Experimental Physical Therapies
Gregor B.E. Jemec 24
Key points
Q Depilation may prove to be a useful adjunct therapy
Q New physical therapies should be tissue conserving
Q New therapies should be tested in a standardized and clinically significant manner
#ONTENTS
24.1 Introduction . . . 177
24.2 Photodynamic Therapy . . . 177
24.3 Depilation . . . 179
24.4 Cryosurgery . . . 179
24.5 Discussion . . . .180
24.6 Practical Guidelines for Testing New Physical Therapies . . . .180
References . . . 181
24.1 Introduction
Whenever there is more than one therapy avail- able for a particular ailment, it is often suspect- ed that none of them is universally effective.
There is definitely scope for improving the physical and surgical methods for treating hi- dradenitis suppurativa (HS). The rationale for physical therapies in the later stages of disease is strong. After the formation of sinus tracts it is unlikely that pharmacological treatment can
achieve the desired therapeutic effect, unless specific biological targets can be found in the epithelial tissue lining the sinus tracts. The treatment options for Hurley Stage III and unre- sponsive Stage II disease are therefore currently restricted to physical destruction of the diseased tissue using different treatment modalities [1].
A series of physical therapies have been suggest- ed (see Table 24.1).
24.2 Photodynamic Therapy
Photodynamic therapy (PDT) provides semi-se- lective tissue destruction and a general antimi- crobial effect. It is currently used extensively for the treatment of precancerous lesions or non- melanoma skin cancer [2]. The treatment is based on the activation of a photosensitizer ap- plied to the tissue (usually absorbed through the skin surface), and subsequent tissue destruc- tion. The photosensitizer most commonly used at the time of writing is either aminolevulinic acid (ALA, 20% cream) or esterified aminolevu- linic acid. Other photosensitizers are available for intravesical therapy, for example, but their effects on skin diseases are as yet unproven.
Similarly, potential photosensitizers, such as methylene blue, are limited in their effects to being antimicrobial. ALA can be purchased from a supplier of analytic substances, or bought as one of two commercially available products (Metvix®, Photocure, Norway or Levulan®, Dusa Pharmaceuicals, USA).
It has been shown that ALA penetrates the
skin and is absorbed, theoretically allowing it to
reach superficial lesions of HS. Following ab-
sorption of the substance it is metabolized along
the heme pathway to protoporphyrin IX, which
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is a potent photosensitizer. The process occurs naturally as the main pathogenic process in porphyria. In healthy tissue the protoporphyrin IX is further metabolized by the enzyme fer- rochelatase to non-phototoxic substances. In metaplastic or neoplastic tissue the activity of ferrochelatase is lower than that in healthy tis- sue, and a semi-selective accumulation of pho- tosensitizer therefore occurs, which allows more targeted destruction of the metaplastic or neo- plastic tissue.
PDT has recently been tested in a number of non-neoplastic diseases. These include acne ro- sacea [3], acne vulgaris [4] and HS [5, 6] (see Table 24.1). For HS two studies have been pub- lished. The first study, by Gold et al. [5], de- scribes four cases treated with PDT (Levulan
®and blue light). Only a short incubation period was used, and the treatment was repeated three to four times. No co-morbidity was reported,
and at follow-up 3 months afterwards all cases had improved 75–100%, suggesting that the treatment may be of benefit. The exact outcome variables were not stated, e.g., VAS scores or Sartorius scores. The study is interesting but not well documented, and the inclusion criteria open the possibility that simple furunculosis rather than HS was treated. In a subsequent se- ries of cases Strauss et al. [6] described four pa- tients treated with generic 20% ALA and either 633 nm laser or a 570–670 nm broad band light source without significant effect. A longer incu- bation time and better case definition were used.
Furthermore the use of red light allows deeper penetration of the light energy and therefore this is theoretically more suitable for the treat- ment of HS. The author’s limited experience is in better accordance with the latter report than with the former. For HS the lesions treated most successfully have apparently been those of
Table 24.1.
