COMMENTARY
THE RARE COEXISTENCE OF LEPROSY AND PSORIASIS BHUSHAN KUMAR, M.D., S.P. RAYCHAUDHURl, M.D., SIAVOSH VOSSOUGH, B.A., AND EUGENE M. FARBER, M.D.
Subsequent to the observations made that the sensory peripheral nerves along with their neuropeptides play a significant role in the pathogenesis of psoriasis, it became relevant to search for the incidence of psoriasis in conditions where peripheral nerves are damaged.' Leprosy is characterized by peripheral nerve damage; therefore, we initiated a study to see whether the incidence of psoriasis is less in leprosy patients. hi our search to find a relationship between psoriasis and leprosy, we collected information from those geographic regions where leprosy is endemic. One of the authors (B.K.) prepared a questionnaire to be filled out by physicians at leprosy centers in different parts of the world. From this questionnaire, we were able to assess the incidence of psoriasis among leprosy patients, but we were unable to identify the exact number of psoriasis cases with lepromatous or tuberculoid leprosy. Nevertheless, our findings (Table 1) clearly demonstrate the rare coexistence of the two diseases; although a few cases of psoriasis and leprosy have been previously documented in the Indian medical literature.^'' Out of 145,661 cases of leprosy, only 20 individuals had clinical signs for both leprosy and psoriasis. On average, these figures translate to 1.4 cases of concurrent psoriasis among a population of 10,000 with leprosy. In this article, we will give possible explanations for our findings.
GENETIC FACTORS AND THE IMMUNE SYSTEM
An early report stating the rarity of psoriasis among leprosy patients was published at the Hadassah University Hospital and the Government Hospital for Hansen's Disease in Jerusalem, Israel.'' In this study, the medical records of 309 leprosy patients, who had received treatment at the Government Hospital for Hansen's disease in Jerusalem from 1950 to 1980, were reviewed. None of the patients displayed any clinical signs of psoriasis on many examinations performed during periods of fol-
From the Psoriasis Research Institute, Palo Alto, California, and the Postgraduate Institute of Medical Education and Research, Chandigarh, India. Address for correspondence: Eugene M. Farber, M.D., Psoriasis Research Institute, 600 Town and Country Village, Palo Alto, CA 94301. .
low-up lasting as long as 40 years. Our study also confirms the rarity of psoriasis among leprosy patients (Table 1). Wahba et al. suggested that genetic factors may play a role in protecting psoriatic patients from the leprosy infection.'* Population studies have associated HLA-DR2 and HLA-DQWl with leprosy, and these findings are statistically significant.'' In addition, HLA-MTl and HLA-DR3 are correlated with susceptibility to leprosy.'' In psoriasis, there is a high frequency of HLA-Al, -B13, -B16, -B17, -B38, -CW6, and DR7 with reference to the general population.^ It has been demonstrated that leukocytes isolated from the peripheral blood of psoriatics are increased in numbers'* and have altered characteristics, and that the activity of the reticuloendothelial system in psoriatics is changed when compared with normal controls. Using the nitroblue tetrazolium test, which is an indirect measure of metabolic activity in polymorphonuclear leukocytes, it can be seen that these cells in psoriatics have a higher phagocytic activity than control polymorphonuclear leukocytes.' In addition to the heightened chemotaxis, psoriatic leukocytes have a greater phagocytic activity as determined by their higher ability to ingest ''''I labeled Shigella flextieri.