Journal of Dermatology 2016; 43: 443–462
LETTERS TO THE EDITOR
Antinuclear antibody formation following administration of anti-tumor necrosis factor agents in Japanese patients with psoriasis anti-TNF agents, although the change was not statistically significant (P = 0.117). There were no statistical differences in ANA positivity between infliximab and adalimumab (data not shown). By contrast, ANA positivity was not significantly changed by ustekinumab at these three different cut-off dilutions. Furthermore, 75% reduction of Psoriasis Area and Severity Index score (PASI-75) response rates were not significantly different between psoriasis patients whose ANA became positive during treatment with anti-TNF agents and those whose ANA were not changed throughout anti-TNF treatment (71% vs 73%, 68% vs 63% and 72% vs 57%, at 1:40, 1:80 and 1:160 dilutions, respectively). None of these patients developed autoimmune disease during treatment. Thus, treatment with anti-TNF agents, unlike ustekinumab, increased the proportion of patients with ANA positivity without affecting efficacy. According to recent reports, the development of ANA is associated with loss of response,3,4 but it has been also shown not to be associated with loss of efficacy.5 Fifty-three percent of psoriasis patients became positive for ANA during infliximab treatment, but PASI-75 response rates were not affected in these patients.5 Although this study showed that ANA development appeared not to affect the efficacy of antiTNF agents, future studies should examine the longitudinal changes in ANA titers and efficacy for longer observation periods. Furthermore, evaluation of the emergence of various autoantibodies and antidrug antibodies is required. Nonetheless, our findings suggest that it is not necessary to terminate anti-TNF treatment immediately because of the observed elevations in ANA titers, although careful observation is needed.
Dear Editor, Recent data suggest that anti-tumor necrosis factor (TNF) agents induce the formation of antinuclear antibodies (ANA) and the development of autoimmune diseases in psoriasis patients.1,2 The present study demonstrated that treatment of psoriasis patients with anti-TNF agents, unlike ustekinumab, significantly increased the proportion of patients who were positive for ANA without the development of autoimmune diseases or loss of response. We retrospectively evaluated the clinical records of 66 Japanese patients with psoriasis treated with anti-TNF agents (infliximab, n = 20; adalimumab, n = 28) or ustekinumab (n = 18) for at least 3 months. The mean (standard deviation) followup period for patients on anti-TNF agents or ustekinumab was 7.4 3.5 and 9.0 6.7 months, respectively. Patients who had been treated with any other biologics were excluded from the study, and none of the included patients had a history of autoimmune disease or concomitant treatment with retinoids, cyclosporin or methotrexate. ANA were identified by indirect immunofluorescence using an ANA test system (BML, Tokyo, Japan). Fisher’s exact probability test was used to compare frequencies. Statistical significance was defined as a P-value of less than 0.05. When ANA positivity was determined at a dilution of 1:40, ANA positivity in psoriasis patients was significantly increased from 48% to 69% during treatment with anti-TNF agents (P = 0.038, Table 1). When a dilution of 1:80 was used, 21% of the patients with psoriasis were positive for ANA at baseline, but 40% were positive for ANA during anti-TNF treatment (P = 0.045). At a dilution of 1:160, the positivity was raised from 13% to 25% during treatment with
Table 1. Changes in ANA positivity in patients with psoriasis after treatment with anti-TNF agents or ustekinumab Anti-TNF (infliximab + adalimumab) (n = 48) (male : female, 36:12; median age, 45 years) Baseline ANA positivity 1:40 23 (48%) (16, 7–43) 1:80 10 (21%) (6, 4–46) 1:160 6 (13%) (5, 1–56)
Ustekinumab (n = 18) (male : female, 13:5; median age, 58 years)
Follow up, months (median, range)
P
Baseline, months
Follow up, months (median, range)
33 (69%) (24, 9–43) 19 (40%) (14, 5–42) 12 (25%) (9, 3–43)
0.038 0.045 0.117
10 (56%) (6, 4–54) 5 (28%) (2, 3–51) 5 (28%) (2, 3–51)
9 (50%) (5, 4–60) 3 (17%) (1, 2–51) 2 (11%) (1, 1–48)
P 0.739 0.691 0.402
Values are numbers. Percentages are given in parentheses. ANA, antinuclear antibodies; TNF, tumor necrosis factor.
