Hydroxychloroquine as a Promising Therapy for Systemic IgG4-Related Disease: A Case Report

Introduction

IgG4-related disease (IgG4-RD) is a systemic fibro-inflammatory disease, which can manifest in almost every part of the body [1–3]. Because of the different clinical presentations, IgG4-RD can be challenging to diagnose. It is prone to be misdiagnosed as other inflammatory or malignant diseases. Untreated disease may lead to fibrosis and secondary amyloidosis [4]. Early recognition and treatment are therefore essential.

The pathogenesis of IgG4-RD is not yet fully understood; however, recently evolving knowledge is leading to a better understanding of this disease. Studies suggest a role of the humoral immune system as well as an important role of T cells in the pathogenesis of IgG4-RD [3–5]. Glucocorticoids are usually the first choice of therapy, but the relapse rate after tapering is high [3]. Previously, a small retrospective study of 32 patients analyzed the effect of hydroxychloroquine in 4 patients, with complete response in 2 patients [6]. Here, we describe the successful treatment of a patient with IgG4-related lung disease with hydroxychloroquine.

Case Report

A 70-year-old male patient without relevant medical history was in 2010 referred to the outpatient gastroenterology department because of general discomfort, abdominal pain, and weight loss. Ultrasonography and computed tomography (CT)-scan showed a tumor of the pancreas head without obstruction of the extra-hepatic biliary ducts and without lymphadenopathy or vascular involvement. Histology after a Whipple procedure excluded malignancy. Diagnosis of auto-immune pancreatitis was established and the patient was started on prednisone 40 mg daily. He recovered quickly, the pancreas normalized, blood levels of C-reactive protein (CRP) and serum IgG4 decreased. Then, the prednisone was successfully tapered and quitted (Figure 1). In September 2010, his complaints returned and serum IgG4 increased, after which prednisone 40 mg daily was restarted in combination with azathioprine 50 mg twice daily. However, azathioprine was quitted because of adverse events. Again, there was a good response to prednisone and the dosage was decreased to 5 mg daily. During follow-up, no signs of recurrence were observed. Because of mild pulmonary symptoms and recurrent complaints of abdominal pain, a positron emission tomography (PET)-CT was performed in 2013, which did not show any flare-up of the pancreatitis, but did show multiple lung abnormalities and FDG-positive hilar and mediastinal lymph nodes. There were no signs of malignancy. Follow-up of the lung abnormalities by CT scan revealed no changes over the years. He was not using any medication at that time, but his serum IgG4 increased (Figure 1). In 2017, the patient developed a tumor of the parotid gland which was surgically removed. Histology revealed inflammation and no signs of malignancy.

In February 2018, he experienced progressive coughing. A CT scan showed new, bilateral nodules/patchy consolidations as well as signs of bronchiolitis and pleural enlargement (Figure 2). A bronchoalveolar lavage showed no lymphocytosis in the cell count, no malignancy, and bronchial cultures including tuberculosis were negative. CRP (80 mg/l), serum IgG4 (4.7 g/l), and serum sIL-2R (463 U/ml) were elevated. Lung function showed only minimal restriction with a total lung capacity (TLC) of 70%. The auto-antibodies anti-neutrophil cytoplasmic antibody (ANCA) and anti-nuclear antibody (ANA) were negative. Suspicion of systemic IgG4-RD arose: histology of the parotid gland and pancreas were revised, revealing IgG4-RD (Figure 3). Treatment with high dose prednisone and possibly rituximab were discussed, but the patient declined these treatments. The patient agreed to start with hydroxychloroquine, 200 mg twice daily. Hydroxychloroquine was chosen because of positive effects seen previously in some patients [6]. At follow-up after 6 months, the patient’s symptoms were improved, serum IgG4 was decreased (2.9 g/L), and a new CT scan demonstrated significant improvements (Figure 2). Spirometry, however, did not show improvements in lung function. Methylprednisolone was started in addition to the hydroxychloroquine, but did not improve lung function and was therefore discontinued. Our patient did not develop any hydroxychloroquine-related adverse effects, such as gastrointestinal complaints or retinopathy.

Discussion

Here we present a case of IgG4-related systemic disease with manifestations in the pancreas, salivary gland, and lungs. The patient showed a good response to hydroxychloroquine, which was initiated because of the progression of IgG4-related lung disease. IgG4-RD can affect all parts of the human body, and is often confused with a malignancy [7,8]. In this case, the diagnosis of IgG4-related pancreatitis and IgG4-related salivary gland disease was established by revision of the histology according to the Boston consensus on IgG4-RD [9]. Even though the manifestation of IgG4 in the lungs had not been histologically proven in this patient, IgG4-RD is the most probable diagnosis. There were no signs of malignancy, infections, or ANCA-positive vasculitis. Furthermore, IgG4-related lung disease has previously been described in several reports [10–12].

IgG4-RD is often initially treated with glucocorticoids, but the relapse rate is high [6]. Emerging data show promising results for rituximab in the treatment of IgG4-RD [6,13]. Several disease-modifying anti-rheumatic drugs (DMARDs) such as azathioprine and methotrexate have been used in the treatment of IgG4-RD, but results demonstrating their efficacy are lacking [6]. Previously, in small numbers of patients with IgG4-RD, hydroxychloroquine appeared to induce complete and partial remissions. The exact immunosuppressive effect of hydroxychloroquine is still unknown, but it is thought to reduce lysosomal function and thereby inhibit antigen presentation. This can be effective in diseases with an overactive immune system as in IgG4-RD [14]. Our patient declined high doses of glucocorticoids and rituximab; therefore, hydroxychloroquine was initiated with good clinical response. Hydroxychloroquine is being used for several inflammatory diseases such as sarcoidosis [15]. It is believed that hydroxychloroquine has anti-inflammatory and anti-fibrotic effects [3]. Since IgG4-RD is a fibro-inflammatory disease, it is reasonable to assume that hydroxychloroquine may be a therapeutic option in IgG4-RD as we have seen in previously described cases and the response in our patient.

Conclusions

In conclusion, hydroxychloroquine may be a therapeutic option for IgG4-RD. To get a better view of its efficacy it needs to be studied in larger cohorts.