Correspondence *Division of Rheumatology, Catholic University of the Sacred Heart, 00168 Rome, Italy

Email gf.ferraccioli@rm.unicatt.it

The case

A 49-year-old man presented at a hospital with an arthritic flare-up and dyspnea on exertion with a cough. He had a 5-year history of symmetrical polyarthritis and suffered from morning stiffness and swelling in his feet, hands and major joints. Since the onset of his symptoms, the patient had taken 5–15 mg prednisolone daily. He had 20 swollen and tender joints, and scored 1.5 on a HEALTH ASSESSMENT QUESTIONNAIRE (HAQ) and 5.6 on the DISEASE ACTIVITY SCORE (DAS). Laboratory analyses revealed elevations in the patient's erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), lipid levels and white-blood-cell count (Table 1). His kidney and liver function were normal. A panel of laboratory assays to detect rheumatoid factor, ANTICARDIOLIPIN ANTIBODY, antinuclear antibody, anti-2-glycoprotein I antibodies and LUPUS ANTICOAGULANT (LA) yielded negative results (Table 1). No significant cardiac abnormalities were detected on electrocardiography and clinical investigation. Chest radiography demonstrated normal heart size and absence of pulmonary involvement or pleural effusions. The patient's blood pressure was normal, he did not have diabetes or hypertension, and he had no family history of cardiovascular disease.

Table 1 Summary of laboratory test results carried out as part of the differential diagnosis in a patient with rheumatoid arthritis.^a

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The patient presented with several American College of Rheumatology classification criteria for rheumatoid arthritis (RA): morning stiffness in more than three joint areas; symmetrical arthritis in the hands; and bone erosions. He was prescribed 20 mg methotrexate weekly, 3 mg/kg ciclosporin daily and 5 mg prednisolone daily. Over the next 3 months, however, this treatment did not alleviate the pain and swelling in the patient's joints. Once a purified protein derivative (Mantoux) test had excluded latent tuberculosis, infliximab—an antibody to tumor necrosis factor (TNF-)—was added to his therapy regimen. This drug was administered intravenously—initially at 3 mg/kg, then at 6 mg/kg per infusion at weeks 2 and 6 and every eighth week thereafter for 6 months. The patient's dose of methotrexate was not altered, but prednisolone therapy was increased to 25 mg daily for 4 weeks, after which it was reduced to 5 mg every month. No adverse side effects were reported while the patient was taking this therapy regimen.

Six months later, however, the patient was admitted to hospital with another arthritic flare-up, acute retrosternal chest pain and stress dyspnea. The patient had 18 swollen and tender joints, a HAQ score of 1.5, a DAS of 5.41, an ESR of 50 mm/h and a CRP level of 136.4 mg/l. His levels of creatinine kinase-MB and troponin were within normal range (Table 1). Echocardiography demonstrated cardiac wall-motion abnormalities with anteroseptal hypokinesis, but the chamber dimensions, ejection fraction and diastolic function of the left ventricle were normal (Figure 1). Aortic valve insufficiency was also detected and deemed moderate according to the two-dimensional view of the regurgitant jet. The aortic cusps were fibrotic and no abnormalities were seen in the aortic root.

Figure 1 An echocardiogram showing septal dyskinesis of the patient's left ventricle.

 

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Technetium-99m-labeled (^99mTc)-methoxyisobutyl-isonitrile stress myocardial scintigraphy revealed hypoperfusion in the medial anterior wall and apex, with normal perfusion at rest (Figure 2). Cardiac catheterization with coronary angiography demonstrated normal viability of the left anterior descending, distal circumflex and posterior descending arteries.

Figure 2 Myocardial scintigraphs showing (A) hypoperfusion of the left ventricular wall during the stress phase and (B) reperfusion of the left ventricular wall at rest.

 

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Since no evidence of atherosclerotic vessel disease was detected by coronary angiography, laboratory assays were carried out to screen for the presence of thrombophilic factors. Although tests for hereditary coagulation factors, anticardiolipin, anti- glycoprotein antibodies, tissue thromboplastin inhibition and kaolin clotting time yielded normal or negative results, the patient's DILUTE RUSSELL VIPER VENOM TIME (DRVVT) and DRVVT ratio were higher than normal, indicating the presence of LA. Assays for rheumatoid factor, anticitrullinated peptide, antinuclear antibodies and anti-double-stranded DNA antibodies were all negative (Table 1).

The acute onset of the patient's stress dyspnea and retrosternal chest pain, and evidence of myocardial ischemia in the absence of coronary atherosclerosis, were indicative of ischemic myocardial microangiopathy. After 2 weeks, the patient was discharged from hospital with the following treatment regimen: 20 mg methotrexate weekly, 100 mg anakinra via subcutaneous injection daily, 100 mg aspirin daily, 75 mg clopidogrel daily and 5 mg prednisolone daily. After 3 months, the patient had 11 swollen and tender joints, his HAQ score had reduced to 0.5, his DAS was 3.38, ESR 29 mm/h and CRP 24 mg/l. A DRVVT of 1.48 s and a DRVVT ratio of 1.6 confirmed the presence of LA. At 6-month follow-up the patient's clinical and serological parameters were stable, but abnormal cardiac kinesis was still evident on echocardiography.

