Interleukin-1 Inhibitors for Management of Recurrent Pericarditis After Thoracic Organ Transplantation

Abstract

There is a growing body of evidence supporting the safety and utility of interleukin-1 inhibitors for treatment of recurrent pericarditis. This therapy has not been investigated specifically as related to postpericardiotomy syndrome or after thoracic organ transplantation. We report on rilonacept use for treatment of recurrent pericarditis in 4 patients after lung or heart transplantation, describing the clinical presentation, infectious complications, and outcomes of these cases. Our single-center experience of this highly comorbid patient population highlights the major considerations of interleukin-1 inhibitor use within these patients, particularly as related to infectious complications and immunosuppression management.

Visual Summary

Visual Summary.

Rilonacept Dosing, Treatment Duration, Infectious Complications, and Follow-Up for 4 Patients After Lung or Heart Transplantation

UTI = urinary tract infection.

Acute pericarditis is defined as inflammation of the pericardium, marked by the presence of pleuritic chest pain with the presence of one or more of the following: pericardial rub, electrocardiographic changes, inflammatory biomarker elevation, and imaging evidence of new or worsening pericardial effusion or pericardial inflammation.^1,2 Of patients with acute pericarditis, 15% to 30% present with recurrence after a symptom-free interval of 4 to 6 weeks.^1,2 While nonsteroidal anti-inflammatory drugs (NSAIDs) and colchicine remain the mainstay of therapy for recurrent pericarditis (RP), corticosteroids may be used for patients with refractory symptoms or specific underlying indications (autoimmune diseases, postpericardiotomy pericarditis, pregnancy).^1,2 Corticosteroid use in refractory cases typically necessitates prolonged tapering, has multiple long-term adverse effects, and is associated with a longer disease course with higher incidence of recurrence.1, 2, 3

Postpericardiotomy syndrome (PPS) presents with symptoms of pericarditis after cardiac surgery and may affect up to 15% of patients after surgery.⁴ PPS is associated with longer hospital stays, readmissions, and a significantly higher risk of recurrent disease.⁴ While current guidelines recommend the use of NSAIDs and colchicine for PPS,¹ NSAIDs are often contraindicated postoperatively, and colchicine may not provide adequate symptom control.

There is a growing body of evidence supporting the efficacy and safety of interleukin (IL)-1 inhibitors for treatment of RP. The IL-1 family of proinflammatory cytokines regulate fever, hyperalgesia, and vasodilation. IL-1ɑ and IL-1β cytokines have been specifically implicated in the pathophysiology of RP.⁵ Randomized controlled trials and registry studies have supported the efficacy and safety of IL-1 inhibitors, particularly anakinra and rilonacept, for the treatment of RP.6, 7, 8 The phase 3, sponsored RHAPSODY trial demonstrated a significant reduction in RP symptoms (6.7% vs 74.2%) with rilonacept versus placebo,⁸ with a durable treatment response at 2 years.⁹ Approximately 15% of patients enrolled in the RHAPSODY trial had post–cardiac injury pericarditis, including PPS. Safety considerations for IL-1 inhibitors include infectious complications, injection-site reactions from subcutaneous administration, and allergic reactions.^5,10

Patients after heart and lung transplantation may present with severe symptoms of PPS and RP, associated with significant morbidity, hospitalizations, and impaired quality of life. IL-1 inhibitors are an effective therapeutic option for RP, although they have not been studied in patients post–thoracic organ transplantation, and they remain of concern in this population given their additive immunosuppressive effects and infectious risk. We report on 4 patients with RP after thoracic organ transplantation treated effectively with rilonacept. We describe the clinical presentation, course, immunosuppression management, and infectious complications of these cases.

Methodology

We describe 4 independent cases of rilonacept use for treatment of RP after thoracic organ transplantation. All patient information was deidentified. Institutional review board approval and patient consents were not obtained, in accordance with institutional policies regarding case reports. RP was defined as a relapse of pericarditis within 4 to 6 weeks after an initial episode of acute pericarditis followed by a symptom-free interval, associated with elevated biomarkers and classic imaging findings.^1,2 Patients with a prior thoracic organ transplantation and a pericardial effusion without other diagnostic criteria for pericarditis were not considered to have pericarditis and were not included in this case report. Clinical response to rilonacept was evaluated as symptom resolution and normalization of biomarkers, with improvement in imaging findings where available.