Correspondence: Koichi Yanaba, M.D., Ph.D., Department of Dermatology, Jikei University School of Medicine, 3-25-8 Nishishimbashi, Minato-ku, Tokyo 105-8461, Japan. Email: [email protected]
© 2015 Japanese Dermatological Association
443
Letters to the Editor
CONFLICT OF INTEREST: H. N. has received consultancy/speaker honoraria and grants from Mitsubishi Tanabe Pharma and AbbVie, and speaker Honoraria from Janssen. All other authors have no conflicts of interest. Koichi YANABA, Yoshinori UMEZAWA, Hiromi HONDA, Reiko SATO, Miki CHIBA, Sota KIKUCHI, Akihiko ASAHINA, Hidemi NAKAGAWA Department of Dermatology, Jikei University School of Medicine, Tokyo, Japan doi: 10.1111/1346-8138.13215
2 Poulalhon N, Begon E, Lebbe C et al. A follow-up study in 28 patients treated with infliximab for severe recalcitrant psoriasis: evidence for efficacy and high incidence of biological autoimmunity. Br J Dermatol 2007; 156: 329–336. 3 Hoffmann JH, Hartmann M, Enk AH et al. Autoantibodies in psoriasis as predictors for loss of response and anti-infliximab antibody induction. Br J Dermatol 2011; 165: 1355–1358. 4 Pink AE, Fonia A, Allen MH et al. Antinuclear antibodies associate with loss of response to antitumour necrosis factor-a therapy in psoriasis: a retrospective, observational study. Br J Dermatol 2010; 162: 780–785. 5 Saraceno R, Specchio F, Torres T et al. The role of antinuclear autoantibodies in patients with psoriasis treated with anti-tumor necrosis factor-a agents: a retrospective long-term study. J Am Acad Dermatol 2012; 66: e180–e182.
REFERENCES 1 Bardazzi F, Odorici G, Virdi A et al. Autoantibodies in psoriatic patients treated with anti-TNF-a therapy. J Dtsch Dermatol Ges 2014; 12: 401–406.
Immunoglobulin A vasculitis associated with HIV infection Dear Editor, Immunoglobulin A vasculitis (IgAV), also known as Henoch– € nlein purpura, is a systemic vasculitis characterized by Scho leukocytoclastic vasculitis and immunoglobulin (Ig)A deposition in the small vessels. Patients are known to develop IgAV secondary to various infections. HIV infection is increasingly being recognized as a rare trigger for IgAV. We report a case of a woman with HIV infection who developed IgAV. A 54-year-old woman from Thailand presented with a 1-year history of palpable purpura on the legs, which had partially developed into an ulcer (Fig. 1a,b). She did not have abdominal pain or arthralgia. Laboratory examinations indicated pancytopenia (white blood cell count, 1.2 9 109/L; red blood cell count, 323 9 109/L; platelet count, 100 9 109/L) and elevated serum IgG and IgA levels (IgG, 2705 mg/dL; IgA, 466 mg/dL). Urinalysis results were normal. Additional investigations indicated positive results for the anti-HIV-1 antibody, a plasma HIV RNA level of 14 9 104 copies/mL and a decreased CD4 T-cell count of 15 cells/mm3. Histopathological examination demonstrated leukocytoclastic vasculitis of the small vessels, characterized by the presence of upper dermal perivascular infiltrates, primarily consisting of neutrophils with karyorrhexis (Fig. 1c,d). Deposition of IgA and complement C3 in the vessel walls was noted on direct immunofluorescence staining (Fig. 1e,f). Accordingly, IgAV and HIV infection were diagnosed. Although we scheduled antiretroviral therapy (ART), she did not return to our hospital. The patient presented with delayed IgAV of more than 1 year’s duration, indicating the likelihood of an underlying disorder that had induced the IgAV. As only HIV infection was