Experimental physical therapies in hidradenitis suppurativa (HS)
Treat-ment
Patients Location Treatment Follow- up
Effect Complications Refer- ence
1 PDT Four
women, aged 19–46 years
One axillary, one axillary and inguinal areas, two in- guinal areas
20% 5-ALA for 15–30 min, followed by blue light, 1- to 2-week intervals;
three to four treatments
3 months Three patients:
75% im- provement;
one patient:
100% im- provement
None [5]
2 PDT Four
patients
Three axillary disease, one groin disease
20% 5-ALA for 4 h, followed by 533 nm laser or 570–670 nm broad band light giving 15 J/cm
2once weekly for 3 weeks
8 weeks No significant improvement
One dropout be- cause of discom- fort,
one experienced worsening
[6]
3 Cryo- therapy
Ten women, aged 24–45 years
Three axillary, one breast, four groin, one axillary and groin, one all three sites
Cryotherapy using liquid nitrogen to freeze single nodules to a core temper- ature of –20 °C
Not stated clearly, but ap- parently up to 6 weeks (end of healing)
Four marked im- provement, four im- provement, two no response
Average healing time 25 days, 6/10 experienced postoperative infection, two experienced ulceration, three graded pain during heal- ing as maximum on a 1–4 score
[13]
Stage I disease, suggesting that sinus tracts are not affected and that either the inflammatory process itself or pro-inflammatory substances are targeted.
The mechanisms by which PDT affects these diseases is not known, but it has been suggested to be via tissue destruction of, for example, hy- perplastic infundibular epithelium in acne, or by a simple antibacterial effect analogous to the use of blue light in acne. Additional practical problems are however involved in the use of PDT for HS. It is well established that up to one- third of all PDT patients experience consider- able pain during illumination. In the study by Strauss et al. [6] one of four patients dropped out due to pain and discomfort. This appears to be particularly associated with larger areas be- ing treated, and with the sensitivity of the areas, e.g., it is usually worse on the nose than on the back. Even if PDT is found to be effective, this factor may prove to be significantly restrictive for the use of PDT in HS.
The discrepancy between the results ob- served strongly suggests the need for a con- trolled trial, and may be due to the stringency of inclusion criteria, variation in the stage of HS being treated, and a number of other factors.
24.3 Depilation
Theoretically depilation could offer some relief to patients with HS. Previously X-ray therapy has been used to treat HS [7, 8]. The dosage var- ied, but often successful therapy induced depila- tion of the treated areas. Earlier papers on the topic have suggested that the positive effects were due as much to depilation as to the anti- inflammatory effects of the treatment (Chap.
23).
Such an effect may be hypothesized from the histology of the early lesions. An element of fol- licular occlusion is found in early lesions, and although pharmacological treatment with reti- noids, for example, has been disappointing in most cases, the physical removal of an obstruct- ing hair shaft may prove even better at draining the follicle. Furthermore, free hair fragments may on occasion be found in lesions, suggesting that they may help to maintain the lesions by
acting as foreign objects and evoking a chronic inflammatory response with, among others, multinucleated giant cells [9]. Removal of hairs may therefore not only aid drainage, but also re- move the necessary seeds for perpetuation of established lesions.
Depilation has however traditionally been suspected as a possible causative factor in HS, but the pattern of use of cosmetic procedures in the areas predisposed to HS does not appear to be different in patients and healthy controls [10, 11]. Furthermore, many patients with HS have never used depilatories in the areas where lesions occur. This makes it unlikely that any depilatory procedure forms a significant etiological factor in the development of HS.
In general, laser depilation has been shown to be a useful technique for hirsute patients, appar- ently using any of several types of available lasers. The absorption of laser light in the hair follicle induces transition to a telogen phase, and apparently shortens subsequent anagen phases of the follicle, consequently resulting in the growth of a shorter and thinner hair shaft [12].
Several unpublished cases among the authors of this book appear to substantiate this claim, although the success rate and duration of any beneficial effect are not known. Some patients apparently experience long-lasting remission, whereas others only have shorter periods of re- lief. Based on the available information, laser depilation nevertheless appears to be a promis- ing area for further studies.
