The management of refractory recurrent pericarditis is challenging. Previous clinical reports have noted a beneficial effect of high-dose intravenous human immunoglobulins (IvIgs) in isolated and systemic inflammatory disease-related forms. In this article, we analyzed retrospectively our clinical experience with IvIg therapy in a series of clinical cases of pericarditis refractory to conventional treatment. We retrospectively analyzed 9 patients (1994 to 2010) with refractory recurrent pericarditis, who received high-dose IvIg as a part of their medical treatment. Nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, or colchicine treatment was not discontinued during IvIg treatment. No patients had a history of autoimmune or connective tissue diseases. During an average period of 11 months from the first recurrence, patients had experienced a mean of 5 relapses before the first IvIg treatment. In 4 cases, patients showed complete clinical remission with no further relapse after the first IvIg cycle. Two patients experienced a single minor relapse, responsive to short-term nonsteroidal anti-inflammatory drugs. In 2 patients, we performed a second cycle of IvIg after a recurrence of pericarditis, with subsequent complete remission. One patient did not respond to 3 cycles of IvIg and subsequently underwent pericardial window and long-term immunosuppressive treatment. No major adverse effect was observed in consequence of IvIg administration in all the cases. In conclusion, although IvIg mode of action is still poorly understood in this setting, this treatment can be considered as an option in patients with recurrent pericarditis refractory to conventional medical treatment and, in our small series, has proved to be effective in 8 of 9 cases.
Acute “idiopathic” pericarditis is a relatively common disease with a good prognosis and a self-limiting course; however, up to 30% of cases develop recurrences. Athough the first episode of acute pericarditis can originate from multiple etiologic factors, it is widely agreed that recurrences are autoimmune processes secondary to a deranged local immune response. According to the European Society of Cardiology guidelines, nonsteroidal anti-inflammatory drugs (NSAIDs) are the mainstay of the treatment of pericarditis. Colchicine appears to be highly effective, especially in the treatment and prevention of recurrences. Corticosteroids are characterized by a quick clinical response and good control of symptoms but are related to a higher incidence of recurrences. Besides, multiple therapeutic schemes have been proposed (azathioprine, cyclophosphamide, cyclosporine, methotrexate, hydroxychloroquine, and anakinra); nevertheless, strong evidence-based clinical data are lacking. Intravenous human immunoglobulins (IvIgs) are used in several immune-mediated diseases such as Kawasaki disease, thrombotic thrombocytopenic purpura, and Guillain-Barré syndrome; moreover, a recent review of a published work highlighted >150 off-label usages of IvIg. The exact mechanism of action of IvIg is not completely understood; nevertheless, the interaction between Fc fragment of IgG and the Fcγ receptor appears to be crucial for most immunomodulatory and anti-inflammatory effects. Previous clinical reports have noted a beneficial effect of IvIg in acute and chronic idiopathic pericarditis, recurrent postpericardiectomy syndrome, and systemic inflammatory disease-related forms. In this article, we analyzed retrospectively our experience with IvIg therapy in recurrent pericarditis through the analysis of medical records of a series of clinical cases refractory to conventional treatment.
Methods
In this retrospective study, we analyzed medical records of 9 patients with recurrent pericarditis, who received high-dose IvIg as a part of their medical treatment. Patients were diagnosed in our center (6 cases) or referred to us after a history of multiple relapses refractory to several combination therapies (3 cases). All patients, at first clinical assessment in our department, were studied with an extensive diagnostic evaluation, including microbiologic and autoimmunity serologic tests, chest x-ray, electrocardiography, and echocardiography. An acute pericarditis episode (first attack or relapse) was defined by the presence of at least 2 features such as chest pain, pericardial rubs, flogosis markers, typical electrocardiographic abnormalities (or worsening abnormalities in case of relapse), and new pericardial effusion. The clinical decision making on IvIg treatment was made after careful evaluation of the patient’s medical history, clinical status, and biohumoral examinations. Criteria for treatment eligibility were (1) failure of at least 3 therapeutic attempts with conventional medical treatment (NSAIDs, steroids, or colchicine) and/or (2) major intolerance to conventional medical treatment. Because IvIg is an off-label therapy when used in patients with recurrent pericarditis, all patients were asked to sign an informed consent before starting the treatment. Thereafter, all of them underwent high-dose IvIg therapy (500 mg/kg/day) for 5 consecutive days. In some cases, >1 cycle was needed, the second one performed at least 4 weeks apart. NSAIDs, steroids, or colchicine treatment was not discontinued during the IvIg treatment and subsequently tapered until definitive withdrawal in 3 to 6 months.
