Successful treatment with tocilizumab of pericarditis associated with rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a systemic inflammatory disease often complicated by vasculitis. Pericarditis is a serious complication caused by vasculitis, resulting in retention of pericardial effusion that sometimes induces cardiac tamponade. We report a patient with RA in whom pericarditis improved after tocilizumab administration. A male patient was diagnosed with RA and chronic renal failure in 1980 and was treated with salazosulfapyridine, but disease activity remained high. In January 2012, at the age of 73 years, he developed organizing pneumonia as a complication and was admitted to our hospital. Treatment with prednisolone 30 mg/day was initiated. However, 20 days after initiation of treatment, chest pain and palpitation developed, and chest computed tomography (CT) and echocardiography (ECG) revealed retention of pericardial effusion without cardiac tamponade. Rheumatoid nodules and interstitial pneumonia were also observed, and serum C3 level was decreased. A diagnosis of pericarditis caused by vasculitis was made based on these findings, and tocilizumab 8 mg/kg was administered. His symptoms improved gradually, and chest CT and ECG showed no pericardial effusion after about 3 weeks. No adverse effects of tocilizumab were observed during the clinical course. Although there are only a few reports of the effects of tocilizumab on vasculitis associated with RA, tocilizumab administration appears worthwhile in RA patients with vasculitis who do not respond to conventional treatment.     

A case of rheumatoid pericarditis with high concentrations of interleukin-6 in pericardial fluid

A case of rheumatoid pericarditis that developed into cardiac tamponade without deterioration of rheumatoid arthritis is described. The concentration of interleukin-6 (IL-6) in pericardial fluid was notably increased compared with serum. IL-6 may be associated with progression or maintenance of rheumatoid pericarditis.


Keywords: rheumatoid pericarditis; cardiac tamponade; interleukin-6     

New directions in diagnosis and treatment of pericardial disease. A project of the Taskforce on Pericardial Disease of the World Heart Federation

New directions in the diagnosis and treatment of pericardial diseases synthesize the achievements of modern imaging with molecular biology and immunology techniques. Comprehensive and systematic implementation of new techniques of pericardiocentesis, pericardial fluid analysis, pericardioscopy, epicardial and pericardial biopsy, as well the application of comprehensive molecular biology and immunology techniques for pericardial fluid and biopsy analyses have opened new windows to the pericardial diseases, permitting early specific diagnosis and creating foundations for etiologic treatment in many cases. In patients with recurrent pericarditis, resistant to conventional treatments, as well as in patients with neoplastic pericarditis an alternative intrapericardial treatment regimen was suggested by the Taskforce on Pericardial Diseases of the World Heart Federation. Intrapericardial application of medication avoids systemic side effects with increased local efficacy. The following protocols are proposed: CIRP (colchicine in recurrent pericarditis)--colchicine vs placebo in chronic/recurring pericarditis without pericardiocentesis; TRIPE (triamcinolone in pericardial effusion)--intrapericardial instillation of triamcinolone + 6 months colchicine vs pericardial puncture without instillation + 6 months colchicine; NEPIN (neoplastic effusion and pericardial instillation)--pericardiocentesis and drainage + intrapericardial instillation of cisplatin or thiotepa.     

Massive intractable pericardial effusion in a patient with systemic lupus erythematosus treated successfully with pericardial fenestration alone

Systemic lupus erythematosus (SLE) is often complicated by pericarditis with effusion, which generally responds well to glucocorticoid. We report herein a Japanese patient with SLE who showed a sign of cardiac tamponade and severe chest and back pain because of massive intractable pericardial effusion. Pulse glucocorticoid and pulse cyclophosphamide gained marginal effects. Pericardial effusion accumulated again soon after ultrasound-guided pericardiocentesis and drainage. Pericardial fenestration performed surgically as a last resort, for draining pericardial fluid into the pleural space, was very effective, and only a much smaller amount of fluid was observed in the space thereafter in comparison with the volume before the surgery. Pathological examination of the retrieved pericardium unfolded intense hyperplasia of small vessels and capillaries. Levels of IL-6 and TNF-alpha in pericardial effusion were extremely higher than those in serum. Pericardial effusion with extensive capillary hyperplasia in SLE would be resistant to medical treatment and require surgical fenestration.     

