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A 54-year-old white man presents to the local emergency department with acute pain affecting both shoulders and his left hand, which also shows diffuse swelling. The patient explains that he had been admitted to the hospital 2 weeks previously, after having a heart attack. Records show that the patient had experienced an ST elevation myocardial infarction (MI); treatment had involved percutaneous intervention (PCI) and drug-eluting stent placement, and antiplatelet treatment with a loading dose of clopidogrel.

Because his MI had been complicated by left ventricular thrombus, the patient is taking dual antiplatelet therapy with clopidogrel and aspirin when he presents to the emergency department with bilateral shoulder pain and pain and swelling of his left hand.

Upon reviewing his medication history, clinicians suspect his symptoms are statin-induced myalgias, and atorvastatin is discontinued. As well, the patient's furosemide dose is adjusted in response to acute renal insufficiency.

Within a week, the man returns to the emergency department reporting that the pain in his shoulders has intensified. He notes that he is now experiencing tingling and some loss of sensation in both hands and arms, as well as new pain affecting his left hand and his right hip.

Clinical Evaluation

The patient is sitting comfortably during his examination; his heart rate is 88 bpm, blood pressure is 156/57 mmHg, and temperature is 100°F (37.8°C). Results of assessment of his cardiovascular system, abdomen, lungs, and skin are within normal limits.

Neurological assessments indicate normal sensory function, normal deep-tendon reflexes, and normal strength in all extremities, with one exception: power in both the proximal and distal muscles of his left upper hand are 4/5.

Examination of the patient's joints identifies numerous problems, including the following:

• Heberden's nodes and Bouchard's nodes on fingers 2 through 5 of both hands

• Swelling and tenderness in the dorsum of the left hand and wrist, with loss of range of motion

• Restricted active and passive range of motion in both shoulders

• Minimal effusion with no tenderness, and normal range of motion in the right knee

Laboratory and Imaging Test Results

• White blood cell count: 13.5 K/mm³ (normal = 3.7-10.5 K/mm³) with 78% neutrophils, 8.1% lymphocytes, and 0.9% normal eosinophils

• Blood urea nitrogen: 38 mg/dL (normal = 10-20 mg/dL)

• Serum creatinine: 1.3 mg/dL (normal = 0.7-1.3 mg/dL)

• Erythrocyte sedimentation rate (ESR): 101 mm/h (normal = 0-15 mm/h)

• C-reactive protein (CRP): 29.7 mg/dL (normal = 0-0.5 mg/dL)

The patient tested within the normal range for serum uric acid level, liver function, and serum creatine kinase.

An MRI of the cervical spine identified severe stenosis at C5–C6 as the cause of the tingling and numbness in both arms as well as the weakness in his left hand. The patient is fitted with a soft cervical collar to stabilize the cervical spine. Clinicians suggest elective surgery at a time when the patient is able to tolerate pre-surgery anticoagulation and dual-antiplatelet agents.

Day 3: Ongoing Investigations

On his third day in the hospital, the patient's left hand is no longer swollen or painful. However, he is now having the same pain in his right hand and arm, and there is evidence of diffuse swelling of the soft tissues.

Inflammation persists, with continued elevated of his ESR (116 mm/h) and CRP (26.6 mg/dL). The possibility of an infectious disease etiology is eliminated after laboratory test results are negative.

Day 4: Diagnosis of Exclusion

Provisional diagnosis of clopidogrel-induced acute polyarticular inflammatory arthritis is made based on exclusion of other potential causes, including statin-induced myalgia, an infectious process, crystal arthropathy, rheumatoid arthritis, and immune-mediated reaction to other medications.

Clinicians discontinue clopidogrel, and replace it with prasugrel 10 mg orally daily along with ongoing aspirin for prevention of post-PCI thrombosis. Within 24 hours, the swelling and pain affecting the patient's right arm resolve. As well, tests show decreasing inflammation, with reductions in the ESR of 11 mm/h and the CRP of 5.1 mg/dL. The symptoms do not recur, making arthrocentesis unnecessary.

While severe stenosis at C5–C6 continues to cause bilateral tingling and numbness in the patient's hands and arms, as well as weakness in his left arm, these symptoms remain stable.



Q2:

Discussion

Clinicians reporting this ¹ note that clopidogrel-related inflammatory arthritis is a rare condition that requires a high level of suspicion. They observe that identifying the etiology of inflammatory arthritis in a patient on clopidogrel involves extensive evaluation, as it is a diagnosis of exclusion.

Other causes to be considered include statin-induced myalgia, infectious crystal arthropathy, rheumatoid arthritis, and immune-mediated reaction to other medications.