After the acute phase, patients were carefully followed up with clinical, biohumoral, and echocardiographic examinations.
Results
From 1994 to 2010, 9 patients with recurrent idiopathic pericarditis, refractory to standard medical treatment, were treated with high-dose IvIg. Clinical and demographic data at first episode of pericarditis are listed in Table 1 . No patients had a history of autoimmune or connective tissue diseases, whereas only 1 patient (case 7; see Table 1 ) was positive to serologic analysis with demonstration of a recent Coxsackie type B virus infection (IgM positive and IgG negative). Moreover, in the same patient, anti-DNA antibody levels were above the normal range but no definite diagnosis of connective tissue disease was made. One patient (case 2; see Table 1 ) had a history of immunodepression secondary to allogenic stem cells transplantation followed by immunosuppressive therapy with methotrexate and cyclosporine. One patient (case 8; see Table 1 ) had a postpericardiectomy syndrome, after coronary artery bypass surgery. Five patients (56%) at first episode presented severe symptoms and large pericardial effusion, whereas 4 (44%) had a milder onset; cardiac troponin I level was within the normal range in all patients. Only 1 patient (case 3; see Tables 1 and 2 ) has had the necessity of pericardiocentesis because of cardiac tamponade. In 2/3 of the cases, a concomitant pleural involvement was evident. The average time from the first episode to the first relapse was 2.5 months. During a mean time of 11 months from the first recurrence, patients experienced a mean of 5 relapses before the first IvIg treatment (see Table 2 ). All patients underwent multiple therapeutic schemes before the first IvIg treatment (see Table 2 and Figure 1 ), and in all cases, conventional medical treatment proved to be ineffective or not tolerated. In detail, all patients have been treated with different therapeutic schemes including NSAIDs and 8 of 9 patients received steroids and colchicine as well. Four patients were subjected to more advanced immunosuppressive therapies (azathioprine in 2 cases, methotrexate in 1 case, cyclosporine and methotrexate in 1 case). Five patients experienced multiple relapses during the tapering phase of steroid treatment, 2 of them were on azathioprine as well; 3 patients had relapses during the tapering of NSAIDs.
| Variable | Cases | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | |
| Age (yrs) | 27 | 29 | 30 | 42 | 69 | 22 | 37 | 47 | 35 |
| Gender | Male | Female | Male | Female | Female | Male | Male | Male | Male |
| Year of first episode | 1994 | 2003 | 2001 | 2004 | 2001 | 2009 | 2010 | 2010 | 2005 |
| History of immunodepression | 0 | + ‡ | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| History of autoimmune or connective tissue disease | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Postpericardiectomy | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Fever >38°C | + | + | + | + | + | + | + | 0 | 0 |
| Large pericardial effusion (>2 cm) | + | + | + | 0 | + | + | 0 | ? | + |
| Increase of cardiac troponin I level | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Pleural involvement | + | + | 0 | + | 0 | 0 | + | + | + |
| Viral serology ∗ | 0 | 0 | 0 | 0 | 0 | 0 | + § | 0 | 0 |
| Autoantibody † | 0 | 0 | 0 | 0 | 0 | 0 | + § | 0 | 0 |
∗ Serum IgG and IgM anti-Epstein-Barr Virus, coxsackievirus, and other enterovirus, cytomegalovirus, adenovirus, influenza A and B, mycoplasma pneumoniae, toxoplasma, borrelia.
† Serum circulating immune complexes, rheumatoid arthritis test, antinuclear, anti-DNA, antimitochondrial, antismooth muscle, antigastric parietal cells, antimicrosomal, antithyroglobulin, and anticardiolipin antibodies.