Cardiac Tamponade During Tocilizumab Therapy in a Patient with Rheumatoid Arthritis and Anti-DNA Antibody Positivity

Drug-induced lupus (DIL) is a drug-mediated immune reaction with the same symptoms as that of lupus erythematosus. We herein report the first case of tocilizumab-induced lupus syndrome presenting with cardiac tamponade. A 65-year-old man presented with cough, exertional dyspnea, and chest pain after 2 months of tocilizumab therapy for rheumatoid arthritis. Echocardiography revealed marked pericardial effusion. Antinuclear antibodies and anti-double-stranded deoxyribonucleic acid antibodies were positive. The diagnosis of cardiac tamponade due to tocilizumab-induced lupus syndrome was made. He had no recurrence of pericardial effusion after tocilizumab discontinuation. Clinicians should be alert for lupus syndrome in patients receiving tocilizumab.     

Gallium-67 citrate scanning for noninvasive detection of inflammation in pericardial diseases

The treatment of acute nonspecific pericarditis is controversial. No study is available that confirms the efficacy of the administration of corticosteroids or nonsteroid anti-inflammatory agents in this condition. There is no reliable invasive marker for pericardial inflammation, because echocardigraphy demonstrates only the presence of fluid. In four patients with pericarditis, gallium-67 citrate scanning was performed, and the isotope was localized to the cardiac silhouette in all. In one patient with effusion the gallium scan was positive and then reverted to negative with corticosteroid therapy. In another, the gallium scan remained positive despite resolution of the pericardial effusion with corticosteroid therapy. This patient eventually required pericardial stripping. Pericardial localization of gallium was useful in detecting the cause of fever in a patient after aortocoronary bypass grafting and in detecting pericardial involvement in a patient with multisystem viral disease. Pericardial localization of gallium-67 may be diagnostically useful and may provide a proper control for the study of the efficacy of corticosteroids versus nonsteroid anti-inflammatory agents in pericarditis.     

A modern approach to tuberculous pericarditis

The human immunodeficiency virus (HIV) epidemic has been associated with an increase in all forms of extrapulmonary tuberculosis including tuberculous pericarditis. Tuberculosis is responsible for approximately 70% of cases of large pericardial effusion and most cases of constrictive pericarditis in developing countries, where most of the world's population live. However, in industrialized countries, tuberculosis accounts for only 4% of cases of pericardial effusion and an even smaller proportion of instances of constrictive pericarditis. Tuberculous pericarditis is a dangerous disease with a mortality of 17% to 40%; constriction occurs in a similar proportion of cases after tuberculous pericardial effusion. Early diagnosis and institution of appropriate therapy are critical to prevent mortality. A definite or proven diagnosis is based on demonstration of tubercle bacilli in pericardial fluid or on histologic section of the pericardium. A probable or presumed diagnosis is based on proof of tuberculosis elsewhere in a patient with otherwise unexplained pericarditis, a lymphocytic pericardial exudate with elevated biomarkers of tuberculous infection, and/or appropriate response to a trial of antituberculosis chemotherapy. Treatment consists of 4-drug therapy (isoniazid, rifampicin, pyrazinamide, and ethambutol) for 2 months followed by 2 drugs (isoniazid and rifampicin) for 4 months regardless of HIV status. It is uncertain whether adjunctive corticosteroids are effective in reducing mortality or pericardial constriction, and their safety in HIV-infected patients has not been established conclusively. Surgical resection of the pericardium is indicated for those with calcific constrictive pericarditis or with persistent signs of constriction after a 6 to 8 week trial of antituberculosis treatment in patients with noncalcific constrictive pericarditis.     

Neue Möglichkeiten der Diagnostik und Therapie der Perikarditis

Pericarditis is an inflammatory disorder of the pericardium with or without an associated pericardial effusion. The diagnosis is based on the clinical manifestations and typical ECG changes. Echocardiography is essential to reveal the size of the pericardial effusion and to determine its hemodynamic significance. The precise etiology of pericarditis may be established by pericardiocentesis, pericardioscopy and targeted biopsy and consecutive pericardial fluid and biopsy analysis by molecular biology, cytology, microbiology and immunological techniques. Non steroidal anti-inflammatory drugs and/or colchicine are the mainstay of anti-inflammatory treatment of pericarditis. Systemic corticoid treatment should be restricted to patients with associated autoimmune disorder, relapsing pericarditis and as a complementary therapy in tuberculous pericarditis. In autoreactive pericarditis intrapericardial instillation of triamcinolone is effective with few side effects. In malignant pericarditis the intrapericardial administration of cisplatin prevents early recurrences.     

Non-surgical treatment of purulent pericarditis, due to non-encapsulated Haemophilus influenzae, in an immunocompromised patient.