detected on various examinations, we concluded that the HIV infection had contributed to the development of IgAV. Gherardi et al.1 have described the association between HIV infection and various types of vasculitis. The prevalence of vasculitis and IgAV in the patients with HIV infection in their study was 20% and 0.6%, respectively. Although the pathogenesis of IgAV in patients with HIV infection remains unclear, increased circulation of immune complexes associated with the HIV infection or local replication of HIV itself may cause vasculitis.1 To our knowledge, four cases of IgAV with HIV infection have been reported.2–5 Three of those cases,3–5 and the current case, showed a high plasma viral load of 3–447 9 104 copies/ mL or a decreased CD4 count of 15–64 9 106/L. Single ART resolved a relapse of the purpura after treatment with steroids in one of the cases4 as well as persistent nephritis in another case,3 while a discontinuation of ART resulted in development of IgAV in one of the cases.5 Thus, it appears that active HIV infection is associated with IgAV, which supports the abovementioned pathogenic mechanism. Cases of HIV-infected patients who develop IgAV have been frequently reported in Asia.3–5 This may be associated not only with the high numbers of HIV-infected patients in Asia but also with the Asian genetic background. Appropriate ART may yield better outcomes in IgAV patients with HIV infection.
CONFLICT OF INTEREST:
None declared.
Akimasa SAITO, Naoko OKIYAMA, Hiroshi MARUYAMA, Manabu FUJIMOTO
Correspondence: Naoko Okiyama, M.D., Ph.D., Department of Dermatology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan. Email: [email protected]
444
© 2015 Japanese Dermatological Association
LETTERS TO THE EDITOR
Antinuclear antibody formation following administration of anti-tumor necrosis factor agents in Japanese patients with psoriasis anti-TNF agents, although the change was not statistically significant (P = 0.117). There were no statistical differences in ANA positivity between infliximab and adalimumab (data not shown). By contrast, ANA positivity was not significantly changed by ustekinumab at these three different cut-off dilutions. Furthermore, 75% reduction of Psoriasis Area and Severity Index score (PASI-75) response rates were not significantly different between psoriasis patients whose ANA became positive during treatment with anti-TNF agents and those whose ANA were not changed throughout anti-TNF treatment (71% vs 73%, 68% vs 63% and 72% vs 57%, at 1:40, 1:80 and 1:160 dilutions, respectively). None of these patients developed autoimmune disease during treatment. Thus, treatment with anti-TNF agents, unlike ustekinumab, increased the proportion of patients with ANA positivity without affecting efficacy. According to recent reports, the development of ANA is associated with loss of response,3,4 but it has been also shown not to be associated with loss of efficacy.5 Fifty-three percent of psoriasis patients became positive for ANA during infliximab treatment, but PASI-75 response rates were not affected in these patients.5 Although this study showed that ANA development appeared not to affect the efficacy of antiTNF agents, future studies should examine the longitudinal changes in ANA titers and efficacy for longer observation periods. Furthermore, evaluation of the emergence of various autoantibodies and antidrug antibodies is required. Nonetheless, our findings suggest that it is not necessary to terminate anti-TNF treatment immediately because of the observed elevations in ANA titers, although careful observation is needed.
