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Serum TNF-α in psoriasis after treatment with propylthiouracil, an antithyroid thioureylene
© Elias et al; licensee BioMed Central Ltd. 2004
Received: 11 January 2004
Accepted: 30 April 2004
Published: 30 April 2004
Tumor necrosis factor-α (TNF-α) and its receptors play important roles in the development and persistence of psoriatic plaques. The antithyroid thioureylenes, propylthiouracil and methimazole, are effective in the treatment of patients with psoriasis with a significant number of patients showing clearing or near clearing of their lesions after a several weeks of treatment.
The present study examined the effect of treatment with propylthiouracil, given in a dose of 100 mg every 8 hours for 3 months, on the serum levels of TNF-α in 9 patients with plaque psoriasis.
Propylthiouracil therapy did not result in a significant decline in serum TNF-α concentrations.
The findings suggest that the therapeutic effect of propylthiouracil in psoriasis appears not to be related to any change in the concentration of TNF-α but occurs via an anti-proliferative mechanism as we have previously speculated.
Psoriasis is a common skin disorder that affects approximately 2.8 percent of the population and is associated with morbidity that is comparable that seen with life threatening disease [1, 2]. There is a clearly established genetic predisposition to the disease [3, 4] that is often triggered by the processing of bacterial, viral or chemical antigens by skin antigen presenting cells (APC) or Langerhans cells [5–9]. The disease is presently believed to be a T cell disorder that leads to keratinocyte proliferation [6, 10, 11]. Plaque formation in the disease reflects both the effects of accelerated proliferation as well as reduced apoptosis in proliferated keratinocytes [12, 13]. The events responsible for keratinocyte proliferation have been extensively reviewed . An important cytokine that is associated with keratinocyte proliferation in psoriasis is TNF-α.. TNF-α concentrations are higher in psoriatic lesions than in unaffected skin of psoriatic patients and tend to decline with clearing of the lesions after effective therapy [14–16]. This cytokine is produced by keratinocytes and leads to an increased expression of cellular adhesion molecules that promote, propagate, and amplify the immune signals that are responsible for maintaining the events that lead to psoriasis. Recently introduced therapeutic approaches in the management of psoriasis depend on blocking TNF-α binding to its receptor by using TNF-α hybrid antibodies. Patients treated with such agents very often show marked improvement in their disease with major clearing in several instances [17–19]. Present day therapy of the disease is not particularly satisfactory and the many therapies currently in use are associated with significant cumulative toxicity . The antithyroid thioureylenes have been used in the treatment of patients with hyperthyroidism, particularly Graves' disease, and have well-defined and very limited toxicity. They have been used for management of patients with Graves' hyperthyroidism for many years without any significant problems. We and others have described the effectiveness of these agents in the treatment of patients with plaque psoriasis [20–24]. The mechanism of action of these drugs in psoriasis is unknown but some evidence points to their ability to act as anti-proliferative agents. The drugs reduce expression of proliferative cell nuclear antigen (PCNA) a marker of cellular proliferation . Since plaque formation is psoriasis is dependent on enhanced proliferation of keratinocytes particularly in the basal layers of the epidermis any agent that could reduce this critical event in the pathogenesis of psoriasis would lead to clinical improvement. The present study was performed to examine the effect of treatment with propylthiouracil on circulating TNF-α in patients with stable plaque psoriasis.
Nine patients (6 male, 3 female) enrolled in the study. The patients ranged in age from 21 to 65 years (mean ± SD, 44 ± 16 yrs). None of the patients received phototherapy or systemic treatment for six weeks and none used topical therapy other than emollients for six weeks prior to entry into the study. Patients with allergies to sulfa medication, pregnant patients, and patients with a known diagnosis of thyroid dysfunction were excluded from participating in the study. All patients signed an informed consent document approved by the Institutional Review Board of the University of California, Irvine. The enrolled volunteers had a complete blood count (CBC) and measurement of thyroid stimulating hormone (TSH) before starting treatment with propylthiouracil (PTU). CBC and TSH measurements were obtained again at 2 weeks and later at 4, 8 and 12 weeks. In addition, blood was removed for measurement of TNF-α prior to PTU treatment and again at 2, and 12 weeks later. The blood for TNF-α measurements was collected in tubes containing peptide inhibitors, and the serum removed and stored at -70°C until assayed. Patients were instructed to take 100 mg PTU every 8 hours for twelve weeks.
