West Meets East and Osteopathic Manipulative Medicine: Combining Treatment Modalities for Atopic Dermatitis

There is currently a paradigm shift in the treatment of atopic dermatitis (AD) in Western medicine. The decade of psoriatic advances is transitioning into the decade of AD. Now more than ever we have a better mechanistic understanding of this disease, enabling physicians to shift from a reactive treatment strategy to a more proactive approach guided by disease severity. However, modern pharmaceutical science and drugs can carry severe adverse effects. Interest in Eastern medicine and Osteopathic Manipulative Medicine stems from every physician’s desire to heal their patients without causing harm. In addition, we are of an age of educated and informed patients who are themselves experimenting with alternative therapies. A remarkable number (50 percent) of patients with inflammatory skin diseases have turned to complementary alternative medicine.1 For this reason it is imperative that physicians, even those without the intention of utilizing alternative therapies in their practice, should be familiar with all modalities. What follows is a review of AD therapies by modern Western, traditional Eastern, and Osteopathic Manipulative Medicine perspectives. Being open minded and knowledgeable in these therapies will ensure appropriate patient education and guidance from a medical provider well versed in global dermatologic disease treatments.

WESTERN

The Western approach to AD begins with teaching patients about the inherent dysfunction of essential stratum corneum proteins that make up their skin barrier. It is imperative that they understand adequate cutaneous hydration is key to management by improving barrier function and thus relieving pruritus.2 Appropriate use of moisturizers can reduce flare-ups of AD, as well as decrease the need for topical steroids.3 Mild disease states can be managed with the proactive use of low potency steroids or topical calcineurin inhibitors to prevent flares.2 However, patients with moderate-to-severe disease, indicating significant cutaneous immune dysregulation in place of more limited skin barrier dysfunction, require a more systemic approach. Well-established systemic therapies include cyclosporine, methotrexate, azathioprine, and mycophenolate mofetil. All have shown efficacy in treating AD but are limited by their side-effect profiles.4

With recent discoveries in immune-driven mechanisms made by researchers at Icahn School of Medicine at Mount Sinai in New York City, we are currently adding to our arsenal of treatment options for AD. Advances in biologic therapy targeting specific immune proteins involved in the major pathogenic pathways of AD are offering promising results. Dupilumab is a human monoclonal antibody IL-4Ra antagonist currently pending FDA approval. Its mechanism of action is to block IL-4 and IL-13, two important drivers of type 2 helper T-cell (Th2) mediated inflammation, which has been implicated in the pathogenesis of atopic dermatitis. Phase 1 and 2 trials show promise for patients suffering with moderate-to-severe AD who have failed traditional topical therapy. One four-week monotherapy study found dupilumab to be associated with a rapid and dose-dependent improvement in eczema area and severity index (EASI) score, investigators global assessment score, and pruritus. Further improvement was observed with 12 weeks of continuous treatment.5,6 Currently dupilumab is undergoing phase 3 clinical trials, with promising early data with regards to efficacy and safety. Many other biologics are currently being examined for the management of moderate-to-severe AD such as pitrakinra, mepolizumab, ustekinumab, and fezakinumab.4 Currently dupilumab has the most data available with regard to its use in the successful management of AD. With many other biologics on the horizon physicians will soon have a wide array of weapons to choose from when managing severe AD patients.

Even within Western culture, alternative therapies aside from steroids and systemics are widely established, probiotics being one option. Probiotics are live microorganisms that, when administered in sufficient doses, are thought to confer health benefits to the host.7,8 The early development of intestinal flora is facilitated by an array of microorganisms, which help to activate the innate and adaptive immune system. Allergic disease pathogenesis has been linked to an imbalance in Th1/Th2 immune responses.7,9-11 Probiotics can help balance the ratio response by suppressing Th2 mediated activity and increasing the regulatory T cell mediated response.7,12-14 A 12-week randomized, double blinded, placebo control study investigated the effects of L. plantarum CJLP133 strain in the prevention of AD symptoms. Results showed improvement in AD scores compared to the control group, along with a decrease in IFN gamma, eosinophils, and IL-4.15 A recent meta-analysis evaluating the effects of probiotics in the treatment of AD concluded significant improvement in patients aged one year or older.7,16 Of note, previous meta-analyses on this topic have produced inconsistent conclusions.7,16-19 The efficacy of probiotics is multifactorial and dependent on the production of specific probiotic strains, time of administration, duration of exposure, and dosage.7 As the paradigm sways toward maintenance over a reactive model in treating AD, the use of probiotics in Western medicine shows promise, but more data is warranted.