^^ Monocytes isolated from psoriatics had 36 to 40% higher phagocytic activity than control monocytes from non-psoriatic individuals." Moreover, a two- to fourfold increase in bactericidal activity was detected when compared with controls. ' With regards to reticuloendothelial activity, workers in Sweden have been able to show an increase among psoriatics, and this activity remained high even in patients with minimal skin involvement.'- The T cells also play a major role in the pathogenesis of psoriasis.'^ It has been proposed that the proliferative lesions that characterize psoriasis are caused by factors generated by the interaction of Tii lymphocytes with Langerhans' cells in the epidermis.''* There is evidence that lL-2 is implicated in the pathogenesis of psoriasis. Psoriatic plaques contain more lL-2 receptor-positive cells in the dermal infiltrate as compared with lesion-free skin. Marked exacerbation of psoriasis in three individuals undergoing IL-2 monotherapy for metastatic renal carcinoma was observed.'^ Cyclosporine produces its effect by inhibiting lL-2 production."' Psoriatic lesions reappeared in a patient after intralesional infection of alpha interferon for warts,'^ and in another at the site of gamma interferon injection."* Although interferon-a levels have not 551
International Journal of Dermatology Vol. 31, No. 8, August 1992
Table 1. Coexistence of Leprosy and Psoriasis Location Argentina Burma Iltaukhyant Hosp. Kengtung Hosp. Cuba India Bomhay Dattapur Jhansi Kashmir Kottayam Madras Rohtak Thanjavur New Delhi Agra Jaipur Bihar Manipal Patiala Cochin Cuntur Malawi (Africa) Mexico San Luis Potosi
Patients with Leprosy
Patients with Leprosy and Psoriasis
2000
6
2500 2500 1500
Q
3975 350 2000 874 3000 1260 1149 3000 25000 75000 4206 10705 3000 462 1000 1200 1000
possible role of sensory nerve fibers in the skin and their release of neuropeptides in the disease process. In order to understand the involvement of neuropeptides in leprosy and psoriasis, it would be useful to summarize the presence of different neuropeptides in cutaneous nerves. Immunocytochemical techniques have revealed the presence of substance P,^^ neuropeptide tyrosine (NPY),^^ vasoactive intestinal polypeptide, (vip),"'^* and calcitonin gene-related peptide (CGRP).^' Both substance P and CGRP are associated with sensory C fibers, and they are believed to be involved in neurogenic inflammation and plasma extravasation.^"-^' vip and NPY have autonomic functions with VIP acting as a vasodilator and secretomotor,^^'^^ whereas NPY acts as a vasoconstrictor.''' In 1965, Wedell et al. were able to show a significant increase in the turnover of neural elements, not only in clinically involved psoriatic skin but also in uninvolved skin, although the effects were more pronounced in the involved sites.^^ A possible role for neuropeptides in psoriasis has been suggested.'-'^ The hypothesis is that psoriasis is triggered by the process of neurogenic inflammation, which is regulated by neuropeptides such as substance P. It is believed that neuropeptides, including substance P, can be released from cutaneous sensory nerves, and that this release can be caused by endogenous and exogenous stimuli. The inflammatory response induced by tbe release of neuropeptides is possibly responsible for triggering psoriasis. Further evidence supporting this hypothesis comes from a recent study examining the altered innervation pattern in psoriasis.^"^ The results indicate that, when compared to nonpsoriatic controls and lesionfree psoriatic skin, the dermis and epidermis in psoriatic lesions have appreciably higher innervation with neurofilament positive fibers, including substance Pcontaining fibers in the epidermis. Successful treatment of moderate and severe psoriasis with topically applied capsaicin has been reported.'^ Capsaicin is an inhibitor of cutaneous vasodilatation, probably acting through depletion of substance P from nerve terminals.
