Allergology International. 2012;61:539-544 ! DOI: 10.2332 allergolint.12-RAI-0485 REVIEW ARTICLE Review Series: Advances in Consensus, Pathogenesis and Treatment of Urticaria and Angioedema Pathogenesis of Cholinergic Urticaria in Relation to Sweating Toshinori Bito1, Yu Sawada2 and Yoshiki Tokura3 ABSTRACT Cholinergic urticaria (CU) has clinically characteristic features, and has been frequently described in the litera- ture. However, despite its comparatively old history, the pathogenesis and classification remains to be clarified. CU patients are occasionally complicated by anhidrosis and!or hypohidrosis. This reduced-sweat type should be included in the classification because the therapeutic approaches are different from the ordinary CU. It is also well-known that autologous sweat is involved in the occurrence of CU. More than half of CU patients may have sweat hypersensitivity. We attempt to classify CU and address the underlying mechanisms of CU based on the published data and our findings. The first step for classification of CU seems to discriminate the pres- ence or absence of hypersensitivity to autologous sweat. The second step is proposed to determine whether the patients can sweat normally or not. With these data, the patients could be categorized into three subtypes: (1) CU with sweat hypersensitivity; (2) CU with acquired anhidrosis and!or hypohidrosis; (3) idiopathic CU. The pathogenesis of each subtype is also discussed in this review. KEY WORDS acetylcholine, acetylcholine receptor, anhidrosis, hypohidrosis, sweat hypersensitivity choline. In fact, acetylcholine stimulation can elicit INTRODUCTION hives as seen in CU, suggesting that the etiology of Cholinergic urticaria (CU) is a rare condition, but its CU includes certain events that are triggered by a incidence might be higher than that expected by gen- cholinergic stimulus. A well-known hypothesis has eral physicians. CU is clinically characterized by been put forward to explain the pathogenesis of CU. pinpoint-sized, highly pruritic wheals. Although the The patients are hypersensitive to unknown sub- symptoms subside rapidly, commonly within one stances in their sweats and develop wheals in re- hour, CU may significantly impair the quality of life, sponse to sweat substance leaking from the syringeal especially sporting and sexual activities.1 This unique ducts to the dermis possibly by obstruction of the disease was described by Duke in 1924,2 however, ducts.5,6 This “sweat hypersensitivity” hypothesis has despite its comparatively old history, the pathogene- been supported by the fact that not all but some pa- sis and classification remains to be clarified. CU is tients with CU exhibit a positive reaction to intrade- typically provoked by stimulation such as exercise, mal injection of the patients’ own diluted sweat as warmth, and emotional distress, which increases the well as acetylcholine.7 Basedonthedistinctre- body core temperature and promotes sweating.3,4 sponses to the autologous factors and clinical charac- Since acetylcholine is known to induce both sweat- teristics, Fukunaga et al. proposed two subtypes in ing and wheals when injected intradermally,4 it has the entity of CU, sweat hypersensitivity (non- been considered that this sweating-associated, syr- follicular) type and follicular type.7 ingeal orifice-coincident wheal is mediated by acetyl- However, sweat hypersensitivity theory lacks suffi- 1Division of Dermatology, Department of Internal Related, Kobe ment of Internal Related, Kobe University Graduate School of University Graduate School of Medicine, Hyogo, 2Department of Medicine, 7−5−1 Kusunokicho, Chuoku, Kobe, Hyogo 650−0017, Dermatology, University of Occupational and Environmental Japan. Health, Fukuoka and 3Department of Dermatology, Hamamatsu Email: [email protected]−u.ac.jp University School of Medicine, Shizuoka, Japan. Received 29 July 2012. Conflict of interest: No potential conflict of interest was disclosed. !2012 Japanese Society of Allergology Correspondence: Toshinori Bito, Division of Dermatology, Depart- Allergology International Vol 61, No4, 2012 www.jsaweb.jp! 539 Bito T et al. cient evidence and can not encompass the whole eti- tion, there are some important issues to be dissolved. ology of CU. CU is occasionally associated with de- CU patients are occasionally complicated by anhidro- pressed sweating, as reported under the name of an- sis and!or hypohidrosis. This reduced-sweat type hidrosis (complete lack of sweating) or hypohidrosis should be included in the classification because the (incomplete lack of sweating).8 There have been re- therapeutic approaches are different from the ordi- ported 29 patients with CU with anhidrosis and!or nary CU. It has been thought that the anhidrosis hypohidrosis