Drug Hypersensitivity
Conditions
Keywords
SCAR, anti-TNF-a
Brief summary
Severe skin adverse drug reactions can result in death. Toxic epidermal necrolysis (TEN) has the highest mortality (30-35%); Stevens-Johnson syndrome and transitional forms correspond to the same syndrome, but with less extensive skin detachment and a lower mortality (5-15%). Hypersensitivity syndrome, sometimes called Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), has a mortality rate evaluated at about 10%. The aims of this project are (1) to compare the effect of treatment between systemic steroid and anti-TNF-α. Including skin healing time, beginning of re-epithelialization time, internal organ recovery time, mortality rate, adverse events and (2) to investigate the molecular mechanism of severe cutaneous adverse reaction after anti-TNF-α treatment.
Detailed description
Severe cutaneous adverse drug reactions, including Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome(SJS), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is a life threatening disease. There is no gold standard in the therapy of SCAR. Treatment with high dose systemic corticosteroids is controversial. Although there have been recent reports of success with various therapies such as plasmapheresis and high-dose intravenous immunoglobulins, their efficacy is not yet proven. Assessment of these therapies is difficult because of their non-specific immunosuppressant or immunomodulating modes of action. Recent studies have shown evidence of the pathogenetic importance of tumour necrosis factor (TNF)-a, suggesting a new therapeutic approach in selective blockade of TNF-a using specific antibodies. We report successful treatment TEN using monoclonal IgG anti-TNF-antibodies. The aims of this project are (1) to compare the effect of treatment between systemic steroid and anti-TNF-α. Including skin healing time, beginning of re-epithelialization time, internal organ recovery time, mortality rate, adverse events and (2) to investigate the molecular mechanism of severe cutaneous adverse reaction after anti-TNF-α treatment.
Interventions
DRUGanti- TNF-a
25mg BIW, SC
DRUGPrednisolone
1-1.5 mg / kg / day
Sponsors
National Science and Technology Council, Taiwan
Chang Gung Memorial Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
4 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female patient with clinical and pathological diagnoses of severe cutaneous adverse drug reactions such as Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis or Durg reaction with eosinophilia and systemic symptoms. 2. Male or female patient aged more than 4 years. 3. Inform consent obtained.
Exclusion criteria
1. Pregnant or breastfeeding female. 2. Allergic to any anti-TNF-α biological product. 3. Active or latent tuberculosis confirmed with Chest X-ray. 4. Severe active infection and septicemia. 5. Active Hepatitis B or C carrier. 6. Suspected HIV carrier with CD4 count less than 200. 7. Patient with poor compliance or with safety concerns judged by investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Skin Healing Time | One to two months for SJS/TEN cases, and one to six months for DRESS cases. | Healing was defined as complete re-epithelialization (i.e., the complete absence of erosions). We recorded the time taken by the skin to heal. |
Countries
Taiwan
Participant flow
Recruitment details
SCAR patients were enrolled in the clinical trial from 2009 to 2015 at Chang Gung Memorial Hospital in Taiwan.
Pre-assignment details
We totally recruited 140 participants, but only 135 SCAR participants (including 91 SJS/TEN patients and 44 DRESS patients) were enrolled to analyze. 5 participants in the control group were not included to analyze (3 cases failed a screening with CD4\<200 cells/mm3 and 2 cases as diagnosis change).
