Multiple courses of steroid pulse therapy are required in treating acquired idiopathic generalized anhidrosis patients with a large anhidrotic area: A retrospective study of 28 cases

Patients with acquired idiopathic generalized anhidrosis (AIGA) demonstrate a sudden loss of sweating function without neurological or endocrine abnormalities. The main treatment is steroid pulse therapy. However, the number of courses required for improvement has been unclear. This study aims to clarify the factors associated with AIGA disease severity and with AIGA patients' responses to steroid pulse therapy. We retrospectively analysed the clinical information of 28 patients with AIGA in our department from the last 10 years. Univariate analysis revealed that patients with a large anhidrotic area need multiple courses of steroid pulse therapy.


INTRODUCTION
Acquired idiopathic generalized anhidrosis (AIGA) is a sudden-onset sweating disorder without neurological abnormalities (Table S1).Although the pathogenesis remains unclear, steroid pulse therapy is known to be an effective treatment. 1,2The treatment guidelines issued by the Japan Dermatological Association (JDA) note that such therapy should be administered to AIGA patients who show severe symptoms. 2However, the number of steroid pulse courses that are needed to improve skin symptoms has been unclear. 2To clarify factors related to AIGA disease severity and those related to patient responses to steroid pulse therapy, we analysed the profiles of 28 AIGA patients who had been diagnosed at our department in the previous 10 years.

Patients
The Institutional Review Board of Hokkaido University Hospital approved this study (approval #22-058), which was carried out in accordance with the Declaration of Helsinki.Written informed consent was obtained before any clinical information was collected.The present study includes all patients diagnosed with AIGA at the Hokkaido University Department of Dermatology from 2013 to 2022.We retrospectively collected the following clinical information from medical records: age; gender; body mass index (BMI); duration from disease onset to consultation; history of heat exposure, heat stroke (Table S2), 3 atopic dermatitis and cholinergic urticaria; disease severity; laboratory data; the pathology of skin biopsies; and the number of steroid pulse courses.No exclusion criteria were set.

Diagnosis
The JDA guidelines 2 define AIGA as non-segmental anhidrosis/hypohidrosis (>25% of the body surface) without neurological or autonomic symptoms.We evaluated the affected skin lesions using the modified Minor test 4 and the Wada method. 5The representative results are shown in Figure S1.The Minor test was used to assess the anhidrotic area 2 (Table S3).The therapeutic effect was determined by medical interview and self-assessment 1 month after the end of steroid pulse therapy, as described by Iida et al. 6

Steroid pulse therapy
A typical steroid pulse therapy regimen was three consecutive pulses of methylprednisolone at 1000 mg daily.For the next course, at least a 1-month interval was required.

Statistical analysis
Statistical analysis was performed using Sigma plot® (ver.14.5, HULINKS, Japan).Odds represent the probability of an event occurring divided by the probability of that event not occurring.Statistically significant differences between groups were analysed using Fisher's exact test and linear regression analysis.p < 0.05 was determined to be statistically significant.

Patients with a large anhidrotic area require multiple courses of steroid pulse therapy
Table S4 summarizes the clinical information from the 28 patients with AIGA.The male-to-female ratio is 6:1.The median age is 25 years (14-64 years).Seventy-five per cent of the patients (21 of 28 patients) are under 40 years old.The median BMI is 23.45 (13.4-31.9).Forty-six per cent (13 of 28 patients) have a history of heat environment exposure.In addition, 25% (7 of 28 patients) have a history of heat stroke.Concerning anhidrotic area evaluated by Minor test, 4 64% (18 of 28 patients) of patients were found to have moderate or severe anhidrosis (scores of 2 or 3).The median duration between onset and referral to our institution is 9.5 months (1-108 months).Fifty-four per cent (15 of 27 patients) have cholinergic urticaria.Eleven per cent (3 of 28 patients) were treated for atopic dermatitis.Forty-eight per cent (13 of 27 patients) have an antinuclear antibody (ANA) value exceeding x80.Skin biopsy specimens revealed the histopathological infiltration of inflammatory cells around the sweat glands in 36% (10 of 26) of patients.Steroid pulse therapy was administered to 64% (18 of 28) of patients.Thirty per cent of cases with mild symptoms were treated with steroid pulse therapy, with a maximum of two courses (3 of 10 patients).Eightythree per cent of cases with moderate-to-severe symptoms were treated with steroid pulse therapy, with a maximum of five courses (15 of 18 patients).According to the clinical interview 4 weeks after steroid pulse therapy, the skin symptoms of all 18 patients showed some improvement.The median number of courses for patients treated with steroid pulse therapy was two.Concerning the required number of steroid pulse courses, patients with greater than F I G U R E 1 Analysis of patients' clinical information.(a) Odds ratios for the required number of steroid pulse courses.Factors with significance are highlighted (red characters).(b) Odds ratios for disease severity evaluated by univariate comparisons.Factors with significance are highlighted (red characters).inf, infinite; LCL, lower control limit; OR, odds ratio; UCL, upper control limit.
To identify factors associated with AIGA severity, we assessed the correlation between disease severity and clinical information or laboratory data by univariate comparisons.Patients with a history of heat stroke were found to have a large anhidrotic area (p* = 0.03).Patients with a high eosinophil count (5% or more) tended to display mild disease severity (p* = 0.001) (Figure 1b).

DISCUSSION
In the present study, we analysed the clinical features of 28 patients with AIGA to identify factors associated with disease severity as well as those associated with response to steroid pulse therapy.There was a positive correlation between the score for anhidrotic area and the history of heat stroke (Figure 1b).Munetsugu et al. found a positive correlation between Dermatology Life Quality Index (DLQI) scores and severity ratings based on three items: anhidrotic areas, area of wheals and heat stroke symptoms. 7The positive correlation between anhidrotic area score and severity in the present study is consistent with Munetsugu et al. 2 Concerning the required number of courses of steroid pulse therapy, our study showed that patients with more than 50% anhidrotic area required multiple courses (Figure 1a).There is insufficient consensus on the number of courses required and the need for oral prednisolone.In addition, the effectiveness of treatment has not been adequately studied. 2 According to our interviews, the patients showed some response at all severities of disease.However, some patients were found to have relapsed at the subsequent follow-up, or additional treatment was given, probably because of insufficient improvement.In previous studies, steroid pulse therapy was often administered in one or two courses of methylprednisolone (500-1000 mg/day). 2,8,9Oral prednisolone at 30-60 mg/day was followed by steroid pulse therapy.Some reports have also shown recovery at lower doses, such as 2.5-5 mg/day. 10atients with early-onset AIGA and concomitant cholinergic urticaria were found to respond well to steroids.It has also been reported that patients with delayed treatment initiation and severe changes in sweat gland tissue may not respond to steroids. 1 A major problem in this study is the inaccuracy of treatment evaluation, because the Minor test was not used after steroid pulse therapy.In addition, the present study should take into account confounding factors regarding the absence of a correlation between the time to treatment initiation and the number of steroid pulse courses and the tendency for the area of anhidrosis/hypohidrosis to be smaller when eosinophils are >5%.There are several limitations to the present study.The 28 patients with AIGA that we enrolled were too few for proper statistical analysis of the clinical information.Also, this research is a retrospective study, so the results could be biased relative to those of a prospective study.

CONCLUSION
Acquired idiopathic generalized anhidrosis patients with greater than 50% anhidrotic area were found to require multiple steroid pulse courses to achieve a satisfactory response.Additionally, AIGA patients with a history of heat stroke were found to have a tendency to display more severe symptoms.