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Abstract

  1. Top of page
  2. Abstract
  3. CASE REPORTS
  4. DISCUSSION
  5. AUTHOR CONTRIBUTIONS
  6. REFERENCES

Recurrent pericarditis occurs in association with various medical conditions, but in most cases the condition appears to be idiopathic. Although high-dose steroid treatment is often effective, it may have serious side effects. Herein we describe 3 children with recurrent pericarditis who were treated at our hospital, during flares, with the interleukin-1β receptor antagonist anakinra, with immediate response. Pericarditis recurred when anakinra treatment was discontinued, and no further episodes occurred after it was resumed. Idiopathic recurrent pericarditis shares several features with autoinflammatory diseases, and anakinra has been efficacious in the treatment of the latter diseases. The findings in these patients suggest that idiopathic recurrent pericarditis may be a previously unrecognized autoinflammatory disease.

Recurrent pericarditis may be a clinical manifestation of various conditions, including rheumatic diseases, familial Mediterranean fever, and infections. However, in most instances recurrent pericarditis appears to be idiopathic, and the etiology of the initial episode, as well as the triggering cause of recurrences, remain unknown.

Clinical symptoms of recurrent pericarditis are characteristic of pericardial disease and include precordial pain, pericardial friction rub, electrocardiographic (EKG) abnormalities, fever, elevated C-reactive protein (CRP) level, and elevated erythrocyte sedimentation rate (ESR); in general, the index attack is the most severe, and subsequent episodes are milder. The number of recurrences and the intervals between episodes vary among patients. The optimal regimen for preventing recurrences has not been established; treatment modalities include nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids, colchicine, immunosuppressive agents, and pericardiectomy (1). Long-term prognosis of recurrent pericarditis is generally good (2, 3); however, in patients with frequent relapses, quality of life may be severely affected, and side effects of steroid treatment may be a concern. Herein we describe 3 children with idiopathic recurrent pericarditis in whom anakinra showed dramatic therapeutic efficacy.

CASE REPORTS

  1. Top of page
  2. Abstract
  3. CASE REPORTS
  4. DISCUSSION
  5. AUTHOR CONTRIBUTIONS
  6. REFERENCES

The 3 patients described below represent all consecutive cases of idiopathic recurrent pericarditis observed at our institution between April 2005 and February 2008. None of them exhibited signs or symptoms consistent with a chronic rheumatic disease. Findings of serologic investigations for antinuclear antibodies, anti–double-stranded DNA antibodies, and rheumatoid factor were negative. An infectious etiology was excluded by means of intradermal skin testing (Mantoux method) and serologic testing for the bacterial and viral agents most commonly responsible for pericarditis in children (Streptococcus, Epstein-Barr virus, Mycoplasma, coxsackievirus, adenovirus). Sequencing of the coding regions of the MEFV gene (exons 1–10) did not reveal the presence of any mutation in any of the patients, and none of them experienced periodic episodes of fever or other clinical manifestations consistent with familial Mediterranean fever. Concomitant autoimmune diseases (systemic lupus erythematosus, systemic-onset juvenile idiopathic arthritis) and metabolic conditions (renal failure, hypothyroidism) and all other possible causes of recurrent pericarditis were ruled out. No family history of recurrent pericarditis or recurrent fever episodes was reported.

Recurrence of pericarditis was defined on the basis of “pericardial” pain and one or more of the following signs: fever, pericardial friction rub, EKG changes, echocardiographic evidence of pericardial effusion, and elevated white blood cell count, CRP level, or ESR (3). Informed consent was obtained from parents and patients.

Patient 1.

Patient 1 was born in 1993 to unrelated parents. In March 2007, she was hospitalized elsewhere for the presence of a pericardial effusion. She was treated with prednisone (initially at 0.7 mg/kg/day), which was subsequently tapered and discontinued. In August 2007, she became dyspneic and was again hospitalized. Echocardiography revealed a massive pericardial effusion that necessitated pericardiotomy, with removal of 860 ml of pericardial fluid. Prednisone therapy (1 mg/kg/day) was reinstituted. In September 2007, while receiving prednisone at 0.5 mg/kg/day, the patient reported experiencing symptoms consistent with tachycardia and precordial chest pain and was referred to us. The EKG findings were consistent with pericarditis, and echocardiography showed the presence of moderate pericardial effusion. The CRP level was 32 mg/dl, and the ESR was 80 mm/hour. She was treated with prednisone 2 mg/kg/day and colchicine 1 mg/day. The prednisone dosage was subsequently tapered.

The patient was again hospitalized 2 months later (November 2007), while receiving prednisone 0.5 mg/kg/day, for a new recurrence of pericarditis. At admission, she reported chest pain and tachycardia symptoms and had a fever; echocardiography revealed a moderate pericardial effusion. The CRP level was 26.95 mg/dl, and the ESR was 60 mm/hour. Since steroid side effects were becoming evident, treatment with anakinra (1 mg/kg/day), an interleukin-1β (IL-1β) receptor antagonist, was initiated, while the prednisone dosage was left unchanged. Administration of anakinra was followed by dramatic clinical response and normalization of the laboratory findings (Figure 1): the fever and chest pain disappeared within 24 hours, and the CRP level returned to the normal range after 48 hours.

