be obtained from each patient (IRB number: B-2004-604-108).

Fig. 1
Findings of a 43-year-old female patient with a cranial idiopathic inflammatory pseudotumor (Tolosa-Hunt syndrome). A: The summarized clinical course of the patient. The blue gradation box displays the symptom severity during follow-up, while the gray and blue-gray gradation boxes indicate the duration and dosage of steroid and tacrolimus, respectively. B and C: Initial MRIs show a heterogeneous contrast-enhanced mass in the left cavernous sinus (circle) without the involvement of extraocular muscles. D and E: The second MRIs obtained after 3 months reveal a decreased size and enhancement of the cavernous sinus lesions (circle), but the left extraocular muscles are newly enlarged. F and G: In the third MRIs obtained 1 year after the onset, the cavernous lesion has disappeared (circle), and the left extraocular muscles are normalized.

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Fig. 2
Findings of a 40-year-old female patient with an orbital idiopathic inflammatory pseudotumor. A: Summary of the clinical course. The representations of the gradation boxes are the same as in Fig. 1. B and C: Initial MRIs show an enlarged right medial rectus muscle with contrast enhancement (solid arrows). There are additional enhancements in the right retrobulbar optic nerve sheath (dotted arrow) and preseptal area (arrowhead). D and E: In the second MRIs, the previous lesions are not notably changed. F and G: The third MRIs obtained after tacrolimus treatment show a remarkable improvement of the right medial rectus enlargement, with disappearance of the enhancement from the retrobulbar optic sheath and preseptal area.

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Fig. 3
Findings of a 56-year-old female patient with a cranial idiopathic inflammatory pseudotumor. A: Summary of the clinical course. The representations of the gradation boxes are the same as in Fig. 1. B and C: Initial MRIs show a contrast-enhanced lesion in the left facial and vestibular nerves at the distal auditory canal (arrow) but a normal left olfactory groove. D and E: The second MRIs obtained 4 months after the onset show no noticeable change in the lesions in the left auditory canal (solid arrow) but reveal a new contrast-enhanced lesion in the left olfactory groove (dotted arrow). F and G: In the third MRIs obtained 7 months after the onset, the previous lesions evident in the second MRIs have decreased slightly. H and I: The fourth MRIs obtained after 12 months of tacrolimus treatment reveal that the lesions have disappeared from both the internal auditory canals and olfactory groove.

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Table 1
Summary of the clinical features of the three patients

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The three patients in this study showed incomplete responses to conventional corticosteroid treatment. In addition, common immunosuppressants could not be administered due to the presence of comorbidities or side effects. However, tacrolimus was able to produce clinical and radiological remission without significant adverse effects.

Intravenous and/or oral corticosteroids are the first-line treatments for orbital or cranial IIP, and marked improvement within 48 hours has been reported in approximately three-quarters of patients.6 However, relapse occurs in more than half of patients with orbital or cranial IIP.2 Recurrence has been found in approximately 78% of patients treated with corticosteroids alone, with this proportion decreasing to 16% through combination treatment with immunosuppressants.7 Therefore, immunosuppressants could be empirically used with corticosteroids to improve symptoms, at least in patients who are resistant to corticosteroids or exhibit recurrence;8 these immunosuppressants include folic acid antagonists, methotrexate, purine analogs, azathioprine, alkylating agents, cyclophosphamide, purine synthesis inhibitors, and mycophenolate mofetil. However, tacrolimus was developed more recently than these other agents, and the present report is the first suggesting that tacrolimus exhibits therapeutic efficacy in patients with orbital or cranial IIP.

Tacrolimus is known to have excellent safety and efficacy. Tacrolimus has less hepatotoxicity than cyclosporine, which belongs to the same group of calcineurin inhibitors as tacrolimus. Dosage adjustment is essential for every patient receiving cyclosporin treatment due to the propensity of multiple drug interactions metabolized by cytochrome P450 3A, but the bioavailability of tacrolimus is superior.9, 10 In addition, tacrolimus is 10- to 100-fold more potently immunosuppressive than cyclosporine at the same weight,9 which results in a higher survival rate and a lower mortality in patients with kidney transplantation.11 Moreover, the rate of reactivation of hepatitis B and C viruses appears to be lower for tacrolimus than for systemic corticosteroids.12, 13, 14, 15, 16 A meta-analysis assessing the risk of adverse events in patients with systemic lupus erythematosus found that the rate of serious adverse events was lower for tacrolimus than for other immunosuppressants such as glucocorticoids, cyclosporine, azathioprine, cyclophosphamide, mycophenolate mofetil, methotrexate, and rituximab.17 Tacrolimus was also suitable for controlling ocular inflammatory diseases including Behçet's disease and Vogt-Koyanagi-Harada syndrome without inducing increases in infection and malignancy.18

The therapeutic mechanism of tacrolimus in orbital or cranial IIP remains to be determined, but at least two mechanisms can be speculated. First, the immunosuppressive mechanism of tacrolimus might be similar to that of cyclosporine, which can also be efficacious in orbital IIP. Second, IIP occurs in the CNS and was histologically revealed to be associated with a high density of IgG4-positive plasma cells, which suggests that a considerable proportion of IIP cases belong to the subgroup of IgG4-related syndromes.19 Specimens obtained from patients with orbital IIP show high levels of interleukin (IL)-2, IL-8, IL-10, IL-12, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α.1 Tacrolimus is known to inhibit IL-2, IL-3, IL-4, TNF-α, CD40L, granulocyte-macrophage colony-stimulating factor, and IFN-γ. It also prevents T-cell activation and inhibits follicular helper T cells, which play a key role in IgG4 production.20 Therefore, unlike steroid and azathioprine that interrupt the cell cycle of lymphoid cells and inhibit the production of both B and T cells, tacrolimus might exert its therapeutic effects on IIP mainly by affecting T-cell immune mechanisms.

There are some aspects to consider when interpreting the findings of this study. First, the effect of tacrolimus observed in all three patients could be distinguished from the delayed effects of steroids or azathioprine. There would have been a belated partial effect of prednisolone, but the duration of anti-inflammatory effects of prednisolone is known to be relatively short, at typically 12–36 hours.21 While tapering steroids, all patients showed the aggravation or recurrence of symptoms. The effects of azathioprine are usually expected to occur at 2–3 months after initiating the therapy.22 In patient 3, azathioprine might have been discontinued before the effects fully developed. Thus, the previous immunosuppressive treatments with azathioprine do not necessarily disprove the effect of tacrolimus in our patients.

The second aspect to consider is whether relapsing or refractory IIP can be clearly differentiated from other disorders including IgG4-related diseases, sarcoidosis, lymphoma, or chronic infection such as tuberculosis. The lack of a histological confirmation would not completely exclude these disorders. However, performing a biopsy of a brain lesion is often difficult. Thus, extensive serological and imaging evaluations along with careful monitoring of treatment responses are necessary, and this protocol can lead to a reliable diagnosis of IIP, as shown by the present study.

In summary, tacrolimus can be an alternative option when treating patients with orbital or cranial IIP who exhibit an insufficient response to steroids, need long-term treatments, or have comorbidities restricting the use of other immunosuppressants. Further investigations are necessary to confirm the efficacy of tacrolimus.