Patient 1

A 71-year-old man with interstitial lung disease underwent bilateral lung transplant (cytomegalovirus [CMV] donor +, recipient –; Ebstein-Barr virus [EBV] donor +, recipient +), with postoperative course complicated by bilateral pleural effusions requiring thoracentesis and acute rejection requiring corticosteroids. Three months post-transplant, he experienced chest tightness and dyspnea on exertion with elevated b-type natriuretic peptide of 284 pg/mL, normal C-reactive protein (1.3 mg/L) and normal erythrocyte sedimentation rate (3 mm/h). Transthoracic echocardiography (TTE) revealed a moderate-sized, loculated, partially organized pericardial effusion. Pericardiocentesis of 200 mL of serosanguinous drainage revealed reactive histiocytes without evidence of malignancy or infection. He was initiated on colchicine 0.6 mg twice daily as treatment for acute pericarditis, and prednisone was increased to 25 mg daily with a prolonged taper, with resolution of symptoms.

One month later, he reported recurrent dyspnea with C-reactive protein of 45.9 mg/L and erythrocyte sedimentation rate of 34 mm/h. He had bilateral exudative pleural effusions requiring thoracentesis without evidence of rejection or infection. TTE showed a large pericardial effusion for which he underwent repeat pericardiocentesis with bland cytology and cultures, and cardiac magnetic resonance imaging (MRI) revealed mild late gadolinium enhancement (LGE) of the pericardium. He was started on rilonacept 6 months post-transplant, with tacrolimus maintained at 10 to 16 ng/mL, mycophenolate mofetil (MMF) maintained at 250 mg twice daily given a history of neutropenia, and prednisone increased to 20 mg daily with a prolonged taper (Table 1). Quantiferon testing for tuberculosis was negative prior to rilonacept initiation, and his opportunistic infection (OI) prophylaxis was maintained (Table 1).

Table 1.

Immunosuppression, Anti-inflammatory Medications, and Opportunistic Infection Prophylaxis Before and After Rilonacept Treatment

	Medications
	Before Rilonacept	Immediately After Rilonacept	Last Follow-Up
Patient 1
Immunosuppression	Tacrolimus 10-16 ng/mL MMF 250 mg BID Prednisone 12.5 mg daily	Tacrolimus 10-16 ng/mL MMF 250 mg BID Prednisone 5 mg daily	Tacrolimus 10-16 ng/mL MMF 250 mg BID Prednisone 10 mg daily
Anti-inflammatory	Colchicine 0.6 mg daily	Colchicine 0.6 mg daily	Colchicine 0.3 mg daily
OI prophylaxis	Letermovir 480 mg daily TMP-SMX 400-80 mg daily	Letermovir 480 mg daily TMP-SMX 400-80 mg daily	Letermovir 480 mg daily TMP-SMX 400-80 mg 3 times weekly
Patient 2
Immunosuppression	Tacrolimus 8-10 ng/mL MPA acid 180 mg BID Prednisone 5 mg daily	Tacrolimus 8-10 ng/mL MPA 180 mg BID Prednisone 5 mg daily	Tacrolimus 8-10 ng/mL MPA 180 mg BID Prednisone 5 mg daily
Anti-inflammatory	Colchicine 0.6 mg daily	None	None
OI prophylaxis	TMP-SMX 400-80 mg daily	TMP-SMX 400-80 mg daily	TMP-SMX 400-80 mg daily
Patient 3
Immunosuppression	Tacrolimus 8-10 ng/mL MPA 180 mg BID Prednisone 40 mg daily	Tacrolimus 8-10 ng/mL MPA 180 mg BID Prednisone 20 mg daily	Tacrolimus 8-10 ng/mL MPA 180 mg BID Prednisone 5 mg daily
Anti-inflammatory	Colchicine 0.6 mg BID	Colchicine 0.6 mg BID	None
OI prophylaxis	Atovaquone 1,500 mg daily	Atovaquone 1,500 mg daily	Atovaquone 1,500 mg daily Isavuconazonium sulfate 372 mg daily Valganciclovir 450 mg every 48 hours
Patient 4
Immunosuppression	Tacrolimus 10-12 ng/mL MMF 1000 mg BID Prednisone 10 mg daily	Tacrolimus 10-12 ng/mL MMF 500 mg BID Prednisone 10 mg daily	Tacrolimus 4-6 ng/mL Sirolimus 4-6 ng/mL MMF 500 mg BID
Anti-inflammatory	Colchicine 0.6 mg BID	Colchicine 0.6 mg BID	Colchicine 0.3 mg daily
OI prophylaxis	Valganciclovir 900 mg daily TMP-SMX 400-80 mg daily Nystatin 50,000 U QID	Valganciclovir 900 mg daily Atovaquone 1,500 mg daily Nystatin 500,000 U QID	TMP-SMX 400-80 mg daily