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Figure 1. Disease flares, C-reactive protein (CRP) levels, and treatment regimens during the disease course in the patients with recurrent pericarditis (patients 1, 2, and 3). CRP peaks correspond to pericarditis recurrences.

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Treatment with anakinra was stopped after 6 weeks, while the prednisone treatment was continued at an unchanged dosage (0.4 mg/kg/day). Two weeks after discontinuation of the anakinra, the patient experienced a new episode of pericarditis, characterized by precordial pain, increased levels of acute-phase reactants (CRP 14.09 mg/dl, ESR 51 mm/hour), and pericardial effusion seen on echocardiography. Anakinra (1 mg/kg/day) was restarted, while the prednisone dosage was left unchanged. Again we observed a dramatic response (Figure 1): the day after administration of anakinra, the patient was asymptomatic and the CRP rapidly normalized. Anakinra therapy was continued, and the prednisone was stopped in March 2008. No additional relapses have been observed after further followup of 3 months.

Patient 2.

Patient 2, born in 1995 to related Tunisian parents (second cousins), was admitted to our hospital in July 2007 because of acute precordial pain, breathing difficulty with orthopnea, fever, and arthralgias. Acute pericarditis was diagnosed and treatment with prednisone (2 mg/kg/day) was started, with prompt clinical improvement. One month later, during steroid tapering (to 0.5 mg/kg/day), he had a new episode of pericarditis; the EKG showed ST-segment elevation and T wave changes, and echocardiography revealed a pericardial effusion. The steroid dosage was increased to 1 mg/kg/day with resolution of symptoms, and colchicine (1 mg/day) was introduced. Two months later, while receiving prednisone (0.5 mg/kg/day) and colchicine, the patient had a new episode of pericarditis with acute precordial pain and fever. The clinical and laboratory abnormalities transiently improved with an increase in the prednisone dosage to 1 mg/kg/day. However, 2 weeks later the pericarditis recurred, with precordial pain, muffled heart sounds, friction rub, and fever.

Since steroid side effects were becoming apparent, therapy with anakinra (1 mg/kg/day) was instituted and the steroid dosage was left unchanged. Prompt and dramatic resolution of the clinical symptoms with normalization of acute-phase reactant levels was observed (Figure 1). During the subsequent weeks the steroid dosage was gradually tapered, and colchicine was stopped.

Two months later, in December 2007, anakinra treatment was discontinued. One week later the patient had a new episode of pericarditis, with a marked increase in acute-phase reactant levels (CRP 18.9 mg/dl, ESR 106 mm/hour) and evidence of pericardial effusion on echocardiography, and he was hospitalized elsewhere. Since anakinra was not immediately available there, he was initially treated with prednisone (1 mg/kg/day); 3 days later, anakinra was reintroduced. In the subsequent weeks the prednisone was gradually tapered and then stopped. After further followup of 4 months, with treatment with anakinra alone, the pericarditis is still in remission.

Patient 3.

Patient 3, born in 1991 to unrelated parents, developed fever, malaise, progressive tachypnea, and chest pain in July 2004. She was hospitalized elsewhere, and echocardiography showed diffuse pericardial effusion; 600 ml of pericardial fluid was removed on pericardiocentesis. Prednisone (2 mg/kg/day) and NSAIDs were started, with prompt clinical remission; in the subsequent months the steroid dosage was gradually tapered. In October 2004, while receiving prednisone 0.2 mg/kg/day, she had a recurrence of pericarditis and was again hospitalized and treated with high-dose steroids. She was first admitted to our hospital in April 2005, because of fever, chest pain, tachycardia, and orthopnea; at that time she was receiving prednisone at a daily dosage of 0.17 mg/kg. The CRP level was 9.27 mg/dl, and the ESR was 50 mm/hour. An EKG showed alterations consistent with pericarditis, and echocardiography revealed moderate pericardial effusion. Increasing the prednisone dosage to 1 mg/kg/day was promptly effective. In June 2006 and in March 2007, while receiving low-dose prednisone (0.18 mg/kg/day and 0.10 mg/kg/day, respectively) the patient had 2 other episodes of pericarditis, characterized by intense precordial pain, increased inflammation as indicated by acute-phase reactant levels, widespread ST-segment elevation, and echocardiographic evidence of pericardial effusion; on both of these occasions she was treated with increased doses of prednisone. Despite the institution of colchicine treatment (1 mg/day) in March 2007, she had 2 further relapses of pericarditis in April 2007 and in July 2007, when colchicine was replaced with methotrexate (15 mg/m2/week).