A 59-year-old woman suffering from rheumatoid arthritis was admitted with pleural empyema and pericarditis due to non-encapsulated H. influenzae, and developed signs of cardiac tamponade. Purulent pericarditis resolved after ultrasound-guided percutaneous aspiration and systemic antimicrobial therapy. Serial echocardiographic examinations showed a slowly vanishing effusion. Long term follow-up revealed no evidence of pericardial constriction. This case illustrates that life-threatening purulent pericarditis in an immunocompromised patient may respond well to non-surgical treatment.     

Procainamide-induced lupus erythematosus pericarditis encountered during coronary bypass sugery

Procainamide is probably the most common offending drug responsible for the drug-induced lupus erythematosus syndrome today. Pericarditis has been reported to occur in from 14 to 18 per cent of the cases of procainamide-induced lupus erythematosus, and occasional reports of massive pericardial effusion, pericardial tamponade and constrictive pericarditis have appeared in the literature. We describe a patient who presented with features of procainamide-induced lupus erythematosus without any clinical evidence of pericarditis. He underwent coronary bypass surgery 12 days after administration of the drug was stopped and was found to have a significant pericardial effusion at the time of surgery; histologic examination of pericardial tissue and pericardial fluid confirmed that the pericardial effusion was related to the procainamide-induced lupus syndrome. The incidence of pericarditis in procainamide-induced lupus erythematosus may be higher than presently accepted figures would indicate. Symptoms and signs related to procainamide-induced lupus pericarditis may cause diagnostic confusion with common postoperative bypass complications; the full implications of this disease entity to the patient undergoing coronary bypass are unknown.     

Diagnosis and management of pericardial effusion

Pericardial effusion is a common finding in everyday clinical practice.The first challenge to the clinician is to try to establish an etiologic diagnosis.Sometimes,the pericardial effusion can be easily related to a known underlying disease,such as acute myocardial infarction, cardiac surgery,end-stage renal disease or widespread metastatic neoplasm.When no obvious cause is apparent,some clinical findings can be useful to establish a diagnosis of probability.The presence of acute inflammatory signs(chest pain,fever,pericardial friction rub) is predictive for acute idiopathic pericarditis irrespective of the size of the effusion or the presence or absence of tamponade.Severe effusion with absence of inflammatory signs and absence of tamponade is predictive for chronic idiopathic pericardial effusion,and tamponade without inflammatory signs for neoplastic pericardial effusion.Epidemiologic considerations are very important,as in developed countries acute idiopathic pericarditis and idiopathic pericardial effusion are the most common etiologies,but in some underdeveloped geographic areas tuberculous pericarditis is the leading cause of pericardial effusion.The second point is the evaluation of the hemodynamic compromise caused by pericardial fluid.Cardiac tamponade is not an"all or none"phenomenon,but a syndrome with a continuum of severity ranging from an asymptomatic elevationof intrapericardial pressure detectable only through hemodynamic methods to a clinical tamponade recognized by the presence of dyspnea,tachycardia,jugular venous distension,pulsus paradoxus and in the more severe cases arterial hypotension and shock.In the middle,echocardiographic tamponade is recognized by the presence of cardiac chamber collapses and characteristic alterations in respiratory variations of mitral and tricuspid flow.Medical treatment of pericardial effusion is mainly dictated by the presence of inflammatory signs and by the underlying disease if present.Pericardial drainage is mandatory when clinical tamponade is present.In the absence of clinical tamponade,examination of the pericardial fluid is indicated when there is a clinical suspicion of purulent pericarditis and in patients with underlying neoplasia.Patients with chronic massive idiopathic pericardial effusion should also be submitted to pericardial drainage because of the risk of developing unexpected tamponade.The selection of the pericardial drainage procedure depends on the etiology of the effusion.Simple pericardiocentesis is usually sufficient in patients with acute idiopathic or viral pericarditis.Purulent pericarditis should be drained surgically,usually through subxiphoid pericardiotomy. Neoplastic pericardial effusion constitutes a more difficult challenge because reaccumulation of pericardial fluid is a concern.The therapeutic possibilities include extended indwelling pericardial catheter,percutaneous pericardiostomy and intrapericardial instillation of antineoplastic and sclerosing agents.Massive chronic idiopathic pericardial effusions do not respond to medical treatment and tend to recur after pericardiocentesis, so wide anterior pericardiectomy is finally necessary in many cases.     