BID = twice daily; MMF = mycophenolate mofetil; MPA = mycophenolic acid; OI = opportunistic infection; QID = four times a day; TMP-SMX = trimethoprim-sulfamethoxazole.

One month after rilonacept initiation, he reported improvement in chest tightness and exertional dyspnea. His C-reactive protein was 0.5 mg/L and erythrocyte sedimentation rate was 6 mm/h. By 2 months after rilonacept initiation, colchicine was tapered to 0.3 mg daily and his MMF was increased to 500 mg twice daily as his leukopenia improved, to mitigate rejection risk.

Five months after rilonacept initiation, the patient was admitted for an empyema requiring thoracentesis, with cultures growing Streptococcus oralis and Streptococcus mitis. He required robotic pleurectomy and 6 weeks of intravenous antibiotics. Cardiac MRI and pericardial biopsy at this time did not show active pericardial inflammation or infection. Rilonacept was stopped and MMF was decreased back to 250 mg twice daily, and he has not experienced further infectious complications or RP.

Patient 2

A 67-year-old man with pulmonary sarcoidosis and hypersensitivity pneumonitis underwent bilateral lung transplant (CMV donor +/recipient +, EBV donor +/recipient +) with uncomplicated postoperative course. Eight months post-transplant, he presented with dyspnea on exertion and bilateral ankle edema. He was treated empirically for acute rejection with corticosteroids. TTE demonstrated normal biventricular function and a moderate-sized anterior pericardial effusion without tamponade physiology.

Over the next 2 months, he reported progressive dyspnea and decline in his exercise tolerance, with repeat TTE demonstrating a persistent pericardial effusion. Simultaneous right and left heart catheterization revealed right atrial pressure 13 mm Hg, pulmonary capillary wedge pressure 14 mm Hg, and left ventricular end-diastolic pressure 28 mm Hg, without ventricular discordance. Cardiac MRI revealed no LGE but did demonstrate an early diastolic septal “bounce,” exaggerated respiratory septal variation, with pericardial thickening and adhesions. Given these findings, he was started on colchicine 0.6 mg daily.

Three months later, the patient developed recurrent edema and diarrhea. C-reactive protein was elevated to 45.9 mg/L. TTE demonstrated a new septal bounce, annulus reversus, and elevated right-sided filling pressures, consistent with constrictive pericarditis. Cardiac MRI showed nonspecific, hazy mid-wall LGE, pericardial LGE with mildly increased T1 relaxation times, and no enhanced T2 signal, further suggesting constrictive pericarditis. A repeat right and left heart catheterization demonstrated elevated biventricular filling pressures with diastolic equalization of pressures and ventricular discordance, consistent with constriction.