EASTERN

Traditional Chinese Medicine (TCM) is a cultural healing practice built on more than 4,000 years of Chinese medical knowledge. Its most popular modalities include Chinese herbal medicine and acupuncture. TCM is focused on curing the underlying cause of disease, believed to be a combination of innate and environmental imbalance of opposing body energy forces coined yin and yang. The body’s vital energy, or “Qi” (pronounced chee), circulates through a meridian system with 12 bilateral channels. Each of these channels has branches to bodily organs. When the flow of Qi becomes unbalanced towards the yin or the yang through physical, emotional, or environmental insults, illness may result.20

American dermatologists may be skeptical of the scientific methodology behind such an ancient medical practice, but the physiologic mechanisms of a number of TCM therapies have been elicited, and many controlled studies on TCM have been conducted.21 In the United States, the National Institute of Health has a National Center for Complementary and Intergrative Health that provides grants to support research on TCM. In addition, acupuncture needles have been approved by the FDA as medical devices.22 The frustration of failing conventional therapies, fear of modern Western medical treatments, and rich cultural diversity of our patient population in America lead many of our AD patients and their parents to seek out alternative options in TCM.

Chinese herbal medicine is the most commonly used TCM therapy in the management of AD. These are botanical-based mixtures often prepared by boiling and simmering, then placing in a sachet or formulating into granules for hot tea preparations called decoctions. Herbs can also be placed in syrups or capsule form for swallowing as well as topical vehicles.21 Hundreds of herbs are utilized in TCM. Pharmacological studies have proven that many bear anti-inflammatory, anti-microbial, sedative, and immunosuppressive actions.23-25 Studies involving herbal treatment for AD patients have shown decreased expression of low affinity IgE receptor and down-regulation of AD-related inflammatory mediators.26,27 Herbal combinations are determined as an individualized prescription based on disease features.

One of the most well received clinical trials of herbal therapy for AD was out of the Hospital for Sick Children in London in 1992. A mixture of 10 herbs commonly used for the treatment of AD in TCM (Ledebouriella seseloides, Potentilla chinensis, Aebia clematidis, Rehmannia glutinosa, Paeonia lactiflora, Lophatherum gracile, Dictamnus dasycarpus, Tribulus terrestris, Glycyrrhiza uralensis, and Schizonepeta tenuifolia) were served as a decoction to 37 pediatric AD patients once daily for eight weeks. After a four-week washout period they received a placebo decoction of plant material of similar appearance, taste, and smell with no known benefit in AD for another eight weeks. This double-blind, placebo-controlled crossover study proved Chinese herbal remedies superior to placebo, with a median percentage decrease in erythema scores of 49 percent and a median percentage decrease in surface damage scores of 57 percent.28 This same research group recruited another 31 patients to take place in an identical trial for adults. The adult study showed similar superiority, with a mean proportional change between end of Chinese herbal treatment and end of placebo treatment of 46 percent for erythema and 49 percent for surface damage.29 There was no evidence of hematological, renal, or hepatic toxicity in participants in either study.