0 0 0 0 1
0 1 1 0
3. 0 3 :
' --. ' -
0 Q 0 3 0
0 0
No reported case of psoriasis and leprosy in the same individual
been assayed, serum levels of interferon-y have been documented to rise following lL-2 infusions." The presence of interferon-y-induced protein 10 in keratinocytes was reported to be associated with psoriasiform hyperplasia in both AlDS-associated and classic psoriasis.^" This is contrary to what is observed with leprosy, which is a disease of the retriculoendotheliai and phagocytic systems. The spectrum of immunologic response observed ranges from the well-developed host cellular immunity in tuberculoid disease to virtually no resistance in the lepromatous form of leprosy.^' The cause of the hyporesponsive state of lepromatous leprosy patients is not yet clear; however, it appears that T-cell proliferation and production of lymphokines in response to M. leprae are impaired in lepromatous patients.^' Reduced activity of peripheral blood mononuclear leukocytes and macrophages and a depressed T-cell functional state have been reported in all types of leprosy.^'"^-^ Reduced lL-2 production has also been reported in all types of leprosy.^''
In a recent report concomitant occurrence of psoriasis and polyneuropathy was cited in support of the theory of a relationship between peripheral nerves and psoriasis.^** Prompt remission of psoriasis following cutaneous nerve section has been reported.^' Integrin B-4 is expressed by epithelial cells, and it functions in Tcell keratinocyte adhesive interactions. The presence of an increased number of nerve fibers, particularly those that interact with basal keratinocytes, probably bas a role in the causation of psoriasis.''" Raised levels of norepinephrine, a neurotransmitter, in psoriasis and their role in the worsening of psoriasis has been suggested.'" More recently, elevated levels of neurotransmitters, especially VIP, have been found in psoriasis.''^ The neuritis seen in leprosy is an important feature, and the causation agent, Mycobacterium leprae, has the
NERVES AND NEUROPEPTIDES
It has been well established that one of the most important characteristics of leprosy is nerve damage, and clinical diagnosis of leprosy usually includes the observations of skin anesthesia and enlarged peripheral In psoriasis, there is strong evidence for the 552
Leprosy and Psoriasis Kumar et al.
5.
special characteristic of invading nerves.''^ The early signs of this nerve involvement are manifested through the loss of sweating, thermal sensation, and touch.''''•''^ A study was performed to determine the cutaneous innervation pattern in 100 leprosy patients and in 50 healthy controls.'"' Through the technique of immunocytochemistry, it was demonstrated that all of the 50 nonleprous skin specimens were immunoreactive for neurofilaments, protein gene product 9.5 (PGP 9.5), which is a general neural marker, and neuropeptides. PGP 9.5 and neurofilament immunoreactivity were detected in all of the indeterminate leprosy cases, in 15 out of 43 tuberculoid cases, and in 33 out of 43 lepromatous cases. Immunoreactivity for neuropeptides was completely absent in all of the tuberculoid and lepromatous cases, but it was detected in 2 out of 14 indeterminate cases. The absence of neuropeptides from leprous skin is a critical observation. It could be that the neuropathy caused by the leprosy infection alters the cutaneous sensory nerves such that the process of neurogenic inflammation, which seems to be an integral part of the psoriatic disease process, is inhibited.
6.
7.
8.
9.
10.
I 1. 12.
CONCLUSIONS
13.
In this study we have provided data to show that the occurrence of psoriasis in leprosy patients is extremely rare. With this clinical finding and considering the present knowledge of these two diseases, we propose the following possible theories to explain the rarity of psoriasis in leprosy patients: (1) The reduced nerves with their depleted content of neuropeptides, especially in lepromatous leprosy, successfully inhibit an important pathway in neurogenic inflammation, which seems to be involved in triggering psoriasis. (2) Altered immune response in leprosy can be a contributing factor for the low incidence of psoriasis in leprosy. (3) The difference in HLA phenotyping and perhaps some other differences in the genetic make up in leprosy and psoriasis patients could be responsible for the rarity of the coexistence of these two diseases.
14.
15. 16.
17.
18.
19.
REFERENCES
1.
2.
3.
4.
20.
