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Analysis of Patient-Reported Symptoms With Respect to TCS Usage: A Self-Identified Cohort of Patients With RSS/TSA/TSW

Tim Berger M.D., Patricia Francis-Lyon Ph.D., Jim Parker M.D., Pamela Friedman MS, Purvi Sengar MS, Tanzir Hasan,Jessica Owens, Arrash Moghaddasi

Download slides with data presented to the American Academy of Dermatologists 2017 meeting

Background

Topical corticosteroids (TCS) have been the mainstay of treatment for inflammatory dermatoses and are felt to be safe when used appropriately. In response to increased reports about Red Skin Syndrome (RSS) and Topical Steroid Addiction/Withdrawal (TSA/TSW), a systematic review (2015) conducted by the National Eczema Association concluded that RSS/TSA/TSW is a potential adverse effect of prolonged use of topical steroids. The phenomenon of RSS/TSA/TSW has been deemed rare. There is no validated definition, no patient registry, and no evidence-based treatment.

Figure 1. Stages of RSS/TSA/TSW before and after cessation of TCS. Figure 1 (A) A typical appearance of TSA, with prurigo-like eruption before withdrawal. (B) Appearance just after trial of decreasing the amount of potent topical steroids. The severity of addiction is so intense that the patient cannot safely withdraw by a gradual-decrease method. (C) The rebound erythema is spreading after complete cessation of steroids. (D) The appearance after 1 year. The rebound has almost subsided but hypersensitivity still remains 1

Source: Mototsugu Fukaya MD, et al.   “Topical Steroid Addiction in Atopic Dermatitis” Drug, Healthcare and Patient Safety, 2014;6: pp.131–138.

Objective

Survey objective is to increase understanding of the relationship between TCS usage and RSS/TSA/TSW, its symptoms, severity and duration.

Methods

An online survey of self-reported RSS/TSA/TSW-affected individuals was conducted between March 2014 and May 2015. The survey garnered 3840 adult responses, 2093 of whom started TCS as children. The survey included TCS user demographics, details of TCS usage, and severity and duration of symptoms after cessation of TCS. The survey consisted of 64 multiple choice, numeric value and open-ended questions. A COSTEX (COrticoSTeroid EXposure) index was developed to quantify exposure reported by respondents. Data analysis and visualization followed.

Survey Cohort




Results

Adult

Figure 2(Adult). Percent skin affected by age category. These histograms represent the percent of skin affected vs counts per 100 respondents for each age group. Top: Side-by-side comparison of age groups for each Percent Skin Affected bin. Lower 3 plots: Tracking from left to right through age groups 18-29, 30-49, and 50+ shows the distribution shifting left to lower percent skin affected for older respondents. A correlation test indicates that the younger the age, the greater the percentage of skin affected (spearman r = -0.21, p =3.93e-.06 ).

Pediatric


Figure 2(Pediatric). Percent skin affected by age category. These histograms represent the percent of skin affected vs counts per 100 respondents for each age group of pediatric patients. Top: Side-by-side comparison of age groups for each Percent Skin Affected bin. Lower 3 plots: Tracking from top to bottom through age groups child, youth, and teen shows the distribution of percent skin affected is fairly uniform for younger children, but doesn’t hit the highest percentages for youth and teens.

Figure 3(Adult). (Top):COSTEX Index by Itch Intensity Level 0 (N=12) and 3 (N=260). (19 values with COSTEX > 650, all of which are in level 3, are not shown). A t-test of association shows that COSTEX index of level 3 (severe) itch is significantly higher than that of level 0 (none) (p = 1.299e-05). (Bottom): COSTEX Index by Duration of Symptoms after Stopping TCS in days: 1-180 (N=45), 181-360 (N=54) and 360+ (N=57). (6 high values at COSTEX > 750, of which 4 are in the highest duration group, are not shown). There were 156 respondents who reported cessation of symptoms. Duration of symptoms is correlated with COSTEX index (spearman, r = 0.27, p < .0005).
Figure 3(Pediatric).(Top):COSTEX Index by Itch Intensity Level 0 (N=4) and 3 (N=75). A t-test of association shows that COSTEX index of level 3 (severe) itch is significantly higher than that of level 0 (none) (p = 2.499e-07). (Bottom): COSTEX Index by Duration of Symptoms after Stopping TCS in days: 1-180 (N=21), 181-360 (N=10) and 360+ (N=12). Duration of symptoms is correlated with COSTEX index (spearman, r = 0.38, p = 0.00998).