Clinical evaluation was performed by a single dermatologist (VSN). Evaluation was performed before enrollment, and again at 4, 8 and 12 weeks after PTU therapy. Assessment was made using the PASI scoring system.
Measurement of TNF-α
TNF-α levels in serum were measured using a highly sensitive commercially available assay from R&D Systems (Minneapolis, MN). The assay is a sandwich enzyme immunoassay (ELISA) with an analytical sensitivity of < 0.2 pg/ml. Intra- and interassay variations are less than 11.3 and 14.7 % respectively. The reference range for normal volunteers is between 1.2 and 15.3 pg/ml.
Statistical analysis was performed using Student's t test for paired and grouped data. P of <0.05 was considered significant.
All patients showed clinical improvement with PASI scores declining from 20.1 ± 6.6 to 15.8 ± 4.9 at 4 weeks (P < 0.02), 11.0 ± 4.8 at 8 weeks (p < 0.0001) and 6.7 ± 4.3 after 12 weeks (p < 0.0001) of PTU therapy.
Serum TNF-α concentrations
Serum TNF-α concentrations were 5.1 ± 2.3 pg/ml before treatment and did not show significant decline at 2 weeks (5.1 ± 2.16 pg/ml) and 12 weeks (4.96 ± 2.8 pg/ml) of treatment.
None of the patients experienced any side effects from PTU treatment. As previously described, white blood count remained within the normal range during the entire study, the serum TSH concentration did not rise above the upper normal range, and neither did any patient develop signs or symptoms of hypothyroidism.
Activated Th1 cells which produce TNF-α and interferon-γ (IFN-γ) are important in the pathogenesis of psoriasis [12, 26]. These cytokines promote expression of adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule (VCAM) on keratinocytes and vascular endothelial cells thereby facilitating migration of additional pro-inflammatory cells to the area of the psoriatic plaque resulting in the cytokine cascade that ultimately results in enhanced keratinocyte proliferation and formation of the lesions characteristic of the disease  Keratinocytes that have undergone proliferation, as well as dendritic cells and skin macrophages, produce TNF-α that leads to an amplification of the Th1 role in formation of the psoriatic plaque. In recent months there have been several studies that have exploited the use of designer antibodies directed against the binding of TNF-α to its receptor (etanercept)  or that prevent the association of leucocyte-function associated antigen (LFA) and ICAM-1 (efalizumab) . There is significant clinical improvement in patients treated with these agents. There is, however, loss of clinical benefit after the drugs are stopped and a small proportion of patients develop antibodies to the agents which is likely to limit there efficacy with repeated use. The antithyroid thioureylenes, in contrast, are easily administered oral medications that cost a mere fraction of the amount necessary to treat a patient with psoriasis with a designer antibody. The mechanism of action of antithyroid thioureylenes in psoriasis is unclear. Based on our previous observations, the drugs do not appear to produce any change in circulating IL-2 receptor or ICAM-1 , and lack effects on pro-inflammatory cytokines such as IL-12 or anti-inflammatory cytokines such as IL-10 . The drugs do, however, produce a significant decline in markers of cellular proliferation, particularly in proliferative nuclear cell antigen (PCNA) expression  suggesting that the principal therapeutic benefit of these drugs in psoriasis may be exerted via their anti-proliferative effect.
The lack of any effect on circulating TNF-α in this study argues against any effect of propylthiouracil on keratinocyte production of TNF-α. Since PTU and other antithyroid thioureylenes cause a decrease in keratinocyte proliferation one would expect a fall in TNF-α concentration after use of these agents in patients showing significant clinical improvement. The fact that this did not occur requires further investigation.