Participants by arm
| Arm | Count |
|---|---|
| Anti- TNF-a Treatment (SJS/TEN) 1. Meet the conditions of inclusion and exclusion, seek the consent of the patient, and fill out the ICF
2. Fill out the case report form
3. Blood test and physiological assessment, and do TNF-alpha serum concentration and peripheral blood mononuclear spherical cDNA expression analysis
4. Etanercept administration:
The experimental group received the first dose of Etanercept (25 mg) i.v., followed by two doses per week and maintain 2 to 3 weeks
anti-TNF a: 25mg BIW, SC | 48 |
| Control Group (SJS/TEN) 1. Meet the conditions of inclusion and exclusion, seek the consent of the patient, and fill out the ICF
2. Fill out the case report form
3. Blood test and physiological assessment, and do TNF-alpha serum concentration and peripheral blood mononuclear spherical cDNA expression analysis
4. Drug administration:
The control group of drug delivery: systemic intravenous steroid therapy, the dose is equivalent to prednisolone 1-1.5 mg / kg / day, according to the treatment of 3-4 days gradually decreased dose. | 43 |
| Anti- TNF-a Treatment (DRESS) 1. Meet the conditions of inclusion and exclusion, seek the consent of the patient, and fill out the ICF
2. Fill out the case report form
3. Blood test and physiological assessment, and do TNF-alpha serum concentration and peripheral blood mononuclear spherical cDNA expression analysis
4. Etanercept administration:
The experimental group received the first dose of Etanercept (25 mg) i.v., followed by two doses per week and maintain 2 to 3 weeks
anti-TNF a: 25mg BIW, SC | 22 |
| Control Group (DRESS) 1. Meet the conditions of inclusion and exclusion, seek the consent of the patient, and fill out the ICF
2. Fill out the case report form
3. Blood test and physiological assessment, and do TNF-alpha serum concentration and peripheral blood mononuclear spherical cDNA expression analysis
4. Drug administration:
The control group of drug delivery: systemic intravenous steroid therapy, the dose is equivalent to prednisolone 1-1.5 mg / kg / day, according to the treatment of 3-4 days gradually decreased dose. | 22 |
| Total | 135 |
Baseline characteristics
| Characteristic | Control Group (SJS/TEN) | Anti- TNF-a Treatment (DRESS) | Anti- TNF-a Treatment (SJS/TEN) | Control Group (DRESS) | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 5 Participants | 0 Participants | 1 Participants | 0 Participants | 6 Participants |
| Age, Categorical >=65 years | 23 Participants | 5 Participants | 12 Participants | 11 Participants | 51 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants | 17 Participants | 35 Participants | 11 Participants | 78 Participants |
| Age, Continuous | 59.84 years STANDARD_DEVIATION 24.2 | 53.95 years STANDARD_DEVIATION 17.41 | 52.73 years STANDARD_DEVIATION 16.78 | 60.95 years STANDARD_DEVIATION 20.39 | 56.53 years STANDARD_DEVIATION 20.2 |
| Region of Enrollment Taiwan | 43 Participants | 22 Participants | 48 Participants | 22 Participants | 135 Participants |
| Sex: Female, Male Female | 23 Participants | 14 Participants | 28 Participants | 15 Participants | 80 Participants |
| Sex: Female, Male Male | 20 Participants | 8 Participants | 20 Participants | 7 Participants | 55 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 15 / 48 | 19 / 43 | 8 / 22 | 8 / 22 |
| serious Total, serious adverse events | 5 / 48 | 9 / 43 | 2 / 22 | 5 / 22 |
Outcome results
Primary
Skin Healing Time
Healing was defined as complete re-epithelialization (i.e., the complete absence of erosions). We recorded the time taken by the skin to heal.
Time frame: One to two months for SJS/TEN cases, and one to six months for DRESS cases.
Population: We determined if the enrolled participants had SJS/TEN and DRESS using the criteria and histopathological examinations.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Anti- TNF-a Treatment (SJS/TEN) | Skin Healing Time | 13.75 days |
| Control Group (SJS/TEN) | Skin Healing Time | 19 days |
| Anti- TNF-a Treatment (DRESS) | Skin Healing Time | 40.5 days |
| Control Group (DRESS) | Skin Healing Time | 34 days |
Comparison: For evaluating the time taken to heal skin erosion, the Kaplan-Meier product-limit estimates method was performed. Differences were considered statistically significant at P values of less than 0.05.p-value: 0.01Kaplan-Meier analysis
Comparison: For evaluating the time taken to heal skin erosion, the Kaplan-Meier product-limit estimates method was performed. Differences were considered statistically significant at P values of less than 0.05.p-value: 0.06Kaplan-Meier analysis