Characteristics of this case that help differentiate migratory polyarthritis from polyarticular gout include that in gouty arthritis, symptoms in each joint typically persist for approximately 3–10 days without any active intervention,² whereas this patient's symptoms migrated to another joint after 1-2 days.

As well, serum uric acid levels are often normal to low during an acute gout attack,³ whereas this patient had elevated serum uric acid levels (which the authors attributed to acute renal insufficiency). And the possible etiology of an acute allergic reaction is excluded by the fact that the patient's eosinophil count was within normal limits.^4-6

In the same report, the authors described a similar reaction to clopidogrel in a 77-year-old white man who presented with pain in the left shoulder and left hip. He had a history of hypertension, lymphoma, and recently diagnosed crescendo angina requiring PCI several weeks previously.

In the case of the second patient, initial symptoms of migratory joint pain and swelling were intermittent -- perhaps due in part to treatment with hydromorphone and colchicine -- and were associated with subjective fever, chills, weight loss, and asthenia.

The authors noted that in the case reported here, only 2-3 days elapsed between clopidogrel treatment and the development of symptoms. This is in contrast to the second patient, whose symptoms developed approximately 1 week after starting dual-antiplatelet therapy with clopidogrel and aspirin. Both patients had received the same initial loading dose of clopidogrel.

Post-MI dual-platelet therapy has been used in the of coronary artery disease for several decades,⁷ and is important to reduce the risk of stent thrombosis, MI, and, possibly, cardiovascular death,^8,9 the case authors note. In all the reported cases, inflammatory markers returned to baseline and the symptoms resolved after clopidogrel was discontinued.

Clopidogrel is a thienopyridine, selective, irreversible adenosine diphosphate (ADP) receptor/P2Y12 inhibitor. While the mechanism of clopidogrel's noted proinflammatory effect is unknown, it may be due to an unidentified effect on cells, rather than on platelets, through an increase in proinflammatory cytokines such as interferon-γ, interleukin (IL)-6, and IL-1β.¹⁰

Although a of inflammatory arthritis has been reported in a patient who received ticlopidine, these rare cases do not appear to represent an effect of the medication class. Alternative antiplatelet therapy options that have not been associated with this adverse effect include ticagrelor or prasugrel.

Notably, the ticlopidine case report¹¹ generated a cautionary ¹² entitled "Careless talk may cost lives in attributing adverse events to ADP receptor antagonists."

The authors of this case emphasize the importance of reporting such adverse effects in order to increase awareness and improve accurate and timely diagnosis.

References

1. Ayesha B, et al: Clopidogrel-Associated Migratory Inflammatory Polyarthritis. Am J Case Rep, 2019; 20: 489-492

2. Schlee S, et al: Crystal arthritides – gout and calcium pyrophosphate arthritis: Part 2: Clinical features, diagnosis and differential diagnostics. Z Gerontol Geriatr 2018; 51(5): 579–584

3. Badulescu M, et al: Acute gout attack with normal serum uric acid levels. Rev Med Chir Soc Med Nat Iasi, 2014; 118(4): 942–945

4. Calogiuri GF, et al: A joint allergist/cardiologist classification for thienopyridines hypersensitivity reactions based on their symptomatic patterns and its impact on the management strategies. Int J Cardiol, 2016; 222: 509–514

5. Dong P, et al: Genetic polymorphism of CYP2C19 and inhibitory effects of ticagrelor and clopidogrel towards post-percutaneous coronary intervention (PCI) platelet aggregation in patients with acute coronary syndromes. Med Sci Monit 2016; 22: 4929–4936

6. Jia M, et al: Novel oral P2Y12 inhibitor prasugrel vs. clopidogrel in patients with acute coronary syndrome: Evidence based on 6 studies. Med Sci Monit 2015; 21: 1131–1137

7. Muller KA, et al: Platelets, inflammation and anti-inflammatory effects of antiplatelet drugs in ACS and CAD. Thromb Haemost 2015; 114(3): 498–518

8. Dalby AJ, et al: Dual antiplatelet therapy in patients with diabetes and acute coronary syndromes managed without revascularization. Am Heart J 2017; 188: 156–166

9. Lettino M, et al: Antiplatelet and antithrombotic treatment for secondary prevention in ischaemic heart disease. Eur J Prev Cardiol 2017; 24(3 Suppl.): 61–70

10. Garcia AE, et al: Clopidogrel, a P2Y12 receptor antagonist, potentiates the inflammatory response in a rat model of peptidoglycan polysaccharide-induced arthritis. PLoS One 2011; 6(10): e26035

11. Dakik HA, et al: Drug points: Ticlopidine associated with acute arthritis. BMJ 2002; 324(7328): 27

12. Green MJ, et al. Commentary: Careless talk may cost lives in attributing adverse events to ADP receptor antagonists. BMJ 2002; 324:1039

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