24.4 Cryosurgery
Cryosurgery has been used extensively in the treatment of both benign and malignant skin tumors. Usually liquid nitrogen is used as the coolant, and the effect of the cryotherapy is to induce necrosis based on hypothermic damage of both cell membrane and cytoplasmic organ- elles.
A study reporting the follow-up of ten pa-
tients treated with cryotherapy has been pub-
lished suggesting that cryotherapy is a feasible
form of therapy in select HS cases [13]. The
treatment is however not unproblematic, and
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several and considerable practical restraints ex- ist. The treatment is associated with additional pain, which is already a dominant clinical prob- lem to HS patients. Additional iatrogenic pain is therefore an a priori drawback of the method. A significant proportion of the cases published furthermore experienced complications with postoperative infection. Finally, cryotherapy is a destructive process and commonly associated with a long healing time. In the published study [13] the healing time was on average 25 days. On the whole cryotherapy does therefore not appear to hold any clinically significant advantages over other forms of physical therapy. Theoreti- cally a more precise delivery of the cryotherapy could overcome some of these drawbacks, but would also obliterate the immediate practical benefits of the method, namely being fast and easy.
24.5 Discussion
Physical therapies may be directed against ei- ther the secondary prevention of early lesions or the destruction of established lesions. For true primary prevention of early lesions the patho- genic process is insufficiently described to allow a causal therapy, although the use of laser de- pilation may yet prove to be fruitful in proper studies. The possible effect of PDT on the hair follicle is at present unclear. It is not convinc- ingly proven that the penetration of ALA-PDT is sufficiently deep to allow treatment of estab- lished lesions of Hurley category II or III. Nor is it established that ALA-PDT has any effect on sinus tracts. The effects may therefore be more in line with the effects of this treatment in acne vulgaris, where a significant clinical effect has been shown in some studies. ALA-PDT is how- ever associated with considerable post-treat- ment pain and inflammation in acne patients and this may also limit its use in HS.
These reservations however stem partly from the paucity of data, and partly from the practi- cal consideration of penetration. It is entirely conceivable that the photosensitizers used do not penetrate the tissue sufficiently because of their formulation. A more liquid preparation may allow deeper penetration of the photosensi-
tizer into the hair follicles. The use of red light is theoretically sufficient, but even here there is room to improve the scope of this modality. In general the paucity of data requires additional well-designed studies, which should initially be relatively small, strongly structured proof-of- concept studies. With current technology the justification of an actual randomized controlled trial is debateable.
Destructive methods have to respect the gen- eral surgical principle of tissue conservation, i.e., that healthy tissue should be left intact. In HS sinus tracts normally occur under healthy skin which need not be destroyed. Precision in the application of destructive methods is there- fore very important. While indiscriminately destructive methods such as cryotherapy, and probably also electrodesiccation, may be ex- pected to work, they also induce unacceptable collateral damage. In addition unnecessary tis- sue destruction induces significant iatrogenic morbidity in the patients, as the lesions are of- ten slow to heal, are susceptible to suprainfec- tion and cause additional scarring. With im- proved imaging techniques and more targeted delivery of treatment this could be overcome to some degree, but is unlikely to be removed alto- gether.
A number of hypothetical and speculative physical approaches may be imagined. Im- proved lesion imaging may for instance also allow future intralesional therapies with appli- cation of light or pharmaceutical substances di- rectly into the lumen of the lesion. Similarly, radiofrequency devices may provide relief via an effect on the connective tissue surrounding the lesions. Finally, UVA1 therapy may provide an anti-inflammatory effect as well as scar re- duction if applied locally. It is most likely that the potential of a series of novel physical thera- pies will be explored over the coming years.
24.6 Practical Guidelines for Testing New Physical Therapies
The option of randomized controlled trials is generally not available for surgical techniques.
