Forty-one cases with major response included plaque (13 cases), diffuse swelling (21 cases) and elephantiasis (seven cases). factors, six risk factors were recognized: thyroid-stimulating hormone (TSH) receptor antibody (TRAb) (OR 42.93), autoimmune thyroid disease (AITD) or AITD history (OR 10.30), local trauma (OR 6.55), venous stasis posture (OR 6.16), cigarette smoking (OR 4.48), and age (OR 1.05). Serum TRAb levels were positively correlated with the severity of PTM. Of notice, 371/400 patients received glucocorticoid treatment, and 330 achieved complete response. The serum TRAb levels after treatment decreased dramatically compared with those before treatment. After stopping glucocorticoid treatment, serum TRAb levels increased significantly when PTM relapsed (P 0.001). In 165 relapse cases, an increase in serum TRAb levels occurred first, followed by prolonged venous stasis posture or local trauma and finally PTM. The RR of elevated serum TRAb levels was 6.73 in PTM relapse cases. In the elevated serum TRAb level group, the RRs of local trauma, venous stasis posture, and local trauma plus venous stasis posture were 8.81, CD1E 6.5, and 8.84, respectively, for PTM relapse cases. Conclusions TSHR autoimmunity and local factors in the six recognized risk factors are the main causes of PTM occurrence. experiments have Varespladib methyl found that the TSH stimulating antibody (TSAb) subtype of TRAbs may mimic the action of TSH to stimulate orbital fibroblasts to produce HA through the PI3K-AKT signaling pathway [12]. It has been thought that TRAb is the causative agent of thyroid gland and extrathyroidal manifestations in GD. However, simple autoimmune theory cannot explain a lower prevalence of PTM in AITD. PTMs preference for the lower legs, ascribed to site-specific properties of fibroblasts, has not been confirmed because PTM can occur at anatomical sites outside of the lower legs. Finally, multi-factorial etiology has been postulated in which local factors (e.g., local trauma and prolonged standing) are superimposed on systemic connective tissue inflammation caused by autoimmunity to TSHR, which might transform a subclinical inflammation into a clinical entity [13]. As PTM is usually a rare dermopathy, the above-mentioned hypotheses have never been tested by any large-sample epidemiological studies. Here, we first designed a large-scale case-control study to identify the risk factors of PTM. Then, the identified main risk factors were tested with an immunosuppressive glucocorticoid treatment intervention and a cohort study in PTM patients with total response. Materials and Methods Participants Participants were as follows: PTM patients who frequented the Department of Dermatology; GD without PTM (GD w/o PTM) patients who frequented the Departments of Nuclear Medicine, Endocrinology and Pediatrics; and normal persons who visited the Health Checkup Center and Department of Pediatrics in the Chinese National Nuclear Corporation (CNNC) 416 Hospital from July 1, 2013 to September 30, 2018. A definite diagnosis for PTM was made under the background of thyroid diseases or thyroid Varespladib methyl disease history, the presence of common skin lesions, or atypical skin lesions (atypical locations and atypical appearances) plus histopathology of mucinous degeneration and positive Alcian blue staining in the dermis (altered from [6] and [14]). GD was diagnosed on the basis of clinical and/or biochemical evidence of thyrotoxicosis plus one or Varespladib methyl more of the following features: serum TRAb positive, thyroid-associated ophthalmopathy and/or dermopathy and/or acropachy, hypoechoic and increase in vascularity shown by thyroid ultrasound with Doppler, and diffuse elevated radioactive iodine uptake (RAIU). Biochemical evidence of thyrotoxicosis is an elevated serum Varespladib methyl triiodothyronine level (T3 2.79 Varespladib methyl nmol/L, normal value 0.92 – 2.79 nmol/L) and undetectable serum TSH level ( 0.01 mU/L) [15, 16]. The definition of normal persons is that they have no symptoms or indicators and have no abnormal findings in physical examinations and laboratory tests for.