Farber EM, Nickoloff BJ, Recht B, Fraki JE. Stress, symmetry and psoriasis: possible role of neuropeptides. J Am Acad Dermatol 1986; 14:305-311. Nagabhushanam P. Case report of psoriasis with rheumatoid arthritis with polyneuritic leprosy. Indian J Dermatol Venereol 1969; 35:97-98. Canapati R, Deshpande D, Chulawala R. Some interesting disease combinations - report on two cases. Leprosy in India 1976; 48:428-430. Wahba A, Dorfman M, Sheskin J. Psoriasis and other common dermatoses in leprosy. Int J Dermatol 1980; 19:93-95. . •
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Todd JR, West BC, Mcdonald JC. Human leukocyte antigen and leprosy: study in northern Louisiana and review. Rev Infect Dis 1990; 12:63-74. Van Eden W, Gonzalez NM, de Vries RR, et al. HLAlinked control of predisposition to lepromatous leprosy. JInfDis 1985; 151:9-14. Arnold C. Psoriatic arthritis a clinical entity or two diseases? In: Farher EM, Nail L, Morhenn V, Jacobs P. eds. Psoriasis: proceedings of the Fourth International Symposium. New York: Elsevier Science Publishing, 1987:306. Eraki JE, Jakoi L, Davies AO, et al. Polymorphonuclear leucocyte function in psoriasis: chemotaxis, chemokinesis, P-adrenergic receptors and proteolytic enzymes of polymorpho-nuclear leukocytes in the peripheral blood from psoriatic patients. J Invest Dermatol 1983; 81: 254-257. Cotteril JA, Roberts NM, Freeman R, et al. Aspects of polymorph function in psoriasis. Proc R Soc Med 1974; 67:874-875. Wahba A, Cohen HA, Bar-Eli M, et al. Neutrophil chemotaxis in psoriasis. Acta Derm Venereol (Stockh) 1979; 59:441-445. Bar-Eli M, Gallily R, Cohen HA, et al. Monocyte function in psoriasis. J Inv Dermatol 1979; 73:147-149. Molin L, Reizenstein P. Hematological changes in psoriasis. Acta Derm Venereol (Stockh) 1974; 54:465-469. Valdimarsson H, Baker BS, Jonsdotter I, et al. Psoriasis a disease of abnormal keratinocyte proliferation induced by T-lymphocytes. Immunol Today 1986; 7:256-258. Baker BS, Swain AF, Griffiths CEM, et al. The effects of topical treatment with steroids or dithranol on epidermal T lymphocytes and dendritic cells in psoriasis. Scand J Immunol 1985; 22:471-477. Lee RE, Gaspari AA, Lotze MT. lnterleukin-2 and psoriasis. Arch Dermatol 1988; 124:1811-1815. Black CDV, Kroczek RA, Barbet J, et al. Induction of IL-2 receptor expression in vivo: response to concanavalin A. Cell Immunol 1988; 111:420-432. Shiohara T, Kohayashi M, Kimiaki A, et al. Psoriasis occurring predominantly on warts. Possible involvement of interferon alpha (observations). Arch Dermatol 1988; 124:1816-1821. Fierlbeck G, Rassner G, MuUer C. Psoriasis induced at the injection site of recombinant interferon gamma. Arch Dermatol 1990; 126:351-355. Lotze MT, Matory Y, Ettinghausen SE, et al. In vivo administration of purified human interleukin-2. J Immunol 1985; 135:2865-2875. Smoller BR, McNutt NS, Gray MH, et al. Detection of interferon gamma - induced protein 10 in psoriasis form dermatitis of acquired immuno deficiency syndrome. Arch Dermatol 1990; 126:1457-1461. Kaplan G, Cohn ZA. The immunohiology of leprosy. Int Rev Exp Pathol 1986; 28:45-78. Makonkawkeyoon S, Kasinrerk W, Dettrairat S, et al. Immunologic defect in leprosy patients. 1. Evidence of immune aberration of suppressor T-lymphocytes in lepromatous leprosy. Int J Lepr 1990; 58:302-310. Rastogi N, Cadou S, Hellio R. Differential handling of bacterial antigens in macrophages infected with Mycobacterium leprae as studied by immunogold labelling of ultrathin sections. Int J Lepr 1991; 59:278-291.