Other Chinese herbal preparations previously investigated in clinical studies include Pentaherb capsules, Hochu-ekki-to granules, Jian Pi Shen Shi granules, and Xiao Feng San granules. A meta-analysis published in the Journal of the American Academy of Dermatology in 2013 evaluated all of the aforementioned herbal therapies in six studies including a total of 432 AD patients. Overall there was significant improvement in disease severity scores when a combination of Chinese herbal medicine and Western medicine was utilized versus Western medicine alone. In addition, Chinese herbal medicine alone versus placebo revealed significant improvement in erythema, surface damage, pruritus, sleep scores, quality of life, and need for concurrent pharmacotherapy. Despite these promising results, it was concluded that due to small cohort size and poor standardization of herbal compounds the studies provided insufficient data to make valid conclusions about modern use of Chinese herbal medicine in AD treatment.30 Lack of evidence-based knowledge is due to insufficient evidence rather than evidence against the benefit of herbal remedies.31 Other systematic reviews of TCM for AD agree that additional randomized controlled studies using larger cohorts, standardized herbal formulations, and appropriate methodology are surely warranted.25,32

Acupuncture has also gained popularity on the Western side of the globe in the past 30 years. An estimated three million adults and 150,000 children in the United States currently use this form of TCM as therapy for musculoskeletal pain, neurological conditions, and several cutaneous diseases.33 There are approximately 365 mainstream acupunture points on the body that connect to one or several of the 12 meridians which in turn are each associated with a body organ, and additional points on the ear, scalp, and hands.34 When acupuncture points are stimulated, Qi flow is restored and organ homeostasis achieved, curing disease at its origin. Acupuncture points can be stimulated in several ways. Corporal acupuncture utilizes metal needle insertion to varying depths by a trained acupuncturist. Acupressure is self massage with rounded movements of the fingers over prescribed acupuncture points; this offers the advantage of non-invasive self-application by the patient at any time. Moxibustion is a form of external thermal stimulation in which the herb wormwood is rolled into a cigar-sized moxa stick and burned in close approximation to the skin above a prescribed acupuncture point. Physicians can also utilize electropuncture using electrodes inserted into the acupuncture point, medicamentous acupuncture in which drugs are injected into the given point, radiation with UV ray, laser acupuncture, and auricle acupuncture with 130 points mapped out in a fetal homunculus on the ear.34

The LI11 acupuncture point is on the lateral end of the transverse cubital crease with the elbow flexed. This is the most utilized point in acupuncture treatment of AD. Three recent studies involving stimulation of the LI11 point via acupuncture and acupressure to treat AD symptoms revealed significant improvement in pruritus and lichenification.35-37 Western medical perspective explanations for itch reduction in AD patients treated with acupuncture include neuromodulation of brain areas that are known to be involved in itch processing, such as the insula, striatum, and putamen. These mechanisms are backed by neuroimaging studies.38,39 Another theory is built upon the foundation that pain and pruritus have similar mechanisms of activation. Basic science studies performed in rat models revealed that the antipruritic effect of acupuncture may involve opioid receptor modulation, improving both pain and itch severity.40,41

OSTEOPATHIC MANIPULATIVE MEDICINE

Structure and function are interrelated. As one of the tenets of osteopathic medicine, this statement applies well to the aspects believed to be part of the pathogenesis of atopic dermatitis. In this condition, a defect in the skin barrier, along with alterations in immune profiles, leads to inflammation within the skin. Osteopathic manipulative medicine (OMM) is based on three additional tenets: 1.) the body is a unit of body, mind, and spirit, 2.) the body has the ability to regulate and heal itself, and 3.) rational treatment is based upon an understanding and application of the preceding tenets. Knowing this, the clinician can apply these tenets to the diagnosis and treatment of atopic patients. The osteopathic structural exam can be beneficial in locating areas of suspected inflammation by identifying tissue texture changes, tenderness, and restricted motion in what is collectively referred to as somatic dysfunction. The role of osteopathic manipulative treatment was described by the founder of osteopathy, Dr. Andrew Taylor Still, back in the 19th century when he contemplated the impact of treating structural alterations in the body on the proper functioning of the body.42

