Treatment-resistant cough: a rare manifestation of IgG4-related disease involving the larynx

Abstract

IgG4-related autoimmune diseases (IgG4 RD) are a relatively recently recognised group of disease processes that can affect multiple organ systems and result in protean symptoms. Here, we present a rare case of a 69-year-old man with a history of IgG4 RD affecting his lacrimal gland and pancreas who developed symptoms of severe laryngitis not responsive to usual therapy. He presented with non-productive cough, hoarseness and dyspnoea. Imaging findings suggestive of aortitis and laryngeal inflammation in the setting of his IgG4 RD history prompted treatment with rituximab, which resulted in resolution of his laryngeal symptoms. Subsequently, his cough returned and he required periodic rituximab infusions to stay symptom-free. IgG4 RD of the larynx is an uncommonly reported manifestation in literature. This disease is very responsive to anti-CD20 monoclonal antibody treatment. IgG4 RD should be considered in patients with airway symptoms that are especially refractory to usual therapy.

Background

IgG4-related autoimmune diseases (IgG4 RD) are a relatively recently recognised group of disease processes that share similar histological findings yet have a protean presentation based on which organ system they affect.

There is limited epidemiological information about IgG4 RD. By some estimates, IgG4 RD may affect at least 1:100 000 people with a slight predominance in older men. As conditions previously considered to be individual diseases, such as autoimmune pancreatitis or Riedel’s thyroiditis, are now recognised as a manifestation of IgG4 RD, these numbers are bound to increase in the coming years. Currently, four main phenotypes of IgG4 RD are recognised, including pancreatic hepatobiliary disease, retroperitoneal fibrosis and/or aortitis, head and neck limited disease and Mikulicz syndrome/systemic involvement.¹

Typically, in IgG4 RD, a preponderance of IgG4 antibodies are noted in the serum; however, this feature is not always present nor is it specific to IgG4 RD. Emerging data suggests that elevated serum IgG4 antibodies are likely a downstream manifestation of the underlying immunological process. One of the theories explaining IgG4 RD postulates that B cells with continuous antigen presentation keep CD4 cytotoxic T cells active, resulting in the creation of IgG4 plasma cells. These plasma cells release IgG4 antibodies in the affected organ, resulting in the hallmark findings of the disease.²

Diagnosis of IgG4 RD is based on tissue biopsy. Characteristic findings include a lymphoplasmacytic tissue infiltrate with a high concentration of IgG4 plasma cells, evidence of storiform fibrosis, increased eosinophils or obliterative phlebitis. Not all of these histological findings are present in every IgG4 RD phenotype. Lacrimal gland disease usually has an absence of storiform fibrosis and obliterative phlebitis.³ A hallmark feature of IgG4 RD is a response to glucocorticoid therapy. Rituximab, an anti-CD20 monoclonal antibody that induces B-cell depletion, has shown promise in the treatment of IgG4 RD.²

Early detection and treatment of IgG4 RD may result in decreased disease burden and improved quality of life. Thus, it is imperative that clinicians gain familiarity with this disease entity and its myriad of potential manifestations. Here, we report an unusual presentation of IgG4 RD manifesting as laryngitis with concomitant aortitis.

Case presentation

Our patient is a 69-year-old Hispanic man, who retired from the US Army as a mechanic, with a medical history notable for multivessel coronary artery disease, lacunar cerebrovascular accident, hypertension, hyperlipidemia, benign prostatic hyperplasia and IgG4 RD. He initially presented with lacrimal gland hyperplasia in 2011, which was biopsied and diagnosed as chronic dacryoadenitis. This was attributed to localised Castleman disease, and he was started on therapy with hydroxychloroquine for a brief period of time. In 2013, he presented with pancreatitis. An absence of traditional risk factors for pancreatitis prompted a thorough investigation for the aetiology, including re-examination of the previous lacrimal gland tissue biopsy. Specialised histochemical testing of that lymphoid tissue led to the diagnosis of IgG4 RD (figure 1). He was subsequently followed by rheumatology with intermittent positron emission tomography (PET) scans to evaluate for disease recurrence.

Figure 1.

Lacrimal gland fibrosis.

In 2015, the patient presented to his primary care physician with complaints of a chronic non-productive cough and hoarseness. He was treated empirically with usual therapy, including a short course of azithromycin, as-needed albuterol inhaler, histamine-2 receptor antagonist (H-2 blocker) and a proton pump inhibitor (PPI). However, his cough persisted and he developed new dyspnoea and wheezing, thus prompting a referral to pulmonology.

Pulmonary function testing did not reveal any obvious abnormality. A laryngoscopy was performed, which showed gross inflammation of the epiglottis and vocal cord dysfunction (VCD) suggestive of laryngopharyngeal reflux. He was started on high-dose PPI therapy in addition to an H-2 blocker and sucralfate. However, his dyspnoea continued to worsen, resulting in inpatient admission.

Investigations

On admission, a chest X-ray was performed, which showed no acute cardiopulmonary process. Routine laboratory evaluation was notable for a C reactive protein of 1.2 mg/dL (0.04–0.5 mg/dL) and erythrocyte sedimentation rate of 105 mm/hour (0–20 mm/hour). No significant peripheral eosinophilia was noted with an absolute eosinophil count of 0.3×10³/μL (0.0–0.4×10³/μL). Review of additional laboratory work obtained 1 month prior to admission revealed a normal IgG4 level of 29 mg/dL (1–291 mg/dL) and an elevated IgE level of 611 IU/mL (0–100 IU/mL). There were no abnormalities on esophagogastroduodenoscopy (EGD). PET scan showed increased metabolic activity in multiple lymph nodes, thoracic aorta and larynx (figure 2).