Figure 4(Adult). Highest level of intense itching in adults over time elapsed since discontinuing TCS. Frequency of level 3 (most severe) itch per 100 respondents in time elapsed group as reported after ceasing TCS treatment. The percentage reporting the most intense itch continued to increase until 18 months after stopping TCS.

Figure 4(Pediatric). Frequency of level 3 (most severe) itch per 100 respondents in time elapsed group as reported after ceasing TCS treatment. The percentage reporting the most intense itch continued to increase until 12 months after stopping TCS.

Figure 5(Adult). Adult respondents who rated their intense itch as level 3 (severe) started using TCS at an earlier age than those at level 0 (does not apply). Age group at starting TCS is negatively correlated with level (0-3) of itch intensity. (spearman r = -0.13, p = 2.231e-08).
Figure 5(Pediatric). Figure 5(Pediatric). Pediatric respondents whose intense itch was rated as level 3 (severe) versus those rated at level 0 (does not apply). There is no statistically significant correlation of pediatric sge group at starting TCS with level (0-3) of itch intensity.
Figure 6(Adult). Distribution of percent skin affected at reporting for age groups first used TCS. The boxplot includes only adult data; however, it tracks the age at which adults first used TCS, which may be in childhood. The younger the age of starting TCS, the greater the skin affected (negative correlation spearman r = -0.26, p = 1.185e-08).
Figure 6(Pediatric).Distribution of percent skin affected at reporting for age groups first used TCS. The boxplot tracks the age at which the pediatric patient first used TCS. Although not statistically significant, a trend is observed that the younger the age of starting TCS, the greater the percentage of skin affected.

Result: Table-1(Adult)

Costex Group Doesnot apply Mild symptom Medium symptom Severe symptom
0-19.9 8% 21% 27% 45%
20-49.9 4% 16% 26% 54%
50-99.9 3% 13% 23% 61%
100-199.9 1% 13% 18% 68%
200-499.9 1% 11% 21% 67%
500-999.9 0% 8% 21% 71%
1000+ 1% 8% 11% 80%

Table 1(Adult). Percentages of each COSTEX Group reporting levels of itch intensity. As COSTEX increases, the percentage of respondents reporting no intense itching decreases and the highest level itch intensity (rightmost column) increases. Pearson’s Chi–squared test shows higher COSTEX is associated with higher level of intense itching (p=2.2e-16).

Result: Table-1(Pediatric)

Costex Group Doesnot apply Mild symptom Medium symptom Severe symptom
0-9.9 7% 24% 24% 45%
10-19.9 1% 15% 28% 55%
20-39.9 0% 11% 16% 73%
40-69.9 2% 11% 23% 64%
70-119.9 3% 8% 17% 72%
120-199.9 0% 7% 21% 71%
200+ 3% 19% 19% 69%

Table 1(Pediatric). Percentages of each COSTEX Group reporting levels of itch intensity.COSTEX numbers are lower than with adults, since children have not had as many years of exposure. As COSTEX increases, the percentage of respondents reporting no intense itching tends to decrease and the highest level itch intensity (rightmost column) tends to increase. Pearson’s Chi–squared test shows higher COSTEX is associated with higher level of intense itching (p=0.0005445).