‡ History of acute myeloid leukemia, diagnosed in 1999 and treated with multiple cycles of chemotherapy and high dose therapy with steroids. In March 2003 underwent allogenic stem cells transplantation followed by immunosuppressive therapy with methotrexate and cyclosporine.
§ Microbiologic tests of case 7 showed a recent Coxsackie type B virus infection (IgM positive, IgG negative); moreover, anti-DNA antibody levels were above the normal range. Serum circulating immune complexes, rheumatoid arthritis test, antinuclear, antimitochondrial, antismooth muscle, antigastric parietal cells, antimicrosomal, antithyroglobulin, and anticardiolipin antibody levels were negative or within the normal range. Human immunodeficiency virus, hepatitis B virus, and hepatitis C virus tests were negative. Connective tissue disease was ruled out.
| Variable | Cases | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | |
| First episode | 1994 | 2003 | 2001 | 2004 | 2001 | 2009 | 2010 | 2010 | 2005 |
| Time from first episode to first recurrence (mo) | ? | 4 | ? | 6 | 2 | 1 | 1 | 1 | 36 |
| Number of recurrences before IvIg therapy | 6 | 3 | 6 | 4 | 5 | 6 | 3 | 7 | 6 |
| Maximum C-reactive protein level (mg/L) | 170 | 53 | 0 | 248 | 38 | 81 | 339 | 107 | 227 |
| Time from first recurrence to first IvIg therapy (mo) | 22 | 6 | 21 | 7 | 12 | 9 | 3 | 7 | 12 |
| Treatments before IvIg therapy | |||||||||
| NSAIDs | ASA (1.6 gr/die) | Indo (100–50 mg/die) | ASA (1.5 gr/die) + Indo (150 mg/die) | Indo (150 mg/die) + Ibup (1.6 gr/die) | Indo (150 mg/die) | Ibup (2 gr/die) | ASA (1.5 g/die) + Ibup (1.2 gr/die) | Indo (150 mg/die) + ASA (3 gr/die) | Ibup (1.8 gr/die) + Indo (150 mg/die) |
| Steroids (dose) | Prednisone (35 mg/die) | Prednisone (25 mg/die) | Prednisone (25 mg/die) | Prednisone (50 mg/die) | Prednisone ? | Prednisone (25 mg/die) | Prednisone (50 mg/die) | 0 | Prednisone (5 mg/die) |
| Colchicine | + | 0 | + | + | + | + | + | + | + |
| Other immunosuppressive treatment | +, (1) | +, (2) | +, (3) | 0 | +, (1) | 0 | 0 | 0 | 0 |
| Ongoing medical treatment at the time of last recurrence before IvIg therapy | Steroids, ∗ (1) | None † | NSAIDs ∗ | Steroids ∗ | Steroids, ∗ (1) | Steroids ∗ | Steroids ∗ | NSAIDs, ∗ Colchicine | NSAIDs, ∗ Colchicine |
| Conventional treatment adverse effects | Iatrogenic CS | Iatrogenic CS, gastric intolerance | 0 | 0 | Iatrogenic CS | 0 | 0 | 0 | Colchicine related diarrhea |
| History of cardiac tamponade or pericardiocentesis | 0 | 0 | + | 0 | 0 | 0 | 0 | 0 | 0 |
| Reason for IvIg decision | Treatment failure + intolerance | Treatment failure + intolerance | Treatment failure | Treatment failure | Treatment failure + intolerance | Treatment failure | Treatment failure | Treatment failure | Treatment failure |
† Steroids withdrawal because of severe secondary hypercortisolism with spontaneous vertebral fractures.
Four patients showed complete clinical remission with no further relapses immediately after the first IvIg cycle (mean follow-up free from relapses: 57 months; see Table 3 ). Two patients experienced a single minor relapse, responsive to short-term NSAIDs treatment. In 2 patients, we decided to perform a second administration of IvIg after a recurrence of pericarditis, with subsequent complete remission ( Figure 2 ). One patient did not respond to 3 cycles of IvIg and subsequently underwent pericardial window and long-term immunosuppressive treatment. No particular clinical, instrumental, or biohumoral features have been identified in this patient.