Dear Editor, Recent data suggest that anti-tumor necrosis factor (TNF) agents induce the formation of antinuclear antibodies (ANA) and the development of autoimmune diseases in psoriasis patients.1,2 The present study demonstrated that treatment of psoriasis patients with anti-TNF agents, unlike ustekinumab, significantly increased the proportion of patients who were positive for ANA without the development of autoimmune diseases or loss of response. We retrospectively evaluated the clinical records of 66 Japanese patients with psoriasis treated with anti-TNF agents (infliximab, n = 20; adalimumab, n = 28) or ustekinumab (n = 18) for at least 3 months. The mean (standard deviation) followup period for patients on anti-TNF agents or ustekinumab was 7.4 3.5 and 9.0 6.7 months, respectively. Patients who had been treated with any other biologics were excluded from the study, and none of the included patients had a history of autoimmune disease or concomitant treatment with retinoids, cyclosporin or methotrexate. ANA were identified by indirect immunofluorescence using an ANA test system (BML, Tokyo, Japan). Fisher’s exact probability test was used to compare frequencies. Statistical significance was defined as a P-value of less than 0.05. When ANA positivity was determined at a dilution of 1:40, ANA positivity in psoriasis patients was significantly increased from 48% to 69% during treatment with anti-TNF agents (P = 0.038, Table 1). When a dilution of 1:80 was used, 21% of the patients with psoriasis were positive for ANA at baseline, but 40% were positive for ANA during anti-TNF treatment (P = 0.045). At a dilution of 1:160, the positivity was raised from 13% to 25% during treatment with
Table 1. Changes in ANA positivity in patients with psoriasis after treatment with anti-TNF agents or ustekinumab Anti-TNF (infliximab + adalimumab) (n = 48) (male : female, 36:12; median age, 45 years) Baseline ANA positivity 1:40 23 (48%) (16, 7–43) 1:80 10 (21%) (6, 4–46) 1:160 6 (13%) (5, 1–56)
Ustekinumab (n = 18) (male : female, 13:5; median age, 58 years)
Follow up, months (median, range)
P
Baseline, months
Follow up, months (median, range)
33 (69%) (24, 9–43) 19 (40%) (14, 5–42) 12 (25%) (9, 3–43)
0.038 0.045 0.117
10 (56%) (6, 4–54) 5 (28%) (2, 3–51) 5 (28%) (2, 3–51)
9 (50%) (5, 4–60) 3 (17%) (1, 2–51) 2 (11%) (1, 1–48)
P 0.739 0.691 0.402
Values are numbers. Percentages are given in parentheses. ANA, antinuclear antibodies; TNF, tumor necrosis factor.
Correspondence: Koichi Yanaba, M.D., Ph.D., Department of Dermatology, Jikei University School of Medicine, 3-25-8 Nishishimbashi, Minato-ku, Tokyo 105-8461, Japan. Email: [email protected]
© 2015 Japanese Dermatological Association
443
Letters to the Editor
CONFLICT OF INTEREST: H. N. has received consultancy/speaker honoraria and grants from Mitsubishi Tanabe Pharma and AbbVie, and speaker Honoraria from Janssen. All other authors have no conflicts of interest. Koichi YANABA, Yoshinori UMEZAWA, Hiromi HONDA, Reiko SATO, Miki CHIBA, Sota KIKUCHI, Akihiko ASAHINA, Hidemi NAKAGAWA Department of Dermatology, Jikei University School of Medicine, Tokyo, Japan doi: 10.1111/1346-8138.13215
2 Poulalhon N, Begon E, Lebbe C et al. A follow-up study in 28 patients treated with infliximab for severe recalcitrant psoriasis: evidence for efficacy and high incidence of biological autoimmunity. Br J Dermatol 2007; 156: 329–336. 3 Hoffmann JH, Hartmann M, Enk AH et al. Autoantibodies in psoriasis as predictors for loss of response and anti-infliximab antibody induction. Br J Dermatol 2011; 165: 1355–1358. 4 Pink AE, Fonia A, Allen MH et al. Antinuclear antibodies associate with loss of response to antitumour necrosis factor-a therapy in psoriasis: a retrospective, observational study. Br J Dermatol 2010; 162: 780–785. 5 Saraceno R, Specchio F, Torres T et al. The role of antinuclear autoantibodies in patients with psoriasis treated with anti-tumor necrosis factor-a agents: a retrospective long-term study. J Am Acad Dermatol 2012; 66: e180–e182.