Result:Table-2(Adult)

Total time on TCS 0
Does not apply
1
Mild sysmpotm
2
Medium symptom
3
Severe symptom
0-2yrs 9% 23% 23% 46%
2-5yrs 4% 19% 28% 46%
5-8yrs 3% 19% 20% 58%
8-11yrs 3% 11% 22% 64%
11-15yrs 4% 15% 25% 56%
15yrs & up 2% 11% 24% 64%

Table 2(Adult). Percentages of each group for Total Time on TCS reporting levels of itch intensity. Pearson’s Chi–squared test shows duration of TCS use is significantly associated with higher level of intense itching (p= 3.687e-13).

Result:Table-2(Pediatric)

Total time on TCS 0
Does not apply
1
Mild sysmpotm
2
Medium symptom
3
Severe symptom
0-2yrs 5% 19% 24% 53%
2-5yrs 1% 21% 21% 64%
5-8yrs 4% 13% 17% 65%
8-11yrs 0% 23% 13% 63%
11-15yrs 3% 11% 17% 69%
15yrs & up 0% 0% 40% 60%

Table 2(Pediatric). Percentages of each group for Total Time on TCS reporting levels of itch intensity. A trend of increasing severity with longer exposure is observed. For those with long-term exposure, all respondents report medium or severe itch intensity.

Costex formula

To calculate the COSTEX (COrticoSTeroid EXposure) index, the number of small tubes of each category were multiplied by the appropriate multiplier and then added together.

Ex: costex <- 1 * x1 + 1.2 * x2 +1.4 * x3 + 1.6 * x4 + 1.8 * x5 + 2.0 * x6 + 2.2 * x7 where xi are the appropriate variable names

Conclusion

Of those respondents who detailed their symptoms, 81% reported moderate to severe intense itching (level 2-3). 77% also reported moderate to severe red burning skin and 69% reported moderate to severe raw painful skin. Younger age of starting TCS (spearman r = -0.26, p = 1.185e-08), longer duration of exposure (p = 5.985e-16), and greater quantity of exposure (p < 2.2e-16) were associated with more severe symptomatology. Higher COSTEX index was associated with longer duration of symptoms. Adults with highest COSTEX index reported the highest itch severity. A trend was observed that intense pruritus worsened for about 1.5 years after discontinuing TCS before improvement was reported. Symptomatology after stopping TCS was prolonged in many cases. Of 31 respondents who reported having stopped TCS for 5+ years, 26% reported that symptoms still persisted. There was a small (r = 0.27) but highly significant (p < .0005) correlation between duration of symptoms and COSTEX.

Summary & Future Directions

Large numbers of patients who have used topical corticosteroids believe they have symptoms related to their use. In this cohort the symptoms were reported as severe and persistent. As previously reported, longer duration and intensity of use of TCS is significantly associated with more severe and prolonged symptomatology. Further study is needed to arrive at an accurate definition, diagnostic criteria, and prevention and treatment strategies for RSS/TSA/TSW.

References

  1. Mototsugu Fukaya MD, et al.   “Topical Steroid Addiction in Atopic Dermatitis” Drug, Healthcare and Patient Safety,  2014;6: pp.131–138.
  2. Furue M, Terao H, Rikihisa W, et al. Clinical dose and adverse effects of topical steroids in daily management of atopic dermatitis. Br J Dermatol. 2003;148(1):128–133.
  3. Haj ar, Tamar, Yael A. Leshem, Jon M. Hanifin, Susan T. Nedorost, Peter A. Lio, Amy S. Paller, Julie Block, and Eric L. Simpson. "A Systematic Review of Topical Corticosteroid Withdrawal (“steroid Addiction”) in Patients with Atopic Dermatitis and Other Dermatoses." Journal of the American Academy of Dermatology 72.3 (2015): n. pag. Web.
  4. RStudio Team (2015). RStudio: Integrated Development for R. RStudio, Inc., Boston, MA URL http://www.rstudio.com/