international journal of Dermatology Vol. 31, No. 8, August 1992
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Makonkawkeyoon S, Kasinrerk W, Supajatura V, et al. Immunologic defects in leprosy patients. II. Interleukin 1, interleukin 2 and interferon production in leprosy patients. IntJ Lepr 1990; 58:311-318. Hastings RC, Gillis TP, Krahenbahl JL, et al. Leprosy. Clin Microbiol Rev 1988; 1:330-348^ Dalsgaard CJ, Jonsson CE, Hokfett T, et al. Localisation of substance P immunoreactive nerve fibers in human digital skin. Experentia 1983; 39:1018-1020. Johansson O. A detailed account of NPY immunoreactive nerves and cells of human skin. Comparison with VIP-substance P and PHI containing structures. Acta Physiol Scand 1986; 128:147-153. O'Shaughnessy DJ, McGregor CP, Chatei MA, et al. Distribution of bombesin, somatostatin, substance P and VIP in feline and porcupine skin. Life Sci 1983; 32: 2827-2836. Bloom SR, Polak JM. Regulatory peptides in the skin. Clin Exp Dermatol 1983; 8:3-18. Lembeck F, Holzer P. Substance P as neurogenic mediator of antidromic vasodilation and neurogenic plasma extravasation. Arch Pharmacol 1979; 310:178. Camse R, Saria A. Potentiation of tachykinin induced plasma extravasation by calcitonin gene related peptide. Eur J Pharmacol 1985; 114:61-66. Lee TJF, Saito AS, Berezin 1. Vasoactive intestinal polypeptide like substance: the potential transmitter of cerebral vasodilation. Science 1984; 224:898-900. Lundberg JM. Evidence for the existence of VIP and acetylcholine neurons in cat exocrine glands. Morphological, anatomical and functional studies. Act Physiol Scan Suppl 1981; 496:2. Rioux F, Bachelard H, Martel JC, St. Pierre S. The vasoconstrictor effect of neuropeptide Y and related peptides in the guinea pig isolated heart. Peptides 1986; 7:27-31.
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Wedell C, Cowan MA, Palmer E, et al. Psoriatic skin. Arch Dermatol 1965; 91:252-256.
36.
Naukkarinen A, Nickoloff BJ, Farber EM. Quantification of cutaneous sensory nerves and their substance P content in psoriasis. J Invest Dermatol 1989; 92:126-129.
37.
Bernstein JE, Parish LC, Rapaport M, et al. Effect of topically applied capsaicin on moderate and severe psoriasis vulgaris. J Am Acad Dermatol 1986; 15:504-507. Sindrup SH, Ibsen HHW, Sindrup JH, et al. Psoriasis and polyneuropathy. Three case histories. Acta Derm Venereol (Stockh) 1990; 70:443-445.
38.
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Dewing SB. Remission of psoriasis associated with cutaneous nerve section. Arch Dermatol 1971; 104:220-221.
40.
Nickoloff BJ. Anti B-44 integron antibody prominently stains nerves in psoriatic skin. Arch Dermatol 1991; 127:271-272.
41.
lonescu C, Kiehl R. Increased plasma norepinephrine in psoriasis. Acta Derm Venereol (Stockh) 1991; 71;169-170. Anand P, Springall DR, Blank MA, et al. Neuropeptides in skin disease: increased VIP in eczema and psoriasis but not axillary hyperhidrosis. Br J Dermatol 1991; 124:547-549. Iyers COS. Predilection of Mycobacterium leprae for nerves. IntJ Lepr 1965; 33:634-645. Dabholkar VR, Caitonde BB. A study of autonomic functions in leprosy. Lepr India 1982; 54:303-307.
42.
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Kalra S, Dhand R, Kumar B, et al. Bronchial reflexes in patients with leprous and other peripheral neuropathies. Natl Med J India 1989; 2:264-266. Karanth SS, Springall DR, et al. Changes in nerves and neuropeptides in skin from 100 leprosy patients investigated by immunocytochemistry. J Pathol 1989; 157: 15-26.
"Roses in the Spring." Paul Wen-Shan Wang, M.D., Kalamazoo, MI. Water Color—Best of Show. American Academy of Dermatology Art Exhibit, Dallas, Texas, 1991. Photograph courtesy of Dermik Laboratories, Inc. SS4
THE RARE COEXISTENCE OF LEPROSY AND PSORIASIS BHUSHAN KUMAR, M.D., S.P. RAYCHAUDHURl, M.D., SIAVOSH VOSSOUGH, B.A., AND EUGENE M. FARBER, M.D.