REFERENCES 1 Bardazzi F, Odorici G, Virdi A et al. Autoantibodies in psoriatic patients treated with anti-TNF-a therapy. J Dtsch Dermatol Ges 2014; 12: 401–406.
Immunoglobulin A vasculitis associated with HIV infection Dear Editor, Immunoglobulin A vasculitis (IgAV), also known as Henoch– € nlein purpura, is a systemic vasculitis characterized by Scho leukocytoclastic vasculitis and immunoglobulin (Ig)A deposition in the small vessels. Patients are known to develop IgAV secondary to various infections. HIV infection is increasingly being recognized as a rare trigger for IgAV. We report a case of a woman with HIV infection who developed IgAV. A 54-year-old woman from Thailand presented with a 1-year history of palpable purpura on the legs, which had partially developed into an ulcer (Fig. 1a,b). She did not have abdominal pain or arthralgia. Laboratory examinations indicated pancytopenia (white blood cell count, 1.2 9 109/L; red blood cell count, 323 9 109/L; platelet count, 100 9 109/L) and elevated serum IgG and IgA levels (IgG, 2705 mg/dL; IgA, 466 mg/dL). Urinalysis results were normal. Additional investigations indicated positive results for the anti-HIV-1 antibody, a plasma HIV RNA level of 14 9 104 copies/mL and a decreased CD4 T-cell count of 15 cells/mm3. Histopathological examination demonstrated leukocytoclastic vasculitis of the small vessels, characterized by the presence of upper dermal perivascular infiltrates, primarily consisting of neutrophils with karyorrhexis (Fig. 1c,d). Deposition of IgA and complement C3 in the vessel walls was noted on direct immunofluorescence staining (Fig. 1e,f). Accordingly, IgAV and HIV infection were diagnosed. Although we scheduled antiretroviral therapy (ART), she did not return to our hospital. The patient presented with delayed IgAV of more than 1 year’s duration, indicating the likelihood of an underlying disorder that had induced the IgAV. As only HIV infection was
detected on various examinations, we concluded that the HIV infection had contributed to the development of IgAV. Gherardi et al.1 have described the association between HIV infection and various types of vasculitis. The prevalence of vasculitis and IgAV in the patients with HIV infection in their study was 20% and 0.6%, respectively. Although the pathogenesis of IgAV in patients with HIV infection remains unclear, increased circulation of immune complexes associated with the HIV infection or local replication of HIV itself may cause vasculitis.1 To our knowledge, four cases of IgAV with HIV infection have been reported.2–5 Three of those cases,3–5 and the current case, showed a high plasma viral load of 3–447 9 104 copies/ mL or a decreased CD4 count of 15–64 9 106/L. Single ART resolved a relapse of the purpura after treatment with steroids in one of the cases4 as well as persistent nephritis in another case,3 while a discontinuation of ART resulted in development of IgAV in one of the cases.5 Thus, it appears that active HIV infection is associated with IgAV, which supports the abovementioned pathogenic mechanism. Cases of HIV-infected patients who develop IgAV have been frequently reported in Asia.3–5 This may be associated not only with the high numbers of HIV-infected patients in Asia but also with the Asian genetic background. Appropriate ART may yield better outcomes in IgAV patients with HIV infection.
CONFLICT OF INTEREST:
None declared.
Akimasa SAITO, Naoko OKIYAMA, Hiroshi MARUYAMA, Manabu FUJIMOTO
Correspondence: Naoko Okiyama, M.D., Ph.D., Department of Dermatology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan. Email: [email protected]
444
© 2015 Japanese Dermatological Association