Toxoplasma pericarditis without immunosuppressant disorder detected by polymerase chain reaction of pericardial fluid: a case report

There have been several case reports, a total of 22 up to the present, of toxoplasma pericarditis. Out of them, in only a few cases the diagnosis was properly made with a proof of the microscopic presence of Toxoplasma gondii. This is the first report of toxoplasma pericarditis in which the presence of Toxoplasma gondii was detected by polymerase chain reaction of pericardial effusion. In addition, the previous reports will be reviewed, and compared to this present case. A 29-year-old woman, without immunosuppressant disorder, suffering from fever and orthopnea was admitted to our hospital. Blood chemistry findings indicated mild liver dysfunction and inflammation. Chest radiography showed cardiac enlargement. Electrocardiography showed sinus tachycardia and ST elevation. Echocardiography revealed a massive pericardial effusion. Pericardiocentesis demonstrated 638 ml of bloody fluid. Cytologic study of the fluid was class II for malignancy, and polymerase chain reaction to tuberculosis was negative. However, a high titer of the anti-toxoplasma antibody of 1: 20,480 (passive hemagglutination) indicated pericarditis caused by Toxoplasma gondii. Subsequently, Toxoplasma gondii was identified in the pericardial effusion by polymerase chain reaction. Clinical symptoms improved after pericardiocentesis, but 2 months later pericarditis recurred. Treatment was started with 800 mg acetylspiramycin daily but failed to improve the symptoms. Because of the development of pleuritis, treatment was changed to sulfadoxine 1,000 mg/pyrimethamine 50 mg. After the treatment with them, her symptoms improved. Only 22 cases of toxoplasma pericarditis have been reported worldwide and 15 of those cases were without immunosuppressant disorder. The usual symptoms at the onset of pericarditis without immunosuppressant disorder are fever, dyspnea and chest pain. Seven patients developed cardiac tamponade. Pericardiocentesis was performed in 8 cases and the pericardial fluid was hemorrhagic in 6. Pericardial thickening was detected in 5 cases. The diagnosis of toxoplasma infection is very difficult, because asymptomatic infection of Toxoplasma gondii is very common. Pericarditis is a disease difficult to confirm the etiology. Detection of Toxoplasma gondii in pericardial effusion by the polymerase chain reaction is very useful for its diagnosis.     

Macrophage migration inhibitory factor in rheumatoid pericarditis.

The pericardial effusion in a case of rheumatoid pericarditis was studied to determine whether immune complexes and mediators of cellular immunity, represented by migration inhibitory factor (MIF), were present. MIF-like activity was detected in the pericardial fluid, but only traces of immune complexes were revealed by ultracentrifugation. The MIF-like activity was partially characterized by column fractionation and sugar inhibition tests. The role of lymphokines in the pathogenesis of this case of rheumatoid pericarditis is strongly suggested.     

Macrophage migration inhibitory factor in rheumatoid pericarditis

The pericardial effusion in a case of rheumatoid pericarditis was studied to determine whether immune complexes and mediators of cellular immunity, represented by migration inhibitory factor (MIF), were present. MIF-like activity was detected in the pericardial fluid, but only traces of immune complexes were revealed by ultracentrifugation. The MIF-like activity was partially characterized by column fractionation and sugar inhibition tests. The role of lymphokines in the pathogenesis of this case of rheumatoid pericarditis is strongly suggested.     

Tamponnade tardive : quatre cas de complication rare du traumatisme fermé du thorax

Delayed post-traumatic pericardial effusion is a rare condition after blunt trauma. The diagnosis of the effusion can be made by the clinical signs, which is not very specific and the cardiac echography. The etiological diagnosis remains difficult because it requires the elimination of the other causes of pericarditis. Their treatment consists in evacuating the pericardial effusion. The evolution thereafter is simple. We report four cases of patients with pericardial effusion late after a thoracic injury. Imaging the blood test, the examination of the pericardial fluid and the anatomopathological examination of the pericardium, eliminates the other etiologies.     

Effusive constrictive pericarditis due to rheumatoid arthritis revealed by pericardiocentesis with simultaneous pressure recording--a case report

A 59-year-old man had a history of rheumatoid arthritis. He presented with incurable pericardial effusion. He was repeatedly treated with pericardiocentesis with only transient attenuation of his symptoms because the underlying pericardial constriction had been overlooked. This time the authors diagnosed effusive constrictive pericarditis due to rheumatoid arthritis using the hemodynamic findings observed before and after pericardiocentesis.     