Subsequent to the observations made that the sensory peripheral nerves along with their neuropeptides play a significant role in the pathogenesis of psoriasis, it became relevant to search for the incidence of psoriasis in conditions where peripheral nerves are damaged.' Leprosy is characterized by peripheral nerve damage; therefore, we initiated a study to see whether the incidence of psoriasis is less in leprosy patients. hi our search to find a relationship between psoriasis and leprosy, we collected information from those geographic regions where leprosy is endemic. One of the authors (B.K.) prepared a questionnaire to be filled out by physicians at leprosy centers in different parts of the world. From this questionnaire, we were able to assess the incidence of psoriasis among leprosy patients, but we were unable to identify the exact number of psoriasis cases with lepromatous or tuberculoid leprosy. Nevertheless, our findings (Table 1) clearly demonstrate the rare coexistence of the two diseases; although a few cases of psoriasis and leprosy have been previously documented in the Indian medical literature.^'' Out of 145,661 cases of leprosy, only 20 individuals had clinical signs for both leprosy and psoriasis. On average, these figures translate to 1.4 cases of concurrent psoriasis among a population of 10,000 with leprosy. In this article, we will give possible explanations for our findings.
GENETIC FACTORS AND THE IMMUNE SYSTEM
An early report stating the rarity of psoriasis among leprosy patients was published at the Hadassah University Hospital and the Government Hospital for Hansen's Disease in Jerusalem, Israel.'' In this study, the medical records of 309 leprosy patients, who had received treatment at the Government Hospital for Hansen's disease in Jerusalem from 1950 to 1980, were reviewed. None of the patients displayed any clinical signs of psoriasis on many examinations performed during periods of fol-
From the Psoriasis Research Institute, Palo Alto, California, and the Postgraduate Institute of Medical Education and Research, Chandigarh, India. Address for correspondence: Eugene M. Farber, M.D., Psoriasis Research Institute, 600 Town and Country Village, Palo Alto, CA 94301. .
low-up lasting as long as 40 years. Our study also confirms the rarity of psoriasis among leprosy patients (Table 1). Wahba et al. suggested that genetic factors may play a role in protecting psoriatic patients from the leprosy infection.'* Population studies have associated HLA-DR2 and HLA-DQWl with leprosy, and these findings are statistically significant.'' In addition, HLA-MTl and HLA-DR3 are correlated with susceptibility to leprosy.'' In psoriasis, there is a high frequency of HLA-Al, -B13, -B16, -B17, -B38, -CW6, and DR7 with reference to the general population.^ It has been demonstrated that leukocytes isolated from the peripheral blood of psoriatics are increased in numbers'* and have altered characteristics, and that the activity of the reticuloendothelial system in psoriatics is changed when compared with normal controls. Using the nitroblue tetrazolium test, which is an indirect measure of metabolic activity in polymorphonuclear leukocytes, it can be seen that these cells in psoriatics have a higher phagocytic activity than control polymorphonuclear leukocytes.' In addition to the heightened chemotaxis, psoriatic leukocytes have a greater phagocytic activity as determined by their higher ability to ingest ''''I labeled Shigella flextieri.^^ Monocytes isolated from psoriatics had 36 to 40% higher phagocytic activity than control monocytes from non-psoriatic individuals." Moreover, a two- to fourfold increase in bactericidal activity was detected when compared with controls. ' With regards to reticuloendothelial activity, workers in Sweden have been able to show an increase among psoriatics, and this activity remained high even in patients with minimal skin involvement.'