In lieu of the randomized controlled trial a lower
degree of evidence is therefore acceptable. The
key features of any investigations should remain the randomization, which has independent value even when assessed in an open or a single-blind- ed fashion. The central problem is one of control, but in an exploratory period abstention from ac- tive treatment is enough. In future cases sham procedures may be carried out when possible, providing there are objective documentation and an adequate follow-up. There must be ran- domization of both patients and lesions to pre- vent bias. Follow-up should be for a minimum of 3–6 months and it is advisable to include both patient-centered subjective methods of assess- ment as well as more objective methods. Subjec- tive methods can include health-related quality of life questionnaires developed for skin diseas- es, e.g., DLQI or Skindex [14, 15], and VAS scores of pain and disease severity. Objective quantifi- cation may include standardized clinical scores such as the Sartorius score [16], ultrasound im- aging and photography.
For bilateral HS lesions randomized intra-in- dividual left to right comparisons of physical therapies are possible. However it is not advised to compare lesions in different regions directly, for example axillary and genitofemoral lesions;
this is because the results of therapy often indi- cate different regional susceptibility in patients,
possibly because of differing shear forces and other local phenomena. Study requirements are summarized in Table 24.2. Early exploratory studies should similarly be aimed at providing the necessary data for the planning of larger controlled and randomized studies, and should therefore preferably use the same outcome vari- ables.
References
1. Jemec GBE. Hidradenitis suppurativa. J Cut Med Surg. 2003; 7: 47–56.
2. Larko O. Photodynamic therapy. Aust J Dermatol Suppl. 2005; 46: S1–2.
3. Nybæk H, Jemec GBE. Photodynamic therapy of acne rosacea. Dermatology 2005; 211: 135–138.
4. Charakida A, Seaton ED, Charakida M, Mouser P, Avgerinos A, Chu AC. Phototherapy in the treat- ment of acne vulgaris: what is its role? Am J Clin Dermatol. 2004; 5: 211–216.
5. Gold M, Bridges TM, Bradshaw VL, Boring M.
ALA-PDT and blue light therapy for hidradenitis suppurativa. J Drugs Dermatol. 2004; 3 (1 Suppl):
S32–35.
6. Strauss RM, Pollock B, Stables GI, Goulden V, Cun- liffe WJ. Photodynamic therapy using aminolaevu- linic acid does not lead to clinical improvement in hidradenitis suppurativa. Br J Dermatol. 2005; 152:
803–804.
7. Zeligman I. Temporary x-ray epilation therapy of chronic axillary hidradenitis suppurativa. Arch Dermatol. 1965; 92: 690–694.
8. Frohlich D, Baaske D, Glatzel M. [Radiotherapy of hidradenitis suppurativa – still valid today?]
Strahlenther Onkol. 2000; 176(6): 286–289.
9. Jemec GBE, Hansen U. The histology of hidradenitis suppurativa. J Am Acad Derm 1996; 34: 994–999.
10. Morgan WP, Leicester G. The role of depilation and deodorants in hidradenitis suppurativa. Arch Der- matol. 1982; 118: 101–102.
11. Jemec GBE, Heidenheim M, Nielsen NH. Hidrade- nitis suppurativa: characteristics and consequences.
Clin Exp Dermatol 1996; 21: 419–423.
12. Tack B. [Laser and intense pulsed light for hair re- moval.] Ann Dermatol Vener. 2005; 132: 75–79.
13. Bong JL, Shalders K, Saihan E. Treatment of per- sistent painful nodules of hidradenitis suppurativa with cryotherapy. Clin Exp Dermatol. 2003; 28:
241–244.
14. Lewis V, Finlay AY. 10 years experience of the Der- matology Life Quality Index (DLQI). J Investig Der- matol Symp Proc. 2004; 9: 169–180.
Table 24.2.
Factors to consider when planning experi- mental studies of physical therapies. Controls are es- sential and should be set up for each lesion and for the patient. Inguinal lesions are not appropriate controls for axillary lesions. (DLQI Dermatology Life Quality Index,
IPL intense pulsed light)Element of study Example
