Idiopathic recurrent pericarditis (IRP) is a debilitating illness which leads to great suffering and multiple hospitalizations. Management of acute pericarditis and subsequent recurrences has evolved significantly as the use of colchicine-based strategies become more prevalent, yet there still remains a subset of patients who remain refractory to colchicine therapy, and these patients require prolonged corticosteroid (CS) therapy for the control of symptoms. Since the 1960s, there have been reports of successful management of these cases with immunosuppressive therapy. Current guidelines support the use of anakinra, intravenous immunoglobulins, and azathioprine for management of IRP, with the goals of both control of symptoms and withdrawal of CS. Recent reports supply evidence for both auto-inflammatory and autoimmune activity in these patients. We herein review the current available reports regarding the evidence regarding the pathophysiology and reported cases and case series of IRP cases managed with immunomodulation therapy.
Acute pericarditis (AP) is documented in about 0.1% of hospitalized patients and 5% of patients admitted to the emergency department for nonischemic chest pain. Up to 30% of patients with AP may suffer subsequent recurrent events, and recurrence rates may be as high as 50% if primary management fails to include colchicine therapy, and particularly in those patients treated with corticosteroids (CSs). Idiopathic recurrent pericarditis (IRP) significantly impairs the patients’ quality of life, yet rarely poses a life-threatening long-term deteriorating illness. CS is most often used as second line therapy in patients with recurrent pericarditis, either primarily or after failure to respond to anti-inflammatory agents. There is growing evidence, however, that the use of CS may increase the risk of recurrences. The recent 2015 European Society of Cardiology guideline for management of pericarditis offer an alternative approach for those patients who do not respond to anti-inflammatory therapies and require continuous administration of systemic CS. Anakinra, intravenous immunoglobulins (IVIGs), and azathioprine are suggested for these cases (class IIb, level of evidence), yet as suggested by the level of evidence grading, this does not stand on a solid evidence-based ground; thus, there is dire need for better empirical data regarding these options.
Methods
We reviewed studies published up to September 2015 regarding immunosuppressive therapy as an advanced line of treatment in patients with IRP. Searches were performed in BioMed Central, Google Scholar, MEDLINE/PubMed, and Scopus. The searches were performed using the following terms: “idiopathic recurrent pericarditis,” “refractory recurrent pericarditis,” “immunotherapy,” “immunosuppressive therapy,” “anakinra,” “intravenous immunoglobulins,” “IVIG,” “azathioprine,” “methotrexate,” and “etanercept” in various combinations. Searches were limited to the English language and for publications available online and not for time, age, or gender. Relevance of all retrieved reports was initially evaluated by the title and abstract. Suitable reports were retrieved as full reports for further review and data extraction.
The information extracted included patient and case data, treatment protocols (dosage, concomitant agents in use, duration, method of withdrawal, tapering of steroids, and/or other relevant medications), and follow-up data. We have also retrieved documentations regarding the relation between immunosuppressive therapy tapering and recurrence of pericarditis, especially in regard of the timing of these events. Reports of adverse events were retrieved when available.
Results
Reports found were assessed according to the method described in Figure 1 . A total of 19 records were eventually further evaluated, after excluding reports of cases that had distinct origins, such as postpericardiotomy syndrome (PPS), posttraumatic pericarditis, or a case in the setting of another systemic inflammatory disease. One specific record was included despite having a small portion of PPS cases in the series, as discussed in the following.
Table 1 describes accounts from 3 case series describing a total of 14 cases of IRP treated with IVIG. Typical described courses were of 0.5 G/kg, either once or twice daily, for 5 days. Most cases received 1 to 2 courses, and the maximum reported number of courses was of a single case who reached complete remission after 9 courses. The described patients were predominantly men (10:4), with an average age of 35.8 years. All but one of these patients achieved full remission of symptoms, with an average follow-up period of 35.8 months for the 11 patients with reported duration of follow-up. All 14 patients previously received CS, all but one received colchicine, and 11 were treated with non steroidal anti inflammatory drugs or aspirin. Seven patients had reportedly undergone previous immunosuppressive therapy, with various combinations including azathioprine, methotrexate, cyclosporine, and cyclophosphamide. The case that was reported as treatment failure went on to undergo a pericardial windowing procedure and receive continuous immunosuppression, yet remained resistant to all therapeutic strategies for 13 years of follow-up.