- The T cells also play a major role in the pathogenesis of psoriasis.'^ It has been proposed that the proliferative lesions that characterize psoriasis are caused by factors generated by the interaction of Tii lymphocytes with Langerhans' cells in the epidermis.''* There is evidence that lL-2 is implicated in the pathogenesis of psoriasis. Psoriatic plaques contain more lL-2 receptor-positive cells in the dermal infiltrate as compared with lesion-free skin. Marked exacerbation of psoriasis in three individuals undergoing IL-2 monotherapy for metastatic renal carcinoma was observed.'^ Cyclosporine produces its effect by inhibiting lL-2 production."' Psoriatic lesions reappeared in a patient after intralesional infection of alpha interferon for warts,'^ and in another at the site of gamma interferon injection."* Although interferon-a levels have not 551
International Journal of Dermatology Vol. 31, No. 8, August 1992
Table 1. Coexistence of Leprosy and Psoriasis Location Argentina Burma Iltaukhyant Hosp. Kengtung Hosp. Cuba India Bomhay Dattapur Jhansi Kashmir Kottayam Madras Rohtak Thanjavur New Delhi Agra Jaipur Bihar Manipal Patiala Cochin Cuntur Malawi (Africa) Mexico San Luis Potosi
Patients with Leprosy
Patients with Leprosy and Psoriasis
2000
6
2500 2500 1500
Q
3975 350 2000 874 3000 1260 1149 3000 25000 75000 4206 10705 3000 462 1000 1200 1000
possible role of sensory nerve fibers in the skin and their release of neuropeptides in the disease process. In order to understand the involvement of neuropeptides in leprosy and psoriasis, it would be useful to summarize the presence of different neuropeptides in cutaneous nerves. Immunocytochemical techniques have revealed the presence of substance P,^^ neuropeptide tyrosine (NPY),^^ vasoactive intestinal polypeptide, (vip),"'^* and calcitonin gene-related peptide (CGRP).^' Both substance P and CGRP are associated with sensory C fibers, and they are believed to be involved in neurogenic inflammation and plasma extravasation.^"-^' vip and NPY have autonomic functions with VIP acting as a vasodilator and secretomotor,^^'^^ whereas NPY acts as a vasoconstrictor.''' In 1965, Wedell et al. were able to show a significant increase in the turnover of neural elements, not only in clinically involved psoriatic skin but also in uninvolved skin, although the effects were more pronounced in the involved sites.^^ A possible role for neuropeptides in psoriasis has been suggested.'-'^ The hypothesis is that psoriasis is triggered by the process of neurogenic inflammation, which is regulated by neuropeptides such as substance P. It is believed that neuropeptides, including substance P, can be released from cutaneous sensory nerves, and that this release can be caused by endogenous and exogenous stimuli. The inflammatory response induced by tbe release of neuropeptides is possibly responsible for triggering psoriasis. Further evidence supporting this hypothesis comes from a recent study examining the altered innervation pattern in psoriasis.^"^ The results indicate that, when compared to nonpsoriatic controls and lesionfree psoriatic skin, the dermis and epidermis in psoriatic lesions have appreciably higher innervation with neurofilament positive fibers, including substance Pcontaining fibers in the epidermis. Successful treatment of moderate and severe psoriasis with topically applied capsaicin has been reported.'^ Capsaicin is an inhibitor of cutaneous vasodilatation, probably acting through depletion of substance P from nerve terminals.