Atopic dermatitis, a disease rooted in epidermal barrier dysfunction, is known to have multifactorial etiology with a portion of the disease process being affected by the environment.43 Both physiologic and psychologic stressors are known to be triggers of atopic dermatits.43,44 As is commonly known, itch is a very powerful complex neural signal that is one of the catalysts of a common exacerbation. The skin contains an impressive network of sensory nerves in addition to expressing many neurotransmitters and neuropeptide receptors found in the central nervous sytem.43,45 The skin interacts with aspects of the nervous, immune, and endocrine systems, and an imbalance in this communication is thought to play some role in AD.43,46-51 Stress causes a variety of biochemical reactions that in healthy patients induces production of cortisol and catecholamine. In atopic patients, however, sub-optimal production of cortisol occurs in response to stress.52-54 Interestingly heart rate, a representative parameter of perturbations in the autonomic nervous system, is at baseline higher in patients with AD even without stress.55 Scratching, psychological stress, and histamine induced itch resulted in increases in low frequency heart rate variability, a parameter of sympathetic tone.56 Of note, it has been described that low vagal tone is observed in inflammatory conditions.57 Based on this information we can conclude that dysregulation of the autonomic nervous system may be a component in the pathogenesis of atopic dermatitis. An appreciation of this connection makes it easier to understand how to apply the concepts of osteopathy to patients with AD.

Using the structure-function interrelationship between the spine and autonomic nervous system, we can look for palpable restrictions in the cranium, subocciput, and upper cervical region that influence vagus nerve function. By doing so, the clinician may help regulate parasympathetic tone and ultimately help reduce the inflammation associated with AD. The thoracic and lumbar vertebrae in the T1 to L2 region represent an area of sympathetic influence because the sympathetic chain ganglia are located lateral to the vertebral bodies in this region and rest on the anterior surface of the ribs. Therefore, examining this spinal region may help identify underlying somatic dysfunctions that upon treatment could help regulate the sympathetic tone in AD patients. Because the sympathetic nervous system innervates blood vessels and sweat glands, regulating its tone could have physiologic effects on the skin. T7 to T11 may have particular influence in the AD patient because the sympathetic innervation of the adrenal glands arise from this region.58 Addressing somatic dysfunction in the T7 to T11 region with manipulative treatment may thus normalize cortisol production in atopic patients. Rib dysfunctions may also contribute to disturbances in the autonomic nervous system due to the sympathetic chain ganglia’s location on the anterior surface of the ribs as described above. Patients with other atopic diseases, such as asthma, may also benefit from treating rib dysfunctions because this would enhance breathing mechanics.

Because atopic dermatitis is a chronic inflammatory disease process, addressing inflammation beyond balancing the autonomic nervous system provides another clinical opportunity to help the patient. The lymphatic system is a large pipeline that circulates many inflammatory cells and mediators. In osteopathy, diaphragms are anatomical transition regions that can particularly influence lymphatic circulation. Somatic dysfunction, such as fascial strain, in the lymphatic diaphragms can prevent the regulatory return of lymphatic fluid into the venous circulation and thus allow for local and/or systemic inflammation. In turn, this could affect disease severity and potentially response to any treatment. Examining patients for lymphatic dysfunctions begins with assessing the supraclavicular fossae bilaterally, where on the left the thoracic duct drains into the left subclavian vein and on the right, the right lymphatic duct drains into the right subclavian vein. Treating this region in patients with AD can “unplug” blocked lymphatic circulation, thus allowing for better drainage and circulation of inflammatory cells and cytokines by preventing systemic and regional buildup of these substances. Additional lymphatic techniques, including petrissage, splenic plump, doming of the abdominal diaphragm, popliteal fossa release, and pedal pump may help promote the proximal flow of lymphatic fluid. This is by no means a complete list of osteopathic techniques that may be used in the management of AD but is instead a representation of what areas could be addressed based on the pathophysiology of the disease and the generally well-tolerated nature of the treatments.