New Directions in Diagnosis and Treatment of Pericardial Disease A Project of the Taskforce on Pericardial Disease of the World Heart Federation

New directions in the diagnosis and treatment of pericardial diseases synthesize the achievements of modern imaging with molecular biology and immunology techniques. Comprehensive and systematic implementation of new techniques of pericardiocentesis, pericardial fluid analysis, pericardioscopy, epicardial and pericardial biopsy, as well the application of comprehensive molecular biology and immunology techniques for pericardial fluid and biopsy analyses have opened new windows to the pericardial diseases, permitting early specific diagnosis and creating foundations for etiologic treatment in many cases. In patients with recurrent pericarditis, resistant to conventional treatments, as well as in patients with neoplastic pericarditis an alternative intrapericardial treatment regimen was suggested by the Taskforce on Pericardial Diseases of the World Heart Federation. Intrapericardial application of medication avoids systemic side effects with increased local efficacy. The following protocols are proposed: CIRP (colchicine in recurrent pericarditis) - colchicine vs placebo in chronic/recurring pericarditis without pericardiocentesis; TRIPE (triamcinolone in pericardial effusion) - intrapericardial instillation of triamcinolone + 6 months colchicine vs pericardial puncture without instillation + 6 months colchicine; NEPIN (neoplastic effusion and pericardial instillation) - pericardiocentesis and drainage + intrapericardial instillation of cisplatin or thiotepa. Zusammenfassung Innovationen in der Diagnostik und Therapie der Perikarderkrankungen stellen die Implementierung molekularbiologischer und immunologischer Methoden und die Anwendung der Perikardioskopie für die gezielte epikardiale und/oder perikardiale Biopsie dar. Damit konnte ein wesentlicher Beitrag zur Ätiologie und Pathogenese der Perikarderkrankungen und zu einer pathophysiologisch und ätiopathogenetisch begründeten Therapie geleistet werden. Bei Patienten mit rezidivierenden Perikarditiden, die nicht auf eine herkömmliche antiphlogistische Therapie ansprachen, oder bei Patienten mit malignem Perikarderguss ergibt sich durch intraperikardiale Instillation von kristalloidem Triamcinolon oder Cisplatin die Möglichkeit einer hoch dosierten, lokoregionalen Therapie ohne gravierende systemische Nebenwirkungen. Folgende Therapieprotokolle wurden dafür vorgeschlagen und sollen im Rahmen einer randomisierten Therapiestudie eingesetzt werden: CIRP (Colchicin bei Patienten mit rezidivierender Perikarditis ohne Perikardpunktion); TRIPE (Perikardpunktion und intraperikardiale Therapie mit Triamcinolon vs. Plazebo + sechs Monate Colchicin); NEPIN (Perikardpunktion und intraperikardiale Therapie mit dem Cisplatin oder Thiothepa).     

Pericardial Tamponade Masquerading as Septic Shock

A 53-year-old man with steroid dependent rheumatoid arthritis presented with fever and serous articular drainage. Oral antibiotics were initially prescribed. Subsequent hemodynamic instability was attributed to septic shock. Further evaluation revealed a pericardial effusion with tamponade. Pericardiocentesis of purulent fluid promptly corrected the hypotension. Proteus mirabilis was later isolated from both the infected joint and the pericardial fluid. This is the first report of combined Proteus mirabilis septic arthritis and purulent pericarditis. It documents the potential for atypical transmission of Gram-negative pathogens, to the pericardium, in patients with a high likelihood of preexisting pericardial disease. In immunocompromised patients, the typical signs and symptoms of pericarditis may be absent, and the clinical presentation of pericardial tamponade may be misinterpreted as one of septic shock. This case underscores the value of a careful physical examination and proper interpretation of ancillary studies. It further illustrates the importance of initial antibiotic selection and the need for definitive treatment of septic arthritis in immunocompromised patients. Potential Financial Conflicts of Interest: The authors do not have any potential financial conflicts of interest to disclose.     

IgG4-related disease manifesting as pericarditis with elevated adenosine deaminase and IL-10 levels in pericardial fluid

A 78-year-old female with massive pericardial effusion fulfilled diagnostic criteria for immunoglobulin G4 (IgG4)-related disease. Although her adenosine deaminase (ADA) level in the pericardial effusion was high, all the tests for tuberculosis infection were negative. Immunostaining of the pericardium biopsy specimen revealed remarkably increased IgG4-positive cells. This is the first report describing IgG4-related pericarditis with elevated ADA level. We also demonstrate the elevated interleukin-10 (IL-10) level in pericardial fluid and IL-10-producing T-cells in the pericardium.     

Acute pericarditis as the initial manifestation in Still's disease in an adult

Almost 90% of primary acute pericarditis are idiopathic. Between specifics forms, a very low percentage of cases are due to chronic rheumatic diseases. A case of adult Still's disease (juvenile chronic rheumatoid arthritis) with acute pericarditis being the first clinical manifestation (besides fever and general syndrome) is presented. Therapy with oral prednisone was rapidly effective, and pericardial effusion resolved after 3 weeks of treatment, as echocardiography showed.