| Study | n | Age | Sex | Months of follow up | Previous therapy | Additional therapy /w IVIG | IVIG cycles ∗ | Complete response | |||
|---|---|---|---|---|---|---|---|---|---|---|---|
| CS | COL | NSAID/ASA | Immunotherapy | ||||||||
| Peterlana et al. | 4 | 11 | M | – | + | + | MTX, AZA, CSA | 9 | + | ||
| 21 | M | – | + | + | ASA | 5 | + | ||||
| 28 | M | 12 | + | + | ASA | 7 | + | ||||
| 29 | M | 20 | + | + | 7 | + | |||||
| Tona et al. | 2 | 19 | F | 32 | + | + | MTX, CSA, CYC | 1 | + | ||
| 30 | M | 42 | + | + | ASA | AZA, CSA, CYC | 1 | + | |||
| Moretti et al. | 8 | 22 | M | 24 | + | + | NS | 1 | + | ||
| 27 | M | 156 | + | + | ASA | AZA | SI, CS | 3 | 0 | ||
| 29 | F | 84 | + | NS | MTX, CSA † | 1 | + | ||||
| 30 | M | 96 | + | + | Both | MTX | 1 | + | |||
| 35 | M | 24 | + | + | NS | 2 | + | ||||
| 37 | M | 12 | + | + | Both | 1 | + | ||||
| 42 | F | 36 | + | + | NS | 2 | + | ||||
| 69 | F | 12 | + | + | NS | AZA | 1 | + | |||
∗ Each cycle consists of IVIG 0.5 mg/Kg/5 days.
† Patient received long-term immunosupression before IRP because of a history of undergoing an allogenic stem cell transplant. Treatment was continued after IVIG therapy.
The use of anakinra is reported in 9 reports with a total of 45 individual cases is listed in Table 2 . The average age was 27.3 years, and the group consisted of 20 male and 25 female patients. This group varies significantly in reported response and clinical course. Of the 42 cases that reported response to anakinra therapy, 38 were reported to have complete clinical response. Finetti et al reported 13 cases included in this review, including 10 pediatric and 3 adult patients. All patients reached complete response and were tapered off any therapy other than anakinra. With the small sample size in mind, we performed further analysis on this data set and found that time to complete response was significantly higher in the adult patients (15 vs 7.2 days, p <0.001). We found no significant differences in the number of pericarditis recurrences or the duration of illness before anakinra therapy between adult and pediatric patients. Of all included cases, 32 had a reported status of therapy withdrawal and a follow-up period of at least 1 year. Twelve patients were successfully weaned off anakinra therapy, and 20 patients had to receive continuous therapy. Reports of relapse during tapering down of anakinra usually occurred within 1 to 4 weeks. We performed further analysis and found no statistically significant difference in successful withdrawal rates according to gender (men 5 of 15, women 6 of 17, p = 0.907), age group (pediatric 5 of 12, adult 6 of 20, p = 0.501), or absolute age (p = 0.931).
| Study | n | Age | Sex | Months of follow up | Previous therapy | Complete response | Treatment withdrawal | |||
|---|---|---|---|---|---|---|---|---|---|---|
| CS | COL | NSAID/ASA | Immunotherapy | |||||||
| Scardapane et al. | 1 | 11 | M | 12 | + | + | NS | + | 0 | |
| 12 | M | 9 | NA | NA | NA | + | 0 | |||
| Picco et al. | 3 | 13 | F | 44 | NA | NA | NA | MTX | + | 0 |
| 14 | F | 15 | NA | NA | NA | + | 0 | |||
| Canatrani et al. | 1 | 26 | F | 6 | + | + | + | – | ||
| Scott et al. | 2 | 28 | M | 60 | + | + | Etanercept | ± | – | |
| 33 ∗ | F | 18 | + | + | MTX | + | 0 | |||
| D’Elia et al. | 1 | 47 ∗ | F | 11 | + | + | NS | ABx | + | + |
| Massardier et al. | 1 | 60 | F | – | + | ASA | + | – | ||
| Finetti et al. | 13 | 12 | M | 53 | + | + | MTX | + | 0 | |
| 12 | M | 14 | + | + | NS | + | 0 | |||
| 13 | M | 39 | + | + | + | |||||
| 13 | M | 15 | + | + | NS | + | 0 | |||