Osteopathy has been used to treat skin diseases since the time of Andrew Taylor Still.59 A biography of Andrew Taylor Still by John Lewis mentions that Still insinuated his belief that eczema had been caused by dysfunctions in the upper cervical and thoracic joints and the consequent nerve irritation disturbing the vasomotor area in the brainstem altering circulation throughout the body.59 Following this, Lewis further mentions a case encountered by Arthur Hildreth, one of the first students of the American School of Osteopathy, where he had been presented with a 60-year-old female with “appalling eczema from head to toe.” He had treated the patient’s dysfunctions specifically at C1 to C3 and T4 to T6 and “over a period of weeks the scales and eruptions peeled and cleared leaving pure unblemished skin.”59 Although eczema can be a relapsing and remitting disease, and some may dismiss this resolution to time alone, one should note the association of this condition with the upper cervical and upper thoracic segments by these two early practitioners and recall that the upper cervical segments and the upper thoracic segments have connections to the vagus nerve (parasympathetic nervous system) and sympathetic nervous system respectively. Thus, this case history illustrates how dysregulation of the autonomic nervous system may indeed play a part in AD exacerbations.

In another case, a 21-year-old female with truncal and extremity eczema of two years duration and not responding to topical corticosteroids was found to have a decreased range of motion in the thoracic spine, a flexion dysfunction of T5 and posterior ribs 5-6 upon presentation.60 Over the course of seven chiropractic manipulative treatments to the thoracic spine, ribs, and sacroiliac region, the patient had reduced intensity of pruritus with no new appearance or disappearance of lesions. The patient noted greater reduction in symptom severity with the addition of treatment of the sacroiliac regions.60 Because of the osteopathic tenet that the body functions as an integrated unit, and the theorized structural-functional interconnection between the cranium and the sacrum, it is hypothesized that treatment of the sacroiliac region resulted in concurrent treatment of the cranium and thus influenced the parasympathetic component of the autonomic nervous system. This rationale, however, was not mentioned by the authors.

Currently, on PubMed the search terms “osteopathic manipulative treatment and atopic dermatitis/eczema” yield no results. As with many complementary or alternative fields of medicine, randomized controlled studies are hard to perform objectively in what many consider to be inherently subjective modalities. One randomized controlled trial in Germany assessed the efficacy of personalized osteopathic manipulative treatment in infants and children with atopic dermatitis.61 Subjects with a mean age of 4.2 years were randomly assigned to the treatment group or control group. Eighteen subjects in the treatment group were treated three times at two- to three-week intervals whereas 19 control subjects were only treated with non-medicated topical therapies. The study found a significant improvement in SCORAD indices, with 72 percent in the treatment group vs. 8.5 percent in the control group.61 This data is promising but longer term studies with adequate follow-up and greater diversity in child age are necessary to assess long-term benefits.

We hope that this article explains the rational basis of manual treatment, in particular osteopathic manipulative treatment, in the care of patients with AD and provides impetus for researchers to further explore its utility in this and other related conditions.

CONCLUSION

Atopic dermatitis is a complicated condition with many different approaches to treatment. Based on the information presented in this article, we can now try to integrate additional treatment strategies into the care of our patients with a combination of modern Western, traditional Eastern, and OMM approaches. Ultimately, Western medical treatment with emollients, proper skincare regimens, and steroids bridged with steroid sparing agents are the backbone of therapy due to their evidence-based efficacy and success. Complementary and alternative therapies provide the clinician with additional tools that may enhance clinical efficacy and patient satisfaction.

The progress being made in targeting different checkpoints within the AD disease process with biologic therapy offers the promise of future treatment options for our most severe eczema patients. However, there may be a role for alternative therapies in states of remission to prolong periods of disease free states.

In addition, chinease herbal medicine, acupunture, and OMM may be used as adjuvants especially in patients on multi-drug/therapy regimens developing resistance. n

1. Simpson EL, Basco M, Hanifin J. A cross-sectional survey of complementary and alternative medicine use in patients with atopic dermatitis. Am J Contact Dermat. 2003;14(3):144-147.