in the literature,8-32 and notably, 26 pa- and!or hypohidrosis are caused by obstruction of tients are Japanese. This type of CU may be caused sweat orifice. However, the sweat reduction is not by reduced expression of acetylcholine receptor but necessarily associated with poral obstruction. not by sweat hypersensitivity, as described below. In Nakamizo et al. proposed four subtypes of CU: (1) addition, two Japanese patients with CU had episodes CU with poral occlusion; (2) CU with acquired gener- of seizures upon occurrence of urticaria.33,34 Given alized hypohidrosis; (3) CU with sweat allergy; and that acetylcholine mediates epileptic seizures,35,36 sei- (4) idiopathic CU.41 The incidence of overlapping of zures possibly occur when steroid therapy induces (1)-(3) is an important issue to elucidate their inde- the re-expression of acetylcholine receptors in the pendence and concurrence. brain. One of the interesting observations in CU is that By exploring the enigmatic relationship between the sweat ducts are obstructed by lymphocytic in- wheal formation and sweating, we have addressed flammation around the ducts, and resultant retention the general mechanism underlying CU.37 In this re- and subsequent leakage of sweat from the damaged view, we show the relationship between sweating and ducts induce wheals because of sweat hypersensitiv- the pathogenesis of CU according to the published ity.5,6 Given this mechanism, CU with anhidrosis findings and propose the classification of CU based and!or hypohidrosis might belong to all of “CU with on the mechanisms. poral occlusion”, “CU with acquired generalized hy- pohidrosis”, and “CU with sweat allergy”. However, CLINICAL SUBTYPES OF CU ACCORDING several observations concerning CU with anhidrosis TO RESPONSES TO SWEAT and!or hypohidrosis are not in accordance with the Since CU is not a homogeneous disease, its classifica- conventional poral occlusion!sweat leakage theory. tion is necessary for the clinical use. However, few at- First, the symptoms are usually exacerbated in winter tempts have been performed to classify CU in the lit- and resolved in summer, although it can be explained erature, and there is no solid consensus on the cate- with the hypothesis that daily sweating in summer in- gorization. Horikawa et al. observed that a strong hy- hibits the formation of keratotic plugs to prevent the persensitivity to sweat was not observed in all CU pa- occurrence of CU.6 However, the vast majority of this tients and assumed other factors than sweat hyper- type of CU have been reported from Asia, whose cli- sensitivity are also involved in the pathogenesis of mate is hot and humid, and the disease is rare in CU.38 Some patients with chronic urticaria have Europe, where it is cool and dry. This regional diver- autoantibodies to FcεRI or IgE, and the autologous gence in the occurrence of the disease is not consis- serum skin test (ASST) has been used to detect the tent with the poral occlusion!sweat leakage theory. autoantibodies.39,40 Horikawa et al. also found that 8 Second, in the literature, few of the patients with CU of 15 patients with CU showed responsiveness to with anhidrosis or hypohidrosis showed positive re- ASST. While the follicular manifestation of wheal was sults of the intradermally injected autologous sweat, mainly associated with positive ASST, the non- suggesting that sweat hypersensitivity is not respon- follicular hives tended to show strong hypersensitiv- sible for this form of CU. In addition, if sweat hyper- ity to sweat and were probably associated with sweat sensitivity is the mechanism, the anhidrotic area ducts. Based on this observation, they proposed to should be the predilection site for wheals, but wheals classify CU into two subtypes: (1) the sweat hyper- cannot occur on the anhidrotic area.37 We found mo- sensitivity type (non-follicular type) showing non- saic distribution of hypohidrotic or anhidrotic areas follicular hives, strong hypersensitivity to autologous onthebodysurface,andthepatientsdevelopwheals sweat, development of satellite wheals following ace- on the hypohidrotic area. Therefore, we suggest that tylcholine injection, and negative ASST; and (2) the “CU with acquired generalized hypohidrosis” and follicular type showing follicular hives and positive “CU with poral occlusion” are mostly independent. ASST without hypersensitivity to autologous sweat or Considering all these findings, the first step for satellite wheals.38 It remains unclear how ASST in- classification of CU seems to discriminate the pres- duces the follicular eruption. It is notable that some ence or absence of hypersensitivity to autologous CU patients have hypersensitivity to both autologous sweat. The second step is proposed to determine sweat and serum.