At this time, the patient was initiated on rilonacept. His immunosuppression remained unchanged, with tacrolimus 8 to 10 ng/mL, mycophenolic acid 180 mg twice daily, and prednisone 5 mg daily (Table 1). Colchicine was discontinued owing to ongoing diarrhea. Quantiferon testing was negative, and his OI prophylaxis was maintained (Table 1). Symptoms resolved within 3 months of rilonacept initiation, with normalization of C-reactive protein. At 8 months after rilonacept initiation, the patient remained without infectious complications or RP. A recent TTE demonstrated some persistent features of constrictive pericarditis (septal bounce with restrictive mitral filling pattern and elevated right atrial pressure, without respiratory variation or annulus reversus), and he is awaiting a repeat cardiac MRI to guide rilonacept wean.

Patient 3

A 44-year-old woman with alpha-1-antitrypsin deficiency and obstructive lung disease underwent bilateral lung transplant (CMV donor +/recipient +, EBV donor +/recipient +). Her post-transplant course was complicated by acute rejection at 1 and 3 months post-transplant, treated with corticosteroids.

Two years after transplant, she presented with dyspnea on exertion, cough, and fever, with initial suspicion for acute rejection, for which she was treated empirically with steroids. At the time, she was on tacrolimus 8 to 10 ng/mL, sirolimus 6 to 8 ng/mL, and prednisone 5 mg daily. Bronchoscopy with biopsies did not show evidence of rejection. TTE showed a moderate-sized pericardial effusion with organization, and pericardiocentesis of 100 mL of serosanguinous drainage demonstrated reactive mesothelial cells with negative cultures and cytology. Mycophenolic acid 180 mg twice daily was started at this time, and sirolimus was discontinued.

Several weeks later, the patient presented with ongoing fevers, dyspnea, and pleuritic chest pain, with C-reactive protein of 306 mg/L and erythrocyte sedimentation rate of 100 mm/h. TTE showed a large pericardial effusion with tamponade physiology, and pericardiocentesis of 600 mL of serous drainage yielded bland cultures and cytology. Cardiac MRI demonstrated pericardial thickening with extensive pericardial LGE and enhanced T2 signal in the pericardium. She was started on colchicine 0.6 mg twice daily with aspirin 650 mg 3 times daily as well as prednisone 40 mg daily. Despite this treatment, she had ongoing symptoms with failure to wean corticosteroids, and she was initiated on rilonacept 4 months later after quantiferon testing was confirmed negative. The remainder of her immunosuppression and OI prophylaxis remained unchanged (Table 1).

After rilonacept initiation, the patient's chest pain improved, C-reactive protein normalized to 2.9, and she did not have any further episodes of pericarditis. Two months later, she was admitted for shortness of breath, with bronchoscopy revealing accelerated bronchiolitis obliterans syndrome, likely secondary to chronic rejection. She received antithymocyte globulin, intravenous corticosteroids and corticosteroids combined with intravenous immunoglobulin, and the rilonacept was held. Over the subsequent months, while symptoms of pericarditis improved, the patient's overall functional status declined with multiple hospitalizations, including one for an Enterococcus faecalis urinary tract infection. The patient died at home 3 years and 6 months after lung transplant and 5 months after initiating rilonacept owing to complications of chronic rejection.

Patient 4

A 48-year-old man with familial cardiomyopathy and HIV underwent heart transplant (CMV donor +/recipient +, EBV donor +/recipient +) with an uncomplicated postoperative course. He was initiated on tacrolimus 10 to 12 ng/mL, MMF 1 g twice daily, and corticosteroids, and continued on antiretroviral therapy for HIV. After a routine right heart catheterization 2 months post-transplant, TTE revealed a large pericardial effusion with tamponade physiology. Pericardiocentesis of 750 mL of serous drainage yielded negative cultures and cytology. He was initiated on colchicine 0.6 mg twice daily, and prednisone was weaned to 10 mg daily, per immunosuppression protocol.