2. Lee JH, Son SW, Cho SH. A Comprehensive Review of the Treatment of Atopic Eczema. Allergy Asthma Immunol Res. 2016;8(3):181-190.

3. Anderson PC, Dinulos JG. Are the new moisturizers more effective? Curr Opin Pediatr. 2009;21(4):486-490.

4. Montes-Torres A, Llamas-Velasco M, Perez-Plaza A, Solano-Lopez G, Sanchez-Perez J. Biological Treatments in Atopic Dermatitis. J Clin Med. 2015;4(4):593-613.

5. Noda S, Krueger JG, Guttman-Yassky E. The translational revolution and use of biologics in patients with inflammatory skin diseases. J Allergy Clin Immunol. 2015;135(2):324-336.

6. Beck LA, Thaci D, Hamilton JD, et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med. 2014;371(2):130-139.

7. Rather IA, Bajpai VK, Kumar S, Lim J, Paek WK, Park YH. Probiotics and Atopic Dermatitis: An Overview. Front Microbiol. 2016;7:507.

8. Hill C, Guarner F, Reid G, et al. Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol. 2014;11(8):506-514.

9. Romagnani S, Maggi E, Parronchi P, Macchia D, Piccinni MP, Ricci M. Increased numbers of Th2-like CD4+ T cells in target organs and in the allergen-specific repertoire of allergic patients. Possible role of IL-4 produced by non-T cells. Int Arch Allergy Appl Immunol. 1991;94(1-4):133-136.

10. Romagnani S. T-cell subsets (Th1 versus Th2). Ann Allergy Asthma Immunol. 2000;85(1):9-18; quiz 18, 21.

11. Schmidt-Weber CB, Blaser K. Immunological mechanisms in specific immunotherapy. Springer Semin Immunopathol. 2004;25(3-4):377-390.

12. Feleszko W, Jaworska J, Rha RD, et al. Probiotic-induced suppression of allergic sensitization and airway inflammation is associated with an increase of T regulatory-dependent mechanisms in a murine model of asthma. Clin Exp Allergy. 2007;37(4):498-505.

13. Kim HJ, Kim YJ, Kang MJ, et al. A novel mouse model of atopic dermatitis with epicutaneous allergen sensitization and the effect of Lactobacillus rhamnosus. Exp Dermatol. 2012;21(9):672-675.

14. Kim JY, Park BK, Park HJ, Park YH, Kim BO, Pyo S. Atopic dermatitis-mitigating effects of new Lactobacillus strain, Lactobacillus sakei probio 65 isolated from Kimchi. J Appl Microbiol. 2013;115(2):517-526.

15. Han Y, Kim B, Ban J, et al. A randomized trial of Lactobacillus plantarum CJLP133 for the treatment of atopic dermatitis. Pediatr Allergy Immunol. 2012;23(7):667-673.

16. Kim SO, Ah YM, Yu YM, Choi KH, Shin WG, Lee JY. Effects of probiotics for the treatment of atopic dermatitis: a meta-analysis of randomized controlled trials. Ann Allergy Asthma Immunol. 2014;113(2):217-226.

17. Boyle RJ, Bath-Hextall FJ, Leonardi-Bee J, Murrell DF, Tang ML. Probiotics for treating eczema. Cochrane Database Syst Rev. 2008(4):CD006135.

18. Lee J, Seto D, Bielory L. Meta-analysis of clinical trials of probiotics for prevention and treatment of pediatric atopic dermatitis. J Allergy Clin Immunol. 2008;121(1):116-121 e111.

19. Michail SK, Stolfi A, Johnson T, Onady GM. Efficacy of probiotics in the treatment of pediatric atopic dermatitis: a meta-analysis of randomized controlled trials. Ann Allergy Asthma Immunol. 2008;101(5):508-516.

20. Baroni A, Ruocco E, Russo T, et al. The use of traditional Chinese medicine in some dermatologic diseases: Part I--Acne, psoriasis, and atopic dermatitis. Skinmed. 2015;13(1):32-38; quiz 39.

