Adult-Onset Asthma with Periocular Xanthogranuloma (AAPOX)
Adult-onset asthma with periocular xanthogranuloma (AAPOX) is a rare non-Langerhans cell class II histiocytosis that was first described in 1993 . It is considered one of the four subtypes of adult orbital xanthogranulomatous diseases (AOXGDs), which include adult onset xanthogranuloma (AOX), adult-onset asthma with periocular xanthogranuloma (AAPOX), Erdheim-Chester disease (ECD), and necrobiotic xanthogranuloma (NBX). These disease entities are characterized by subcutaneous, subconjunctival, and periocular locally invasive xanthogranulomatous inflammatory lesions. [2,3]
AAPOX uniquely presents with adult-onset asthma, lymphadenopathy and periocular xanthogranulomatous disease. The periocular lesions are typically yellowish xanthomatous plaques that are often painless and slow growing, with reports of both unilateral and bilateral findings. [4,5] Depending on the depth and extent of the lesions, associated clinical exam findings may include periorbital swelling, diplopia, exophthalmos, blepharoptosis, and extraocular motility limitations. [6,7] Imaging (such as orbital CT or MR scan) is typically utilized to assess the extent and involvement of the lesions.
The defining feature of this condition is the association of the above findings with adult-onset asthma. In most cases, patients develop mild to severe asthma within months to a few years after the onset of periocular symptoms, although asthma has also been shown to precede orbital symptoms by up to 9 years. [2,5,8]
While the exact etiology of AAPOX is unknown, an atopic etiology has been proposed with associations having been demonstrated with chronic rhinosinusitis, sinonasal polyposis, elevated serum IgE, and eosinophilic infiltration of affected periorbital tissue. [1,2,4] Additionally, AAPOX has been frequently associated with elevated serum polyclonal IgG, benign reactive lymphadenopathy, paraproteinemia, and rarely other lymphoproliferative disorders (which may imply B-cell involvement in disease pathogenesis). [4,8,9]
Over the years, an association between AAPOX and IgG4-related disease (IgG4-RD) has been established, with evidence that they may be on the same disease spectrum. Like AAPOX, IgG4-RD shows associations with atopic manifestation in addition to elevated IgG levels and lymphadenopathy. [8-11] One study demonstrated that fluorodeoxyglucose PET/CT imaging in AAPOX patients can also show increased avidity within organs usually effected by IgG4-RD (lacrimal glands, lymph nodes, and peri-rectal fat).  Additionally, at least 15 cases of AAPOX associated with elevated IgG4 have been reported, with 5 of these patients having had a history of autoimmune pancreatitis, which can be a systemic manifestation of IgG4-RD. [8,12,13] Furthermore, IgG4-positive plasma cells have been present on orbital biopsies in many patients with AOXGD including those with AAPOX. [8,14] A recent study by McKelvie et al showed that eyelid involvement in systemic IgG4-RD was rare and that while some AOXGD cases showed IgG4 levels meeting criteria for IgG4-RD, they were significantly lower than in patients with true IgG4-RD. 
AAPOX lesions appear histologically similar to other AOXGDs, demonstrating sheets of mononuclear xanthoma cells (foamy histiocytes), Touton giant cells, and variable lymphoid infiltration. On immunohistochemistry, these foamy histiocytes are typically positive for CD68, CD163, and factor XIIa, but negative for CD21, CD35, S100, and CD1a and lack Birkbeck granules.  Lymphocytes in AOXGDs are typically seen in two general patterns: lymphoid aggregates with typical B cell-containing germinal centers (most common in AAPOX) and diffuse lymphocytic infiltrate (CD8+ T cell predominate) admixed with proliferating fibroblasts (most common in ECD). 
To date, there have been no formal diagnostic criteria established for AAPOX. Diagnosis is typically reliant on biopsy demonstrating the histological findings referenced above, along with the appropriate exam findings and a clinical history of adult-onset asthma.
Laboratory evaluation demonstrating elevated serum IgE, or elevated serum polyclonal IgG may also raise suspicion for this diagnosis. If there is a high suspicion for the condition, further work-up for an associated paraproteinemia or other lymphoproliferative disorder can be considered.
Given the common clinical and histopathological features, other AOXGDs (AOX, NBX, and ECD) should be considered as differential diagnoses.
AOX is the rarest of these four entities and is characterized by isolated pre-septal, and anterior orbital lesions that can sometimes be self-limited. 
