Immunoglobulin G4-related Dacryoadenitis Successfully Treated with Baricitinib

Abstract

A 48-year-old woman visited our hospital because of bilateral lacrimal gland enlargement. Her serum immunoglobulin G4 (IgG4) level was high, and positron emission tomography-computed tomography showed significant positive findings in the bilateral lacrimal gland. A biopsy revealed a considerable increase in IgG4/CD138, leading to a diagnosis of IgG4-related dacryoadenitis. The disease did not respond to steroid therapy, so treatment was started with baricitinib because of exacerbation of the original atopic dermatitis and dacryoadenitis after the second dose of the coronavirus disease 2019 (COVID-19) vaccine. Baricitinib was effective for resolving both dermatitis and dacryoadenitis, and steroids were able to be discontinued. The IgG4 level also improved.

Introduction

IgG4-related dacryoadenitis has been reported as a major lacrimal gland complication of IgG4-related diseases (RD). Treatment has been attempted with steroid therapy and surgical treatment in steroid-resistant patients, but an adequate treatment approach has not yet been established (1,2). Although the cause of IgG4-RD remains unknown, it has been suggested that it is related to allergic diseases, as patients with IgG4-RD often suffer from allergic diseases, such as asthma, rhinosinusitis, and atopic dermatitis (3).

We herein report a case of steroid-resistant IgG4-related dacryoadenitis that improved after treatment with baricitinib for the patient's existing atopic dermatitis.

Case Report

A 48-year-old woman presented to our hospital with bilateral lacrimal gland enlargement (Fig. 1a). Positron emission tomography-computed tomography showed significant positive findings in the bilateral lacrimal glands (Fig. 2a-2d), and the affected area was biopsied. Inflammatory cell infiltrate was confirmed not only on the outside of the lymph follicle-like structures but also in the lacrimal gland tissue. Many IgG4-positive plasma cells were observed, and more than 70% of CD138-positive plasma cells were also positive for IgG4 (Fig. 3a-3d). The serum IgG4 level was 300 mg/dL (normal range, <135 mg/dL). IgG4-related dacryoadenitis was diagnosed, and the patient was observed without treatment.

Figure 1.

Photographs of the eyelid. a: Puffiness of the eyelid, predominantly on the left, as seen in a 48-year-old woman. b: Eyelid puffiness was increased four years after the diagnosis of IgG4-related dacryoadenitis (52 years old). c: Eyelid puffiness was increased again after the second dose of the COVID-19 vaccine. d: Eyelids normalized with baricitinib treatment.

Figure 2.

Positron emission tomography-computed tomography. a-d: Positron emission tomography-computed tomography showed significant positive findings in the bilateral lacrimal glands, mainly on the left. Arrows indicate an immunoglobulin G4-associated inflammatory mass.

Figure 3.

A biopsy of the lacrimal gland. a: Lymph follicle-like structures were observed within the lacrimal gland tissue (Hematoxylin and Eosin staining, original magnification ×40). b: CD-138 immunostaining showed CD138-positive plasma cells not only on the outside of the lymph follicle-like structures but also in the lacrimal gland tissue (original magnification ×40). c: More than 70% of CD138-positive plasma cells were immunoglobulin G4-positive (original magnification ×40). d: Enlarged image of (c) (original magnification ×200).

However, four years later, lacrimal gland enlargement developed, and visual impairment was noted (Fig. 1b). The IgG4 levels rose to 1,050 mg/dL, so prednisolone (PSL) was started at 20 mg/day. The lacrimal glands decreased in size, and 5 years later, the serum IgG4 level was 195 mg/dL at a PSL dose of 5 mg/day.

However, after the second dose of the Pfizer-BioNTech coronavirus disease 2019 (COVID-19) vaccine, the patient's preexisting atopic dermatitis worsened, and the lacrimal glands became enlarged again (Fig. 1c), with the IgG4 level rising to 369 mg/dL. The PSL dose was increased to 10 mg/day because the patient did not want to increase the dose to 20 mg at the first dose due to significant moon face and weight gain problems. However, the drug was not effective. Therefore, baricitinib was started at a dose of 4 mg/day.

Lacrimal gland enlargement and atopic dermatitis improved considerably, so PSL was discontinued. Even 1 year after the discontinuation of PSL, the IgG4 level was only 145 mg/dL, and the lacrimal glands were not enlarged (Fig. 1d).

Discussion

Baricitinib is an inhibitor of JAK1 and JAK2 in the Janus kinase (JAK) family of nonreceptor tyrosine kinases; it is indicated for use in patients with rheumatoid arthritis who are resistant to other drug treatments and is also effective in the treatment of atopic dermatitis (4).

Recently, many cases of exacerbation of rheumatic diseases and renal disease have been reported following COVID-19 vaccination. The mechanism underlying this exacerbation of rheumatic diseases, including IgG4-related diseases, after vaccine administration is not fully understood. However, the following mechanisms can be inferred, based on a review of previous reports: many cases have developed or recurred in patients with underlying diseases originally involving immune abnormalities, characterized by a high incidence of onset after the second vaccine administration. This indicates that atopic dermatitis and IgG4-related dacryoadenitis are diseases associated with immune abnormalities. The increased immunogenicity produced by this vaccine leads to treatment against COVID-19 viruses but can also lead to unexpected and perhaps nonspecific immune activation. It is likely that this underlying immune dysregulation is a risk factor for the development of atopic dermatitis or exacerbation of IgG4-related dacryoadenitis (5).

In the present case, vaccination resulted in exacerbation of atopic dermatitis even though the patient was being treated with a steroid. Administration of baricitinib led to improvement of not only the dermatitis but also the IgG4-related lacrimal gland inflammation.

IgG4-RD appears to involve some of the same pathogenic mechanisms observed in allergic disease, such as T helper 2 (Th2) and regulatory T-cell (Treg) activation, IgG4 and IgE hypersecretion, and blood/tissue eosinophilia. In addition, IgG4-RD tissue fibrosis appears to involve activation of basophils and mast cells and their consequent release of alarmins and cytokines (6).

Baricitinib (Olumiant^Ⓡ) is an oral small-molecule inhibitor of JAK1 and JAK2 and exerts anti-inflammatory effects by reducing the expression of proinflammatory cytokines, including interleukin (IL)-6, IL-12, IL-17, IL-22, and IL-23 and interferon-gamma, which have been implicated in the pathogenesis of allergic diseases, including atopic dermatitis (7). Baricitinib has been shown to be a potential treatment for IgG4-related diseases that do not respond well to steroid therapy, and these findings are supported by animal studies (8).

Kanda et al. noted that IgG4-RD is closely related to allergic diseases and reported that the antiallergic drug dupilumab was effective for IgG4-RD (9). JAK inhibitors other than baricitinib, which targets JAK1 and JAK2, may also be effective against IgG4-RD, and the potential clinical applications of these agents are promising.

Patients with IgG4-RD appear to be at an increased risk for cancer overall, especially pancreatic cancer and lymphoma. However, there is also concern that JAK inhibitors may be promoters for cancer patients. These issues need to be carefully discussed when JAK inhibitors are implemented in the treatment of IgG4-RD in the future (10).

We herein report the first clinical case of IgG4-related dacryoadenitis successfully treated by baricitinib.

The present report conforms with the Declaration of Helsinki, and the patient gave her informed consent for the case report to be published.

The authors state that they have no Conflict of Interest (COI).