21. Koo J, Desai R. Traditional Chinese medicine in dermatology. Dermatol Ther. 2003;16(2):98-105.

22. Wang J, Li XM. Chinese herbal therapy for the treatment of food allergy. Curr Allergy Asthma Rep. 2012;12(4):332-338.

23. Lin X, Tu C, Yang C. [Study on treatment of eczema by Chinese herbal medicine with anti-type IV allergic activity]. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2000;20(4):258-260.

24. Xu XJ, Banerjee P, Rustin MH, Poulter LW. Modulation by Chinese herbal therapy of immune mechanisms in the skin of patients with atopic eczema. The British journal of dermatology. 1997;136(1):54-59.

25. Hon KL, Chan BC, Leung PC. Chinese herbal medicine research in eczema treatment. Chin Med. 2011;6:17.

26. Bedi MK, Shenefelt PD. Herbal therapy in dermatology. Archives of dermatology. 2002;138(2):232-242.

27. Leung TF, Wong KY, Wong CK, et al. In vitro and clinical immunomodulatory effects of a novel Pentaherbs concoction for atopic dermatitis. The British journal of dermatology. 2008;158(6):1216-1223.

28. Sheehan MP, Atherton DJ. A controlled trial of traditional Chinese medicinal plants in widespread non-exudative atopic eczema. The British journal of dermatology. 1992;126(2):179-184.

29. Sheehan MP, Rustin MH, Atherton DJ, et al. Efficacy of traditional Chinese herbal therapy in adult atopic dermatitis. Lancet. 1992;340(8810):13-17.

30. Tan HY, Zhang AL, Chen D, Xue CC, Lenon GB. Chinese herbal medicine for atopic dermatitis: a systematic review. Journal of the American Academy of Dermatology. 2013;69(2):295-304.

31. Goddard AL, Lio PA. Alternative, Complementary, and Forgotten Remedies for Atopic Dermatitis. Evid Based Complement Alternat Med. 2015;2015:676897.

32. Armstrong NC, Ernst E. The treatment of eczema with Chinese herbs: a systematic review of randomized clinical trials. Br J Clin Pharmacol. 1999;48(2):262-264.

33. Barnes PM, Bloom B, Nahin RL. Complementary and alternative medicine use among adults and children: United States, 2007. Natl Health Stat Report. 2008(12):1-23.

34. Iliev E. Acupuncture in dermatology. Clin Dermatol. 1998;16(6):659-688.

35. Pfab F, Huss-Marp J, Gatti A, et al. Influence of acupuncture on type I hypersensitivity itch and the wheal and flare response in adults with atopic eczema - a blinded, randomized, placebo-controlled, crossover trial. Allergy. 2010;65(7):903-910.

36. Salameh F, Perla D, Solomon M, et al. The effectiveness of combined Chinese herbal medicine and acupuncture in the treatment of atopic dermatitis. J Altern Complement Med. 2008;14(8):1043-1048.

37. Lee KC, Keyes A, Hensley JR, et al. Effectiveness of acupressure on pruritus and lichenification associated with atopic dermatitis: a pilot trial. Acupunct Med. 2012;30(1):8-11.

38. Pfab F, Valet M, Tolle T, Behrendt H, Ring J, Darsow U. Recent progress in unraveling central nervous system processing of itch sensation. World Allergy Organ J. 2008;1(10):168-173.

39. Napadow V, Li A, Loggia ML, et al. The brain circuitry mediating antipruritic effects of acupuncture. Cereb Cortex. 2014;24(4):873-882.

40. Han JB, Kim CW, Sun B, et al. The antipruritic effect of acupuncture on serotonin-evoked itch in rats. Acupunct Electrother Res. 2008;33(3-4):145-156.

41. Kim KH, Lee MS, Choi SM. Acupuncture for treating uremic pruritus in patients with end-stage renal disease: a systematic review. J Pain Symptom Manage. 2010;40(1):117-125.

