Volume 27, Issue 2 , Pages 101-103, February 2004
Successful treatment of CRPS 1 with anti-TNF
Article Outline
To the Editor:
Complex regional pain syndrome type 1 (CRPS 1) is a complication that usually occurs in an extremity following surgery or trauma. CRPS 1 is characterized by spontaneous pain, allodynia, and hyperalgesia, is not restricted to the region of a single peripheral nerve, and is often disproportionate to the precipitating injury. Clinical signs include edema, disturbed blood flow to the skin, or abnormal sudomotor activity in the affected limb. The diagnosis of CRPS 1 is excluded by the existence of other conditions that account for the degree of pain and dysfunction.1
The pathophysiology of CRPS 1 has been ascribed to peripheral afferent, efferent, and central mechanisms, or combinations of all of the above.2 Consequently, there has been no clear consensus about treatment. CRPS 1 may be resistant to therapeutic strategies used to treat neuropathic pain. The disease itself can be self-limiting, but is often associated with a high morbidity.
Recently, we showed evidence of an inflammatory process in CRPS 1 by detecting the presence of cytokines IL-6 and TNFα.3 As a result of these findings, we concluded that anti-TNF could play a role in the treatment of CRPS 1 and choose to treat 2 CRPS patients with anti-TNF. Biochemical and clinical parameters were monitored as described in our article.3 Pain was measured using a visual analogue scale, temperature using a local infrared temperature measurement, edema using a volumeter, and motor function by the measurement of active range of motion in the most involved joints. Levels of IL-6 and TNFα were measured in blister fluid drawn from both the affected and unaffected limb using the enzyme-linked immunoassay techniques.
1. Case 1
A 50-year-old woman had CRPS affecting both legs. Onset in the left leg occurred spontaneously five years previously and was followed two years later by CRPS in her right leg. The patient described continuous pain, hyperesthesia, red discoloration, and warmth in both legs. Clinical examination revealed edema, increased sweating, trophic changes, decreased range of motion, weakness, and tremor. Physical examination showed hyperalgesia to pinprick and allodynia to light touch. After 5 years, the patient still had symptoms and signs of a full-blown CRPS 1, despite treatment with all conventional forms of therapy. A sympathetic blockade was the only form of treatment that resulted in a short duration of improvement in her clinical condition. We treated the patient with infliximab (Remicade) and administered 3 mg/kg three times during a 3-week period. Clinical and biochemical parameters were measured at the start and end of treatment. Local concentrations of TNFα and IL-6 measured in blister fluid showed a dramatic fall (Table 1). We observed a slight improvement in clinical signs (Table 2). Pain, temperature, and edema decreased and motor function improved. The patient also reported an improvement in general well being.
Table 1. Levels of Pro-Inflammatory Cytokines in Blister Fluid
| Start | End | |
|---|---|---|
| TNFα (pg/ml) | ||
 Patient 1 | ||
| Affected extremity | 129 | 6.6 |
| Unaffected extremity | 1.6 | 0.4 |
| Patient 2 | ||
| Affected extremity | 32 | 0.4 |
| Unaffected extremity | 3.9 | 0.2 |
| IL-6 (pg/ml) | ||
| Patient 1 | ||
| Affected extremity | 339 | 26 |
| Unaffected extremity | 3.2 | 1.5 |
| Patient 2 | ||
| Affected extremity | 76 | 9.5 |
| Unaffected extremity | 1.8 | 0.7 |
Table 2. Clinical Parameters in the CRPS-Affected Extremity of Patients 1 and 2
| Start | End | |
|---|---|---|
| Pain (visual analogue scale in mm [0–100]) | ||
| Patient 1 | 51 | 40 |
| Patient 2 | 33 | 23 |
| Temperature (degrees Celcius dorsal side affected extremity) | ||
| Patient 1 | 35.6 | 33.8 |
| Patient 2 | 33.1 | 32.1 |
| Edema (volume in ml affected extremity) | ||
| Patient 1 | 2168 | 1957 |
| Patient 2 | 437 | 340 |
| Motor function (percentage normal active range of motion [0–100]; flexion/extension affected extremity) | ||
