Inflammatory serum cytokines are produced by lymphocytes and target organs in inflammatory skin diseases [1-3]. Changes in cytokines fluctuate daily during disease activity. Comparisons of serum cytokine levels, cytokine species, or flow cytometric changes during the disease course might not be adequate. In addition, daily target organ examinations are difficult.

In this report, we determined disease-specific cytokine balances by continuously measuring the levels of inflammatory cytokines (interleukin-6 [IL-6], interferon gamma [IFN-gamma], and tumor necrosis factor-alpha [TNF-alpha, TNF-a]) in patients with Bechet’s Disease (BD), Pustular Psoriasis (PP), Palmoplantar Pustulosis (PPP), and Stevens-Johnson Syndrome (SJS) during the course of the disease. We compared these cytokines in various cutaneous inflammatory diseases activities. Furthermore, participation of inflammatory lymphocyte subsets was considered.

All 4 patients showed typical clinical appearances, blood and serological tests, and histopathologies. The BD patient was treated with colchicine; the PP patient was treated with cyclosporine MEPC. The PPP patient was treated with etretinate, and the SJS patient was treated with methylprednisolone pulse therapy and oral prednisolone.

IL-6, TNF-alpha, and IFN-gamma levels were measured with an enzyme-linked immunosorbent assay (Figure 1). Maximal TNF-alpha and IL-6 levels were 40 pg/mL and 7.2 pg/mL, respectively, in the BD patient. Maximal TNF-alpha and IL-6 levels were 77 pg/mL and 21.2 pg/mL in the PP patient. Maximal TNF-alpha and IL-6 levels were 24.8 pg/mL and 4.2 pg/mL, respectively, in the PPP patient. Levels of TNFalpha, IL-6, and IFN-gamma were 93 pg/mL, 33.9 pg/mL, and 8.6 IU/ mL, respectively, in the SJS patient (Figure 2). Although the maximal TNF-alpha levels were not disease-specific, they most correlated with clinical severity like as fever, arthralgia, skin rash, elevation of CRP and so on, in SJS, which was followed by PPP, BP, and PP (Figure 1).

Figure 1: Cytokine patterns of each patient with pustular psoriasis, palmoplantar pustulosis, Stevens-Johnson syndrome, and Bechet’s disease. We measured cytokine levels until they were undetectable.

Values at the start and after improvement are shown for each cytokine measured

Figure 2: Tumor necrosis factor (TNF)-alpha/interleukin (IL)-6 calculated values.

IL-6 is produced by macrophages and/or target organ chronic inflammation and is synchronized with TNF-alpha [1,2]. The IL-6 and IL-17 produced by Th17 was suppressed by IFN-gamma from Th1 stimulated by IL-12 from macrophages [1,2]. In addition, IL-6 induction was promoted by IL17A by positive feedback loop in autoimmune diseases [3] and IL-6 levels from keratinocytes were up-regulated by IL-17 stimulation [4]. The relative ratio of IL-6 and TNF-alpha might show a disease-specific pattern of changes among IL-6, TNF-alpha, and IL-17A during the disease course (Figure 3). If maximal IL-6 and TNFalpha levels were synchronized, the expected ratio would be 2.74, 5.9, 5.56, and 3.63 in SJS, PPP, BD, and PP, respectively. Approximately similar these values that were evaluated by calculating the ratio between IL-6 and TNF-alpha showed to remove the specificity of each disease.

Figure 3: Comparison of the levels of each cytokine among patients with Stevens-Johnson syndrome, palmoplantar pustulosis, Bechet’s disease, and pustular psoriasis. Note that the diseases that showed lower measurement values may have been affected by treatment with immunosuppressive drugs, such as anti-TNFalpha.

However, the actual measurements were 56, 22.6, 12.5, and 3.63, respectively (Figure 2). The most marked difference was detected in SJS. SJS is assumed to be a disease of Th1 cytokines. The difference between the expected and actual TNF-alpha/IL-6 values might be explained by scattering produced Th1 cytokines. Interestingly, the PP patient exhibited actual values that were similar to the expected value. This result is consistent with the close relationship between psoriasis and Th17 lymphocytes [5]. Furthermore, in psoriasis, there is the paper that

clarified the relation between IL-6 and metabolic syndrome [6]. Recent reports showed that Th17 lymphocytes have been shown to be closely associated to BD [7]. Our examination is in harmony with previous report, because the actual TNF-alpha/IL-6 values were close to the expected ratio in BD. The lower actual TNF-alpha/IL-6 ratio in these diseases might be shown by the effectiveness by immuno-modulation therapy (Figure 2).

The continuous measurement of cytokines may be useful for determining disease-specific helper T-cell functions, which may fluctuate during the course of the disease. This procedure may also be useful to clarify the effectiveness of the biological drugs, for example, anti-TNF-alpha/anti-IL-6 drugs, for each disease.