The patient stopped colchicine after 2 weeks, and 3 days after discontinuation presented with dyspnea, chest pain, abdominal pain, and weight gain. Laboratory evaluation revealed B-type natriuretic peptide of 871 pg/mL, erythrocyte sedimentation rate of 6 mm/h, and C-reactive protein of 22.2 mg/dL. TTE showed a recurrent large pericardial effusion with tamponade physiology, and pericardiocentesis of 1.5 L of serous fluid revealed chronic inflammatory cells with negative cultures and cytology. He was started on anakinra 100 mg daily as an inpatient, as this was available for immediate use in the inpatient setting. After hospital discharge, anakinra was switched to rilonacept per patient preference and for ease of administration for a planned 6-month course.

At this time, tacrolimus was maintained at 10 to 12 ng/mL, MMF was decreased to 500 mg twice daily given concern for interaction and added neutropenia risk with rilonacept, and prednisone was maintained at 10 mg daily. Colchicine was decreased to 0.6 mg daily and was eventually weaned to 0.3 mg daily (Table 1). After initiation of rilonacept, the patient was noted to have mild leukopenia, owing to which his trimethoprim-sulfamethoxazole was switched to atovaquone 1,500 mg daily for Pneumocystis jirovecii prophylaxis.

After rilonacept initiation, the patient had no recurrence of symptoms and was able to exercise normally. Rilonacept was stopped after a 6-month course with sustained remission of symptoms and normalization of C-reactive protein to 1.4 mg/L. Over this time period, his tacrolimus goal was weaned to 8 to 10 ng/mL per post-transplant protocol, and MMF was increased back to 1,000 mg twice daily as he neared completion of his rilonacept course. Prednisone was able to be weaned off. Routine TTE 2 months after stopping rilonacept demonstrated preserved biventricular function without pericardial effusion, and colchicine was stopped. The patient remained free of any infectious complications during this time. A routine 1-year post-transplant left heart catheterization revealed ISHLT (International Society for Heart and Lung Transplantation) grade 0, Stanford class IV cardiac allograft vasculopathy, owing to which sirolimus was initiated at 4 to 6 ng/mL and MMF was discontinued. After rilonacept discontinuation, the patient's leukopenia improved, and he was transitioned from atovaquone to trimethoprim-sulfamethoxazole for P jirovecii prophylaxis. His remaining OI prophylaxis was weaned per protocol.

Discussion

To the best of our knowledge, this case series is the first report of IL-1 inhibitor use for RP in the post–thoracic transplant population. RP may be associated with significant morbidity and hospitalizations within the post-transplant population. Many of these patients fail conservative management with NSAIDs or colchicine, and they may be committed to prolonged corticosteroids with associated adverse events. In our experience, IL-1 inhibitor use has been associated with significant symptom improvement and has facilitated weaning patients off these adjunctive therapies. In each of the aforementioned cases, rilonacept was favored over anakinra owing to patient preference and ease of weekly versus daily injections, ready approval for treatment of RP, and the lack of dose-adjustment required for renal dysfunction. Given the ideal duration of IL-1 treatment in RP is not well described, the duration of therapy in each case varied and was guided by individual patient-specific factors, including clinical and imaging-based response to RP therapy as well as associated infectious or post-transplant rejection complications.

There remain a paucity of data on immunosuppression management in conjunction with an IL-1 inhibitor in the post-transplant population. While 15% of patients in the RHAPSODY trial had post–cardiac injury pericarditis, none of these patients had undergone thoracic organ transplantation, and patients on concomitant immunosuppression were excluded from the trial. In our series, baseline immunosuppression for solid organ transplantation was adjusted in 2 patients with rilonacept initiation: MMF dose reduction preceding rilonacept initiation in patient 1 owing to concern for neutropenia, and tacrolimus dose reduction with MMF dose increase in patient 4 (Table 1). Given the concern for blunted response to infectious insults with IL-1 inhibitors, it seems logical to reduce the dosage of antiproliferative agents that may inhibit leukocyte proliferation. Both IL-1 inhibitors and antiproliferative agents are associated with neutropenia, further supporting dose adjustment when used in conjunction.¹⁰ We recommend absolute neutrophil count monitoring immediately before and 2 weeks after rilonacept initiation to monitor for neutropenia and considering dose-adjustment of antiproliferatives in these instances.