| Patient 1 | ||
| Knee | 67 | 74 |
| Ankle | 0 | 0 |
| Digiti 1 | 0 | 0 |
| Patient 2 | ||
| Wrist | 27 | 67 |
| Digiti 2 Metacarpophalangeal joint | 33 | 58 |
| Digiti 2 Proximal interphalangeal joint | 45 | 70 |
2. Case 2
A 55-year-old woman had a 2-month history of CRPS 1 in her arm. She developed the disease following a Colles fracture. Pain commenced while the arm was casted. After 6 weeks of immobilization, consolidation of the fracture was adequate. On removal of the cast, her arm showed a clinical picture of disuse. Her clinical picture failed to improve and she complained of continuous pain in her wrist and hand. Examination revealed a warm hand with slight skin discoloration, edema, a glove-sized allodynia to light touch, temperature asymmetry, and a decreased range of motion. The patient was treated with infliximab (Remicade). We administered 3 mg/kg twice during a 4-week period. Clinical and biochemical parameters were measured at the start and end of treatment. Concentrations of local TNFα and IL-6 in blister fluid decreased substantially at the end of treatment (Table 1) and the patient showed a considerable improvement in the clinical picture. Signs of local inflammation like pain, temperature, edema and motor abnormalities, adjusted as active range of motion, showed improvement (Table 2).
3. Comment
Anti-TNF has been successfully used in Crohn's disease, rheumatoid arthritis, and a few other inflammatory disorders in which TNFα contributes to the clinical symptoms of the disease.4., 5. In our two patients, we confirmed our earlier observation of the involvement of the cytokines IL-6 and TNFα in CRPS 1. This is direct evidence of an inflammatory process in CRPS 1. A possible genetic predisposition and, specifically, a role for the TNF2 allele in CRPS 1 has been described by Vaneker.6 In the chronic constriction injury model, it has been shown that IL-6 and TNFα play a key role in the development of clinical signs, especially those related to neuropathic pain.7 Antagonism of TNFα in this model resulted in an improvement of the clinical manifestations.8
While it remains disputable as to whether this model is representative for CRPS 1, we feel that on the basis of these findings there are sufficient indications to presume a role for anti-TNF in the treatment of CRPS 1. In the chronic stages of CRPS 1, central as well as local inflammatory mechanisms contribute to the clinical picture of the disease. We assume that this is the reason that the improvement in the clinical parameters, especially in motor function, was less impressive in the first patient than in the second patient. These two cases confirm a possible role for anti-TNF in the therapy of CRPS 1.
Further investigations in patients with CRPS 1 are warranted to study the efficacy of anti-TNF treatment in this disabling disease.
References
- Reflex sympathetic dystrophy: changing concepts and taxonomy. Pain. 1995;63:127–133
- Neuroimmune alterations in the complex regional pain syndrome. Eur J Pharm. 2001;429:101–113
- Evidence for local inflammation in complex regional pain syndrome type 1. Mediators Inflamm. 2002;11:47–51
- . Integrating anti-tumor necrosis factor in inflammatory bowel disease: current and future perspectives. Am J Gastroenterol. 2001;96:1977–1997
- . Treating rheumatoid arthritis with tumor necrosis factor alpha blockade. BMJ. 2002;234:212–213
- Genetic factors associated with Complex Regional Pain Syndrome (I: HLA DRB and TNF alfa promotor gene polymorphism). Disability Med. 2002;2:69–74
- . Schwann cells produce tumor necrosis factor alpha: expression in injured and non-injured nerves. Neuroscience. 1996;73:625–629
- Effects of neutralizing antibodies to TNF-alpha on pain-related behavior and nerve regeneration in mice with chronic constriction injury. Brain Res. 2000;866:15–22
PII: S0885-3924(03)00498-6
doi:10.1016/j.jpainsymman.2003.12.006
© 2004 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.
Volume 27, Issue 2 , Pages 101-103, February 2004