- Linden KG, Weinstein GD: Psoriasis: current perspectives with an emphasis on treatment. Am J Med 1999, 107: 595–605. 10.1016/S0002-9343(99)00284-3View ArticlePubMedGoogle Scholar
- Greaves MW, Weinstein GD: Treatment of psoriasis. N Engl J Med 1995, 332: 581–588. 10.1056/NEJM199503023320907View ArticlePubMedGoogle Scholar
- Krueger GG, Duvic M: Epidemiology of psoriasis: clinical issues. J Invest Dermatol 1994, 102: 14S-18S.View ArticlePubMedGoogle Scholar
- Bowcock AM, Barker JN: Genetics of psoriasis: the potential impact on new therapies. J Am Acad Dermatol 2003, 49: S51–56. 10.1016/S0190-9622(03)01135-6View ArticlePubMedGoogle Scholar
- Barker JN: The pathophysiology of psoriasis. Lancet 1991, 338: 227–230. 10.1016/0140-6736(91)90357-UView ArticlePubMedGoogle Scholar
- Nickoloff BJ, Schroder JM, von den Driesch P, Raychaudhuri SP, Farber EM, Boehncke WH, Morhenn VB, Rosenberg EW, Schon MP, Holick MF: Is psoriasis a T-cell disease? Exp Dermatol 2000, 9: 359–375. 10.1034/j.1600-0625.2000.009005359.xView ArticlePubMedGoogle Scholar
- Nickoloff BJ, Wrone-Smith T: Superantigens, autoantigens, and pathogenic T cells in psoriasis. J Invest Dermatol 1998, 110: 459–460. 10.1046/j.1523-1747.1998.00158.xView ArticlePubMedGoogle Scholar
- England RJ, Strachan DR, Knight LC: Streptococcal tonsillitis and its association with psoriasis: a review. Clin Otolaryngol 1997, 22: 532–535. 10.1046/j.1365-2273.1997.00068.xView ArticlePubMedGoogle Scholar
- Skov L, Baadsgaard O: Bacterial superantigens and inflammatory skin diseases. Clin Exp Dermatol 2000, 25: 57–61. 10.1046/j.1365-2230.2000.00575.xView ArticlePubMedGoogle Scholar
- Nickoloff BJ: Creation of psoriatic plaques: the ultimate tumor suppressor pathway. A new model for an ancient T-cell-mediated skin disease. Viewpoint. J Cutan Pathol 2001, 28: 57–64. 10.1034/j.1600-0560.2001.280201.xView ArticlePubMedGoogle Scholar
- Nickoloff BJ: The immunologic and genetic basis of psoriasis. Arch Dermatol 1999, 135: 1104–1110. 10.1001/archderm.135.9.1104PubMedGoogle Scholar
- Asadullah K, Docke WD, Volk HD, Sterry W: The pathophysiological role of cytokines in psoriasis. Drugs Today (Barc) 1999, 35: 913–924.Google Scholar
- Wrone-Smith T, Mitra RS, Thompson CB, Jasty R, Castle VP, Nickoloff BJ: Keratinocytes derived from psoriatic plaques are resistant to apoptosis compared with normal skin. Am J Pathol 1997, 151: 1321–1329.PubMedPubMed CentralGoogle Scholar
- Mussi A, Bonifati C, Carducci M, D'Agosto G, Pimpinelli F, D'Urso D, D'Auria L, Fazio M, Ameglio F: Serum TNF-alpha levels correlate with disease severity and are reduced by effective therapy in plaque-type psoriasis. J Biol Regul Homeost Agents 1997, 11: 115–118.PubMedGoogle Scholar
- Bonifati C, Carducci M, Cordiali Fei P, Trento E, Sacerdoti G, Fazio M, Ameglio F: Correlated increases of tumour necrosis factor-alpha, interleukin-6 and granulocyte monocyte-colony stimulating factor levels in suction blister fluids and sera of psoriatic patients – relationships with disease severity. Clin Exp Dermatol 1994, 19: 383–387.View ArticlePubMedGoogle Scholar