42. Still AT. Philosophy of osteopathy. Kirksville, Mo.,: A. T. Still; 1899.

43. Suarez AL, Feramisco JD, Koo J, Steinhoff M. Psychoneuroimmunology of psychological stress and atopic dermatitis: pathophysiologic and therapeutic updates. Acta Derm Venereol. 2012;92(1):7-15.

44. Morren MA, Przybilla B, Bamelis M, Heykants B, Reynaers A, Degreef H. Atopic dermatitis: triggering factors. Journal of the American Academy of Dermatology. 1994;31(3 Pt 1):467-473.

45. Slominski A, Wortsman J. Neuroendocrinology of the skin. Endocr Rev. 2000;21(5):457-487.

46. Roosterman D, Goerge T, Schneider SW, Bunnett NW, Steinhoff M. Neuronal control of skin function: the skin as a neuroimmunoendocrine organ. Physiol Rev. 2006;86(4):1309-1379.

47. Chuong CM, Nickoloff BJ, Elias PM, et al. What is the ‘true’ function of skin? Exp Dermatol. 2002;11(2):159-187.

48. Steinhoff M, Vergnolle N, Young SH, et al. Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nat Med. 2000;6(2):151-158.

49. Steinhoff M, Neisius U, Ikoma A, et al. Proteinase-activated receptor-2 mediates itch: a novel pathway for pruritus in human skin. J Neurosci. 2003;23(15):6176-6180.

50. Arck P, Paus R. From the brain-skin connection: the neuroendocrine-immune misalliance of stress and itch. Neuroimmunomodulation. 2006;13(5-6):347-356.

51. Arndt J, Smith N, Tausk F. Stress and atopic dermatitis. Curr Allergy Asthma Rep. 2008;8(4):312-317.

52. Buske-Kirschbaum A, Jobst S, Wustmans A, Kirschbaum C, Rauh W, Hellhammer D. Attenuated free cortisol response to psychosocial stress in children with atopic dermatitis. Psychosom Med. 1997;59(4):419-426.

53. Buske-Kirschbaum A, Geiben A, Hollig H, Morschhauser E, Hellhammer D. Altered responsiveness of the hypothalamus-pituitary-adrenal axis and the sympathetic adrenomedullary system to stress in patients with atopic dermatitis. J Clin Endocrinol Metab. 2002;87(9):4245-4251.

54. Rupprecht M, Rupprecht R, Kornhuber J, et al. Elevated glucocorticoid receptor concentrations before and after glucocorticoid therapy in peripheral mononuclear leukocytes of patients with atopic dermatitis. Dermatologica. 1991;183(2):100-105.

55. Seiffert K, Hilbert E, Schaechinger H, Zouboulis CC, Deter HC. Psychophysiological reactivity under mental stress in atopic dermatitis. Dermatology. 2005;210(4):286-293.

56. Tran BW, Papoiu AD, Russoniello CV, et al. Effect of itch, scratching and mental stress on autonomic nervous system function in atopic dermatitis. Acta Derm Venereol. 2010;90(4):354-361.

57. Tracey KJ. Understanding immunity requires more than immunology. Nat Immunol. 2010;11(7):561-564.

58. Nelson KE, Glonek T, American College of Osteopathic Family Physicians. Somatic dysfunction in osteopathic family medicine. Philadelphia: Lippincott Williams & Wilkins; 2007.

59. Lewis JR. A.T. Still: From the Dry Bone to the Living Man. Dry Bone Press 2012.

60. Eldred DC, Tuchin PJ. Treatment of acute atopic eczema by chiropractic care: a case study. Australasian Chiropractic & Osteopathy. 1999;8(3):96.

61. Ozbay I. Therapeutic effectiveness of an osteopathic treatment of infants and children with atopic dermatitis. A randomized controlled trial. 9Th International Congress of the German Osteopathic Association; 2006; Schlangenbad / Wiesbaden / Germany.