Figure 2.

Positron emission tomography scan showing aortitis.

Differential diagnosis

The patient initially presented with a chronic cough, a condition commonly encountered by primary care physicians. He was not on any medications to which his symptoms were likely attributable. Empiric treatment for common causes of chronic cough, including gastro-oesophageal reflux disease, postnasal drip, bronchitis and medication side effects failed to relieve his symptoms. He was therefore referred to pulmonology for additional evaluation, in part due to the development of dyspnoea. VCD due to laryngopharyngeal reflux was considered as the aetiology of his cough and hoarseness, based on laryngoscopy findings. However, his symptoms did not improve with maximum acid suppression therapy. After EGD did not identify an underlying aetiology, there was concern that he either had an idiopathic chronic cough or an unusual manifestation of his known autoimmune disease. The latter process was deemed most likely after a PET scan showed increased uptake in the larynx and thoracic aorta, confirming ongoing inflammation consistent with an exacerbation of his IgG4 RD.

Treatment

Due to the significant complications that can result from untreated aortitis, which include retroperitoneal fibrosis and aneurysm formation, the decision was made to treat the patient empirically for probable exacerbation of IgG4 RD. He initially received 40 mg of prednisone per day for a 2-week course. He noted some improvement in his cough, but endorsed persistent dyspnoea and some wheezing. This prompted treatment with two infusions of 1 g of intravenous rituximab over a period of 2 weeks, which resulted in complete resolution of symptoms.

Outcome and follow-up

The patient’s cough, dyspnoea and hoarseness resolved completely with rituximab therapy. A repeat laryngoscopy was performed, which confirmed complete resolution of the inflammation. Subsequently, he was followed longitudinally by rheumatology with an 8-month post-treatment PET scan showing resolution of the aortitis (figure 3). When he developed recurrence of his cough 1.5 years later, a decision was made to re-treat him with one dose per 2 weeks of rituximab. Once again, he achieved symptom resolution. Thus, he was placed on scheduled rituximab to maintain remission. He is currently receiving a rituximab infusion every 6 months, with no recurrence of symptoms.

Figure 3.

Post rituximab treatment positron emission tomography scan showing resolution.

Discussion

IgG4 RD with laryngeal involvement is a very uncommon manifestation of this disease process, with less than 10 reported cases in literature. Of these reported cases, symptoms varied among patients but the symptoms of hoarseness, cough, dysphagia and throat discomfort were present in most cases.⁴

Our patient, who had known IgG4 RD based on his prior lacrimal gland biopsy presented with cough and hoarseness that progressed to dyspnoea. Complement and gammaglobulin levels, both of which may be abnormal in IgG4 RD, were unfortunately not obtained on admission. However, in addition to elevated inflammatory markers at presentation, he had a documented recent elevation in serum IgE level, consistent with IgG4 RD. Although his IgG4 level was within normal limits at that time, IgG4 levels do not necessarily correspond to IgG4 RD or disease activity and had historically fluctuated in this patient.⁵ We chose to empirically treat our patient prior to the establishment of a definitive diagnosis, which would have required a tissue sample. This was done in part due to the significant morbidity associated with untreated aortitis, which was evident on his PET scan. The rapid improvement of symptoms and resolution of laryngeal inflammation with anti-CD20 monoclonal antibody therapy is highly indicative that IgG4 RD was responsible for his clinical presentation.

Currently, no guidelines exist regarding long-term treatment options for IgG4 RD. Although patients may have symptomatic improvement with systemic glucocorticoids, relapse is common and prolonged glucocorticoid therapy is fraught with many potential adverse effects. Flow cytometry testing to directly determine the concentration of plasmablasts, immature plasma cells that may play a regulatory role in IgG4 RD, has shown promise as a method to monitor disease activity and recurrence.⁵ Thus, using this technique may be a way to help guide management and minimise unnecessary immunosuppression in the future. Rituximab, a B-cell depleting anti-CD20 monoclonal antibody, has also shown promise as a steroid-sparing agent for managing this disease.⁶ Our patient achieved sustained remission with rituximab therapy administered every 6 months.

IgG4 RD of the larynx is uncommon; however, it should be considered in patients who present with upper airway symptoms that are refractory to usual therapy, particularly in patients with a known history of the disease.

Patient’s perspective.

This condition can be subtle in nature and deceiving in presentation. Due to its ability to represent itself as being a common bodily ailment, close attention to symptoms is needed for accurate diagnosis. For me, the most successful treatment was rituximab infusions. At the present time, I have remained free of any recurrences that are associated with this condition.

Learning points.

• IgG4-related autoimmune diseases (IgG4 RD) is a protean disease process unified by common histological findings on biopsy.

• Four main phenotypes of IgG4 RD are currently recognised, which include pancreatic hepatobiliary disease, retroperitoneal fibrosis and/or aortitis, head and neck limited disease and Mikulicz syndrome/systemic involvement.

• Laryngeal involvement is an uncommon manifestation of IgG4 RD; however, it should be suspected in patients with IgG4 RD who have refractory upper airway symptoms.

• IgG4 RD is very responsive to anti-CD20 monoclonal antibody therapy.