- Ettehadi P, Greaves MW, Wallach D, Aderka D, Camp RD: Elevated tumour necrosis factor-alpha (TNF-alpha) biological activity in psoriatic skin lesions. Clin Exp Immunol 1994, 96: 146–151.View ArticlePubMedPubMed CentralGoogle Scholar
- Gottlieb AB, Chaudhari U, Mulcahy LD, Li S, Dooley LT, Baker DG: Infliximab monotherapy provides rapid and sustained benefit for plaque-type psoriasis. J Am Acad Dermatol 2003, 48: 829–835. 10.1067/mjd.2003.307View ArticlePubMedGoogle Scholar
- Chaudhari UP, Romano P, Mulcahy LD, Dooley LT, Baker DG, Gottlieb AB: Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial. Lancet 2001, 357: 1842–1847. 10.1016/S0140-6736(00)04954-0View ArticlePubMedGoogle Scholar
- Leonardi CL, Powers JL, Matheson RT, Goffe BS, Zitnik R, Wang A, Gottlieb AB: Etanercept as monotherapy in patients with psoriasis. N Engl J Med 2003, 349: 2014–2022. 10.1056/NEJMoa030409View ArticlePubMedGoogle Scholar
- Elias AN, Barr RJ: Low-dose oral propylthiouracil in the treatment of plaque psoriasis. Int J Dermatol 1995, 34: 519–520.View ArticlePubMedGoogle Scholar
- Elias AN, Goodman MM, Liem WH, Barr RJ: Propylthiouracil in psoriasis: results of an open trial. J Am Acad Dermatol 1993, 29: 78–81.View ArticlePubMedGoogle Scholar
- Elias AN, Goodman MM, Rohan MK, Alpern K, Barr RJ: Methimazole (2-mercapto 1-methyl imidazole) in psoriasis – results of an open trial. Dermatology 1993, 187: 26–29.View ArticlePubMedGoogle Scholar
- Kose K, Utas S, Yazici C, Akdas A, Kelestimur F: Effect of propylthiouracil on adenosine deaminase activity and thyroid function in patients with psoriasis. Br J Dermatol 2001, 144: 1121–1126. 10.1046/j.1365-2133.2001.04221.xView ArticlePubMedGoogle Scholar
- Utas S, Kose K, Yazici C, Akdas A, Kelestimur F: Antioxidant potential of propylthiouracil in patients with psoriasis. Clin Biochem 2002, 35: 241–246. 10.1016/S0009-9120(02)00294-1View ArticlePubMedGoogle Scholar
- Elias AN, Barr RJ, Rohan MK, Dangaran K: Effect of orally administered antithyroid thioureylenes on PCNA and P53 expression in psoriatic lesions. Int J Dermatol 1995, 34: 280–283.View ArticlePubMedGoogle Scholar
- Baadsgaard O, Fisher G, Voorhees JJ, Cooper KD: The role of the immune system in the pathogenesis of psoriasis. J Invest Dermatol 1990, 95: 32S-34S.View ArticleGoogle Scholar
- Uyemura K, Yamamura M, Fivenson DF, Modlin RL, Nickoloff BJ: The cytokine network in lesional and lesion-free psoriatic skin is characterized by a T-helper type 1 cell-mediated response. J Invest Dermatol 1993, 101: 701–705.View ArticlePubMedGoogle Scholar
- Gordon KB, Papp KA, Hamilton TK, Walicke PA, Dummer W, Li N, Bresnahan BW, Menter A: Efalizumab for patients with moderate to severe plaque psoriasis: a randomized controlled trial. JAMA 2003, 290: 3073–3080. 10.1001/jama.290.23.3073View ArticlePubMedGoogle Scholar
- Elias AN, Goodman MM, Rohan MK: Serum ICAM-1 concentrations in patients with psoriasis treated with antithyroid thioureylenes. Clin Exp Dermatol 1993, 18: 526–529.View ArticlePubMedGoogle Scholar
- Elias AN, Nanda VS, Barr RJ: Effect of PTU on IL-12 and IL-10 in psoriasis. J Drugs Dermatol 2003, 2: 645–648.PubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-5945/4/4/prepub
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