0 0 0 0 1
0 1 1 0
3. 0 3 :
' --. ' -
0 Q 0 3 0
0 0
No reported case of psoriasis and leprosy in the same individual
been assayed, serum levels of interferon-y have been documented to rise following lL-2 infusions." The presence of interferon-y-induced protein 10 in keratinocytes was reported to be associated with psoriasiform hyperplasia in both AlDS-associated and classic psoriasis.^" This is contrary to what is observed with leprosy, which is a disease of the retriculoendotheliai and phagocytic systems. The spectrum of immunologic response observed ranges from the well-developed host cellular immunity in tuberculoid disease to virtually no resistance in the lepromatous form of leprosy.^' The cause of the hyporesponsive state of lepromatous leprosy patients is not yet clear; however, it appears that T-cell proliferation and production of lymphokines in response to M. leprae are impaired in lepromatous patients.^' Reduced activity of peripheral blood mononuclear leukocytes and macrophages and a depressed T-cell functional state have been reported in all types of leprosy.^'"^-^ Reduced lL-2 production has also been reported in all types of leprosy.^''
In a recent report concomitant occurrence of psoriasis and polyneuropathy was cited in support of the theory of a relationship between peripheral nerves and psoriasis.^** Prompt remission of psoriasis following cutaneous nerve section has been reported.^' Integrin B-4 is expressed by epithelial cells, and it functions in Tcell keratinocyte adhesive interactions. The presence of an increased number of nerve fibers, particularly those that interact with basal keratinocytes, probably bas a role in the causation of psoriasis.''" Raised levels of norepinephrine, a neurotransmitter, in psoriasis and their role in the worsening of psoriasis has been suggested.'" More recently, elevated levels of neurotransmitters, especially VIP, have been found in psoriasis.''^ The neuritis seen in leprosy is an important feature, and the causation agent, Mycobacterium leprae, has the
NERVES AND NEUROPEPTIDES
It has been well established that one of the most important characteristics of leprosy is nerve damage, and clinical diagnosis of leprosy usually includes the observations of skin anesthesia and enlarged peripheral In psoriasis, there is strong evidence for the 552
Leprosy and Psoriasis Kumar et al.
5.
special characteristic of invading nerves.''^ The early signs of this nerve involvement are manifested through the loss of sweating, thermal sensation, and touch.''''•''^ A study was performed to determine the cutaneous innervation pattern in 100 leprosy patients and in 50 healthy controls.'"' Through the technique of immunocytochemistry, it was demonstrated that all of the 50 nonleprous skin specimens were immunoreactive for neurofilaments, protein gene product 9.5 (PGP 9.5), which is a general neural marker, and neuropeptides. PGP 9.5 and neurofilament immunoreactivity were detected in all of the indeterminate leprosy cases, in 15 out of 43 tuberculoid cases, and in 33 out of 43 lepromatous cases. Immunoreactivity for neuropeptides was completely absent in all of the tuberculoid and lepromatous cases, but it was detected in 2 out of 14 indeterminate cases. The absence of neuropeptides from leprous skin is a critical observation. It could be that the neuropathy caused by the leprosy infection alters the cutaneous sensory nerves such that the process of neurogenic inflammation, which seems to be an integral part of the psoriatic disease process, is inhibited.
6.
7.
8.
9.
10.
I 1. 12.
CONCLUSIONS
13.
In this study we have provided data to show that the occurrence of psoriasis in leprosy patients is extremely rare. With this clinical finding and considering the present knowledge of these two diseases, we propose the following possible theories to explain the rarity of psoriasis in leprosy patients: (1) The reduced nerves with their depleted content of neuropeptides, especially in lepromatous leprosy, successfully inhibit an important pathway in neurogenic inflammation, which seems to be involved in triggering psoriasis. (2) Altered immune response in leprosy can be a contributing factor for the low incidence of psoriasis in leprosy. (3) The difference in HLA phenotyping and perhaps some other differences in the genetic make up in leprosy and psoriasis patients could be responsible for the rarity of the coexistence of these two diseases.
14.
15. 16.
17.
18.
19.
REFERENCES
1.
2.
3.
4.
20.
Farber EM, Nickoloff BJ, Recht B, Fraki JE. Stress, symmetry and psoriasis: possible role of neuropeptides. J Am Acad Dermatol 1986; 14:305-311. Nagabhushanam P. Case report of psoriasis with rheumatoid arthritis with polyneuritic leprosy. Indian J Dermatol Venereol 1969; 35:97-98. Canapati R, Deshpande D, Chulawala R. Some interesting disease combinations - report on two cases. Leprosy in India 1976; 48:428-430. Wahba A, Dorfman M, Sheskin J. Psoriasis and other common dermatoses in leprosy. Int J Dermatol 1980; 19:93-95. . •
21. 22.
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"Roses in the Spring." Paul Wen-Shan Wang, M.D., Kalamazoo, MI. Water Color—Best of Show. American Academy of Dermatology Art Exhibit, Dallas, Texas, 1991. Photograph courtesy of Dermik Laboratories, Inc. SS4