| 14 | F | 52 | + | + | + | + | ||||
| 14 | M | 29 | + | + | NS | + | 0 | |||
| 15 | M | 28 | + | + | NS | AZA, HCQ | + | + | ||
| 16 | F | 57 | + | MTX | + | 0 | ||||
| 16 | F | 24 | + | + | NS | + | + | |||
| 16 | M | 20 | + | NS | + | + | ||||
| 28 | F | 56 | + | + | NS | + | 0 | |||
| 38 | M | 6 | + | + | NS | + | 0 | |||
| 56 | M | 48 | + | + | NS | + | + | |||
| Lazaros et al. | 10 | 19 | F | 35 | + | + | Both | + | + | |
| 22 | M | 26 | + | + | NS | + | 0 | |||
| 26 | M | 49 | + | + | Both | AZA | + | 0 | ||
| 34 | M | 17 | + | + | Both | + | 0 | |||
| 36 | F | 53 | + | + | NS | + | + | |||
| 42 | M | 12 | + | + | NS | – | – | |||
| 51 | F | 7 | + | + | NS | – | – | |||
| 53 | F | 18 | + | + | NS | + | 0 | |||
| 59 | M | 15 | + | + | Both | AZA | + | + | ||
| 74 | F | 8 | + | + | NS | – | – | |||
| Jain et al. | 13 | 33 | F | 22.6 | + | + | NS | AZA, HCQ | + | 0 |
| 38 | M | 15 | + | + | NS | + | 0 | |||
| 38 | F | 18 | + | + | NS | + | + | |||
| 44 | F | 33.5 | + | + | NS | ± | – | |||
| 46 | M | 20 | + | + | NS | HCQ | + | 0 | ||
| 48 | F | 26 | + | + | NS | MMF | + | 0 | ||
| 49 | F | 41.5 | + | + | NS | + | 0 | |||
| 53 | M | 21 | + | + | NS | + | 0 | |||
| 55 | F | 43 | + | + | NS | HCQ | ± | – | ||
| 58 | F | 33 | + | + | NS | ± | – | |||
| 58 | F | 17.5 | + | + | NS | AZA | + | + | ||
| 69 | F | 26 | + | + | NS | + | 0 | |||
| 73 | F | 29.5 | + | + | NS | MTX | + | 0 | ||
∗ These patients were reported to have colchicine administered along with anakinra.
Table 3 summarizes reports of cases managed with azathioprine. A report of 46 accounts of azathioprine use included 40 cases of IRP and 6 that were of either PPS, port-infarction, or posttraumatic, with data reported mostly for the both groups combined. The total reported success rate was 85%, and there was a concordance between azathioprine cessation and rechallenge and clinical flares. We attempted to further extract data regarding specifically the group of patients with IRP, and found it had a noticeably lower rates of complete response than the non-IRP group, yet this was nonsignificant (83% and 100%, respectively; relative ratio 6.34, 95% CI 0.43 to 92.69, p = 0.177). It should also be noted that all patients without IRP in this report responded fully to azathioprine, with no flares when CS were tapered down. Azathioprine was also reported in 7 other individual cases, with inconclusive results. In summary, of the total, 47 patients with IRP had an overall complete response rate of 78%.
| Study | n | Age | Sex | Months of follow up | Previous therapy | Reported therapy | Complete response | Treatment withdrawal | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CS | COL | NSAID/ASA | Immunotherapy | Immunotherapy | Additional therapy | |||||||
| Dalla pozza et al. | 2 | 7 | F | 68 | NA | NA | NA | AZA, MTX, Anti-TNF | NSAIDS, COL | 0 | 0 | |
| 12 | F | 12 | NA | NA | NA | AZA or MTX | ± | 0 | ||||
| Bird and Mustchin | 1 | 32 | M | 60 | Y | AZA | + | + | ||||
| Imazio et al. | 1 | 45 | F | 63 | Y | Y | AZA or MTX + CSA | SI, CS, COL | 0 | 0 | ||
| Asplen and Levine | 1 | 53 | F | 30 | Y | NS | AZA | + | + | |||
| Marcolongo et al. | 2 | 19 | M | 7 | Y | AZA | + | – | ||||
| 56 | F | 21 | Y | AZA | + | – | ||||||
| Vianello et al. | 16 | 39.7 ∗ | 20 M20 F | Y | NS | AZA | 33 Complete7 No | – | ||||
| 19 | Y | Y | NS | |||||||||
| 2 | Y | MTX, CSA, CYC | ||||||||||
| 1 | Y | Y | MTX, CSA | |||||||||
| 1 | Y | CSA | ||||||||||
| 1 | Y | Y | CYC | |||||||||
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