IL-1 inhibitors may mask fever and leukocytosis, leading to delayed recognition of infection.¹⁰ Infectious complications were observed in 2 patient cases: patient 1 developed a Streptococcus empyema 5 months after rilonacept initiation, coinciding with an escalation in MMF dose, and patient 3 developed an Enterococcus urinary tract infection 4 months after rilonacept initiation, coinciding with administration of antithymocyte globulin and high-dose corticosteroids. It remains unclear to what extent rilonacept initiation versus immunosuppression escalation contributed to infection in these cases, though certainly the dramatic escalation of immunosuppression in patient 3 for treatment of rejection significantly increased this patient's risk. Whether rilonacept was associated with delayed recognition of infection or more severe sepsis in these cases also remains unknown. The current literature on IL-1 inhibitors primarily describes risk of upper respiratory and skin infections, particularly at the site of administration, which were not observed in our experience.⁵

More data are needed to guide the appropriate duration of IL-1 therapy necessary to achieve sustained remission of symptoms, as well as possible tapering protocols.⁵ Current research suggests that rilonacept should be used for a minimum of 6 to 8 months,⁵ with results from the RHAPSODY extension study demonstrating a sustained response at 2 years.⁹ One patient in our experience (patient 4) completed therapy after a prespecified 6-month course and has demonstrated sustained treatment response at 14 months. The remainder of our patients were maintained on IL-1 inhibitors for a mean of 6 months, with sustained response at a mean of 12 months. It is challenging to discern whether rilonacept use meaningfully reduced steroid exposure within this cohort (Table 1). IL-1 inhibitors are used as a steroid-sparing treatment in the management of RP, and given our clinical concern that these patients required long-term therapy, they were initiated on IL-1 inhibitors to mitigate long-term steroid exposure. Patient 3 was able to be weaned from high-dose prednisone to low doses over the follow-up period but intermittently received higher doses of steroids for management of rejection. Patient 4 was weaned off corticosteroids entirely within the follow-up period, in accordance with standard post-transplant protocol. Given the significant adverse effects associated with corticosteroid use in both post-transplant patients and RP patients, we believe IL-1 inhibitor use can help reduce steroid exposure meaningfully in this cohort.

It is important to highlight that our experience remains anecdotal, and while our work is meant to be hypothesis generating, it has notable limitations. Our experience is limited by significant selection bias given the small cohort size within a single center. These patients were maintained on varying degrees of immunosuppression and OI prophylaxis, all of which meaningfully affect their treatment course for RP with rilonacept, and which were not standardized. Moreover, patients were not followed with a standardized imaging schedule or objective measures of symptom change, all of which could further formalize and inform protocols for rilonacept use in similarly high-risk patient populations in the future.

Conclusions

The incorporation of IL-1 inhibitors into the treatment armamentarium for RP has led to sustained symptom remission, improved quality of life, and an ability to safely taper off corticosteroids. These agents have not previously been evaluated for PPS and particularly not in the thoracic organ transplantation population. We have successfully used rilonacept for RP within patients who underwent heart and lung transplantation on triple immunosuppression. These patients demonstrated rapid and effective treatment response to IL-1 inhibitors, with infectious complications observed in 2 instances (Table 1). Our preliminary single-center experience suggests that IL-1 inhibitors may be safe, effective therapies in a carefully selected group of patients who undergo thoracic organ transplantation and develop RP. Further studies are needed to confirm the safety profile of these agents within this population as well as immunosuppression interactions.

Funding Support and Author Disclosures

Dr Garshick has received consulting fees from Argenx, Agepha, BMS, Novo Nordisk, and Kiniksa. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Take-Home Messages

• •Recurrent pericarditis is a source of significant morbidity, and management of this disease remains particularly challenging in the post–thoracic organ transplant population. There are increasing data on the safety and efficacy of rilonacept, an interleukin-1 inhibitor, for management of recurrent pericarditis.
• •Rilonacept use may be effective for treatment of pericarditis in the post–thoracic organ transplant population and involves careful monitoring for immunosuppression interactions and infectious complications.