ECD typically has the most tenuous clinical course and is most clinically dissimilar to the other AOXGDs. While ECD does not commonly present with ocular symptoms, it can present with xanthogranulomatous eyelid lesions. [2,3] Furthermore, ECD is associated with significant morbidity due to associated long bone osteosclerosis, central diabetes insipidus, retroperitoneal infiltration causing possible renal dysfunction, cardiac involvement, and interstitial lung disease. [2,5,16]
NBX is the most frequently reported AOXGD.  Clinically, it presents with yellow-orange or reddish-brown indurated nodules and plaques that, over time, can begin to ulcerate and fibrose leading to local tissue destruction.  These lesions are most frequently seen in the periorbital region and anterior orbit (60-80%), but can involve multiple sites including the trunk, face, arms, and legs. [4,17] This condition is highly associated with the development of paraproteinemia (80% of patients) as well as multiple myeloma, B cell lymphoma, chronic lymphocytic leukemia, and other lymphoproliferative disorders. 
As mentioned previously, AAPOX has been shown to be associated with IgG4-RD and may be part of a common disease spectrum, so the latter should also be considered on the differential. IgG4-RD is a systemic fibrosing autoimmune disorder associated with raised serum IgG4 levels and histological IgG4-positive plasma cell infiltration. It has been shown to cause a wide range of systemic diseases including autoimmune pancreatitis, sclerosing cholangitis, and retroperitoneal fibrosis, among others.  It can also cause ophthalmic disease such as chronic lid swelling, orbital inflammatory disease (dacryoadenitis, orbital myositis), scleritis, and nasolacrimal duct obstruction. [2,5,18, 19]
Other conditions to consider include xanthelasma, normo-lipemic plane xanthomas, juvenile xanthogranuloma, and periorbital syringomas.
Because of the rarity of this disease, there have been no randomized control trials to date studying the efficacy of various treatments for AAPOX. The current recommendations are limited to evidence from existing case reports/series of AAPOX and other AOXGDs.
In some patients, intralesional corticosteroid treatment for periorbital xanthogranulomas has been shown to be effective. [2,5] A study by Elner et al. showed that periocular triamcinolone injection alone led to improvement in lid lesions as well as improvement in some cases of diplopia in AOX and NBX.  However, it has also proven to be ineffective for substantial symptom control in other patients.  There seems to be a paucity of reports related to AAPOX specifically, though its efficacy is likely to show mixed results.
Systemic steroids have also been shown to be somewhat effective in the treatment of AAPOX. While there are reports of sustained regression with low dose steroid treatment, there are many cases of disease recurrence with cessation of oral steroids. [2,5,6] Because of the numerous reports of treatment failure with oral steroid discontinuation, it is likely that long-term low dose steroid therapy may be necessary to maintain disease remission for some patients. These doses have been shown to be associated with only minimal systemic adverse effects in these patients. [2,5,6]
Antimetabolite agents and other immune modulators have also been trialed in the treatment of this condition. In particular, maintenance low-dose methotrexate and azathioprine have been used to successfully achieve disease remission in AOXGDs including AAPOX. [4,12,17,22-25] The addition of other immunosuppressive agents, such as cyclophosphamide and cyclosporin, have also shown efficacy in patients with this disease and it has been suggested that their respective B-cell and T-cell suppressive effects could be used to tailor treatments based on histopathological lymphocyte characteristics.  Rituximab has also shown to have a durable response in patients with AAPOX due to the likely B-cell driven pathophysiology, though it remains unclear whether histological evidence of strongly positive CD20+ lymphocytes is necessary for successful treatment. 
Finally, radiotherapy has also been successfully employed, mostly as an adjunctive treatment, in patients with AOXGDs. It has shown some variable yet promising results in patients with NBX and ECD, but reports are very limited specifically for AAPOX and AOX and show mixed results. [4,19,25]
Medical follow up
Periodic hematologic monitoring with complete blood counts, inflammatory markers, and serum protein electrophoresis should be considered given the potential risk of associated lymphoproliferative disorders. Attention should also be made to the development of other systemic diseases that may suggest an alternative diagnosis.
Surgical debulking can be a reasonable treatment in patients with visual axis obstruction or discomfort who have shown inadequate improvement with initial medical treatment alone.4 However, surgical treatment does not treat the underlying disease process, and symptoms have been shown to frequently recur anywhere from 6 months to up to 9 years later. [5,26]
The diagnosis of AAPOX generally portends favorable prognosis with morbidity stemming from concomitant asthma or potential associations with lymphoproliferative disorders. Correctly diagnosing an AOXGD is critical as their orbital manifestations are often intraconal and can include diffuse, apical, or even intracranial tissue infiltration, potentially leading to vision-threatening complications.  Differentiation of this condition from the other AOXGDs and IgG4-RD, utilizing pre-existing IgG4-RD diagnostic criteria, is also important in overall prognostication.
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