To the Editor:
Complex regional pain syndrome (CRPS) is characterized by persistent regional pain associated with sensory, motor, sudomotor, vasomotor, and/or trophic changes that are disproportionate to an inciting event.
1
Although CRPS after trauma, infection, or surgery has been well documented, drug-induced CRPS is uncommon and has been reported anecdotally after use of phenobarbital,2
cocaine,3
and cyclosporine.4
Only one case of CRPS after infliximab infusion has been reported in the pediatric literature.5
We report the first case of CRPS in an adult after infliximab infusion.Case Report
The patient, a 36-year-old woman with ankylosing spondylitis and psoriatic arthritis since the age of 10, had multilevel spine and diffuse joint involvement requiring bilateral arthroplasty of the knees, shoulders, and hips. Previously, she had been treated with methotrexate and steroids. For the last seven years, her immune-modulating regimen consisted of infliximab 600 mg (10 mg/kg) administered intravenously every four weeks, with diphenhydramine, acetaminophen, and hydrocortisone premedication.
Two days after receiving her usual dose of infliximab through peripheral intravenous access in her right arm, the patient awoke with severe right lower extremity pain, swelling, and weakness that precluded standing and ambulation. There was no history of trauma, insect bites, infection, bowel or bladder incontinence, or involvement of any other extremity. On examination, there was marked edema of the right lower extremity, with a circumference of 41 cm at its largest diameter around the calf, compared with 37 cm in the left leg. The right leg was exquisitely tender throughout, with hyperalgesia and allodynia to the extent that the patient reported pain with waving of the examiner's hand above her leg. Muscle tone and strength were difficult to assess due to pain and guarding, but the patient was unable to lift the right leg against gravity, compared with the left, which was at baseline strength. Capillary refill and pulses were normal bilaterally, with no difference in skin temperature or color. Deep tendon reflexes were absent at the ankles and knees, with flexor plantar responses bilaterally. The remainder of the examination was unremarkable except for limited range of motion of proximal joints due to long-standing arthropathy.
Initial work-up included an ultrasound of her lower extremities and routine laboratory studies, which were negative except for a urinary tract infection. Magnetic resonance imaging (MRI) of the right leg showed increased fluid in the soft tissue of the thigh, but no clear evidence of infection. MRI of the lumbar spine was remarkable only for spondylotic changes that were not significantly changed from prior imaging. The patient was diagnosed with CRPS and treated with narcotic medications and physical therapy, with significant improvement of symptoms over five days. On follow-up three weeks later, electromyography of the right leg was normal and the patient had returned to her baseline level of functioning. She has since resumed her regularly scheduled infusions of infliximab without further complication.
Comment
The diagnosis of CRPS in our patient was established clinically based on recently proposed diagnostic criteria and the absence of other pathology despite an extensive evaluation.
1
Although a variety of infusion reactions have been reported to occur with infliximab, CRPS associated with infliximab has been described only once before in a 15-year-old boy who developed burning pain and paresthesias in the right lower extremity two days after receiving 5 mg/kg of infliximab intravenously for Crohn's disease.5
He was treated with pain medications and physical therapy, and had a full recovery within three weeks.The pathophysiology of CRPS is unclear, especially in association with medications. CRPS associated with phenobarbital may be related to its effects on sympathetic ganglia, disinhibition of lower level pain control neurons, or the paradoxical increase in neuronal firing seen in vitro at lower phenobarbital concentrations.
2
The pathophysiology of cocaine-induced CRPS may be related to ischemic autonomic injury secondary to vasoconstriction.3
Direct neurotoxicity may explain cyclosporine-associated CRPS.4
The occurrence of CRPS in patients being treated with infliximab is particularly intriguing given reports of anti-tumor necrosis factor-α (TNFα) agents being used to successfully treat CRPS. Elevated levels of TNFα and interleukin-6 have been demonstrated in patients with CRPS and may explain this treatment effect.
6
, 7
Kachko et al.
5
suggest a hypersensitivity reaction as a possible explanation for the occurrence of CRPS in their pediatric patient. In contrast, our patient continued to receive infliximab infusions with no further complications to date. This may represent a negative rechallenge phenomenon, which was previously reported in three patients who developed leukocytoclastic vasculitis associated with infliximab, but with lack of recurrence after rechallenge.8
Our patient represents the first reported case of CRPS in an adult after infliximab infusion. CRPS is likely a rare complication associated with infliximab, but when other causes have been excluded, it should be suspected in patients with localized pain and sensorimotor changes temporally related to the infusion.
References
- Proposed new diagnostic criteria for complex regional pain syndrome.Pain Med. 2007; 8: 326-331
- Reflex sympathetic dystrophy associated with antiepileptic drugs.Epilepsia. 1994; 35: 394-399
- Cocaine-induced reflex sympathetic dystrophy.Clin Nucl Med. 2000; 25: 863-865
- Reflex sympathetic dystrophy syndrome of the lower limbs in renal transplant patients treated with cyclosporin A.Arthritis Rheum. 1991; 34: 625-630
- Complex regional pain syndrome type I after infliximab infusion.Paediatr Anaesth. 2007; 17: 1112-1114
- Successful treatment of CRPS 1 with anti-TNF.J Pain Symptom Manage. 2004; 27: 101-103
- Evidence for local inflammation in complex regional pain syndrome type 1.Mediators Inflamm. 2002; 11: 47-51
- Leukocytoclastic vasculitis associated with tumor necrosis factor-alpha blocking agents.J Rheumatol. 2004; 31: 1955-1958
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Published online: July 22, 2008
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© 2008 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc.
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