Discussion of diagnosis

Patients with RA have an increased risk of acute myocardial infarction or unrecognized myocardial infarction and sudden death. This elevated risk is caused mainly by the development of atherosclerosis and, in addition traditional atherosclerotic risk factors and endothelial dysfunction have an important role in this process. Endothelial dysfunction has been associated with both macrovascular disease and microangiopathy. Some studies indicate that proinflammatory cytokines and metabolic abnormalities associated with systemic inflammation can lead to chronic endothelial injury.^{1, 2}

Here we describe a patient with RA refractory to treatment with disease-modifying antirheumatic drugs and TNF- blockers who developed LA and myocardial ischemia without evidence of coronary atherosclerosis. Signs of localized cardiac hypokinesia on echocardiography were confirmed by myocardial scintigraphy, which revealed hypoperfusion in the corresponding area of tissue.

In our opinion, the patient's persistent inflammatory condition and the presence of thrombophilic autoantibodies point to a diagnosis of ischemic microangiopathy. In patients with RA, ischemic microangiopathy occurs less frequently than myocardial infarction secondary to accelerated atherosclerosis, although several case reports describe thrombotic microangiopathy associated with RA and ANTIPHOSPHOLIPID SYNDROME.³

ANTIPHOSPHOLIPID ANTIBODIES have been associated with myocardial infarction in the absence of clinical or subclinical atherosclerosis (e.g. carotid intima–media ratio, carotid plaque, helical CT coronary calcium).⁴ In this case, antiphospholipid-mediated endothelial cell activation and chronic systemic inflammation might have acted together to sustain a proadhesive, proinflammatory and procoagulant phenotype leading to ischemic microangiopathy. Moreover, the patient's aortic valve abnormality could be considered a manifestation of antiphospholipid-associated cardiac valve disease.⁵ Persistence of LA after an ischemic event despite discontinuation of infliximab therapy led to suspicions of antiphospholipid syndrome. Indeed, persistence of LA after 12 weeks is one of the revised classification criteria for antiphospholipid syndrome.⁶ Drug-related autoimmune disease was excluded as a possible cause of cardiac involvement in this case and negative results for antinuclear antibody and anti-double-stranded DNA ruled out a systemic lupus erythematosus-like disease and variant types of angina.

Treatment and management

In this particular case, the patient's risk of myocardial ischemia might have been increased by switching to another TNF- blocker. In an attempt to control his RA symptoms, while avoiding persistent ischemic damage to the heart, therapy with anakinra was started. This drug blocks the action of interleukin 1 (IL-1) and belongs to the class of drugs called interleukin-receptor antagonists. Anakinra is an effective treatment for RA and in clinical trials to date has not been linked with increased risk of adverse cardiovascular events or induction of autoantibodies.⁷ Methotrexate treatment was continued in this patient for the control of inflammation and disease progression. Antiplatelet therapy with clopidogrel and aspirin was also administered to reduce the patient's risk of an acute coronary syndrome.⁸

TNF- is a cytokine that has a significant role in the initiation and perpetuation of inflammatory processes in both RA and atherogenesis. Controlling inflammation with TNF- blockers can, therefore, reduce vascular endothelial damage. Anti-TNF- therapy can also improve endothelial function; this improvement has been demonstrated by flow-mediated vasodilatation of the brachial artery and increased blood flow in the forearm after provocation testing with acetylcholine.⁹ Autoantibodies can, however, occur as a consequence of TNF- blockade, possibly by promotion of humoral autoimmunity and inhibition of TNF-, which is normally released as part of the cytotoxic T-lymphocyte response that suppresses autoreactive B cells.¹⁰ Antinuclear antibodies and anti-double-stranded DNA have been detected in patients with RA after anti-TNF- therapy along with antiphospholipid antibodies, but to our knowledge this is the first report of LA.¹¹ Although these autoantibodies are not usually linked with clinical manifestations, the presence of antiphospholipid autoantibodies in this case, together with a high level of inflammation, is likely to have resulted in endothelial damage and a thrombophilic status.

Conclusion

Here we describe a patient affected by RA, who developed LA and myocardial ischemia while receiving infliximab therapy. Patients with active RA have a high risk of cardiovascular manifestations independent of traditional risk factors for coronary atherosclerosis. In such cases, particularly when patients have or develop antiphospholipid antibodies, RA therapy needs to be tailored to manage the cardiovascular effects. Persistent chronic systemic inflammation in this patient, despite therapy with disease-modifying antirheumatic drugs and TNF- blockers, might have contributed to development of an antiphospholipid-like syndrome and ischemic myocardial microangiopathy.

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