In October 2007, she had another episode of pericarditis, with fever, tachypnea, tachycardia, precordial pain, increased levels of inflammation parameters (CRP 10.2 mg/dl, ESR 87 mm/hour), and evidence of pericardial effusion on echocardiography. Steroids and methotrexate were stopped and the patient was given anakinra (1.25 mg/kg/day). Dramatic clinical improvement occurred within 12 hours (Figure 1). After 5 days of anakinra therapy, the CRP level was 0.83 mg/dl and echocardiographic results were normal.

Treatment with anakinra was discontinued 9 days later. The patient remained asymptomatic until December 2007, when a further episode of pericarditis occurred, with chest pain and EKG abnormalities; The CRP level was 7.69 mg/dl, and the ESR was 50 mm/hour. Anakinra treatment (1.25 mg/kg/day) was reinstituted. One day later the patient was asymptomatic, and the CRP level rapidly normalized (Figure 1). Treatment with anakinra alone was continued. After further followup of 4 months, no additional episodes of pericarditis have developed.

DISCUSSION

  1. Top of page
  2. Abstract
  3. CASE REPORTS
  4. DISCUSSION
  5. AUTHOR CONTRIBUTIONS
  6. REFERENCES

Herein we describe a dramatic therapeutic response to IL-1β receptor antagonist (anakinra) in 3 pediatric patients with steroid-dependent idiopathic recurrent pericarditis. Anakinra administration was associated with very rapid disappearance of clinical symptoms and normalization of acute-phase reactant levels. In all 3 patients anakinra was stopped after complete remission was achieved; in all cases this withdrawal was followed after a few weeks by a disease flare. The reinstitution of anakinra was again associated with immediate response, similar to that observed with high-dose steroids. Continuous treatment with anakinra allowed rapid tapering and then discontinuation of steroid treatment. At a mean followup of 6 months from the initial administration of anakinra, none of the patients have experienced a new disease relapse. Although the duration of followup is still limited, the observation that in all patients the disease recurred shortly after anakinra withdrawal, along with the high rate of recurrences that had characterized the earlier course in all patients, strongly suggest that anakinra therapy is able to prevent disease relapses.

A satisfactory therapy for recurrent pericarditis has not yet been established (4). NSAIDs are the initial treatment of choice, but patients with numerous episodes and those in whom recurrences are very frequent are often treated with steroids. However, corticosteroid therapy is associated with serious side effects and is thought to possibly promote recurrence (5). A recent prospective, randomized, open-label trial (3) showed that addition of colchicine to the treatment regimen reduces the recurrence rate at 18 months from 32.3% to 10.7%.

The results obtained in our patients strongly suggest that anakinra is a valid alternative to currently used regimens in patients who, despite treatment with NSAIDs, steroids, and colchicine, continue to have frequent disease recurrences and develop significant steroid side effects. Controlled trials in a large patient population are needed to validate our findings.

The pathogenesis of idiopathic recurrent pericarditis is unknown. Several mechanisms have been hypothesized to explain recurrence. They include insufficient treatment during the first episode, augmented viral DNA/RNA replication in the pericardial tissue secondary to steroid therapy, reinfection, and an autoimmune reaction following the initial episode of pericarditis, presumed to be of viral origin (6).

However, idiopathic recurrent pericarditis also has many features that are consistent with autoinflammatory disease. Indeed, recurrent episodes of apparently unprovoked inflammation are the characteristic feature of this latter group of diseases (7), serosal inflammation is very common during disease flares (7), and familial Mediterranean fever is a well-known cause of recurrent pericarditis (8). Moreover, familial cases of recurrent idiopathic pericarditis have been reported, and in a large series of patients, ∼10% had an affected relative (2).

In autoinflammatory diseases caused by mutations of cryopyrin, a central component of the inflammasome that is essential in IL-1β, anakinra has been shown to have dramatic therapeutic effect (9, 10). Moreover, anecdotal reports have described the efficacy of anakinra in other autoinflammatory diseases, such as familial Mediterranean fever (11, 12), tumor necrosis factor receptor–associated periodic syndrome (13, 14), and hyperimmunoglobulinemia D with periodic fever syndrome (15).

The above-described similarities between idiopathic recurrent pericarditis and autoinflammatory diseases, together with the marked efficacy of anakinra observed in our patients, strongly suggest that at least a subset of patients diagnosed as having idiopathic recurrent pericarditis could be affected by a not-yet-identified autoinflammatory disease, possibly related to gene mutations leading to dysregulation of IL-1β production and secretion. Anakinra may be very effective in the treatment of recurrent pericarditis in these patients.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. CASE REPORTS
  4. DISCUSSION
  5. AUTHOR CONTRIBUTIONS
  6. REFERENCES

Dr. Picco had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study design. Picco, Loy, Martini.

Acquisition of data. Brisca, Traverso.

Analysis and interpretation of data. Gattorno.

Manuscript preparation. Picco, Gattorno, Martini.

REFERENCES

  1. Top of page
  2. Abstract
  3. CASE REPORTS
  4. DISCUSSION
  5. AUTHOR CONTRIBUTIONS
  6. REFERENCES