Clinical Overview
Emergence of Antinuclear Antibodies in Psoriatic Patients Treated with Infliximab: Personal Experience and Literature Review
DDR
DRUG DEVELOPMENT RESEARCH 75 : S61–S63 (2014)
Maria Sole Chimenti,1 Francesca Romana Spinelli,2* Alessandro Giunta,3 Francesco Martinelli,2 Rosita Saraceno,3 Fabrizio Conti,2 Roberto Perricone,1 and Guido Valesini2 1 Dipartimento di “Medicina dei Sistemi”—Reumatologia, Allergologia e Immunologia Clinica, Università di Rome “Tor Vergata”, 00163 Rome, Italy 2 Dipartimento di Medicina Interna e Specialità Mediche—Reumatologia, Sapienza Università di Roma, 00161 Rome, Italy 3 Dipartimento di “Medicina dei Sistemi”—Dermatologia, Università di Roma “Tor Vergata,” 00163 Rome, Italy
Strategy, Management and Health Policy Enabling Technology, Genomics, Proteomics
Preclinical Research
Preclinical Development Toxicology, Formulation Drug Delivery, Pharmacokinetics
Clinical Development Phases I-III Regulatory, Quality, Manufacturing
Postmarketing Phase IV
ABSTRACT Psoriasis is a chronic inflammatory skin disease affecting up to 2.5% of the population, with joint involvement in approximately 30% of patients. Given the role of tumor necrosis factor (TNF) in the pathogenesis of psoriasis, anti-TNF therapies have been developed; several studies have demonstrated the efficacy of infliximab (IFX) as induction and maintenance therapy in the treatment of moderate to severe plaque psoriasis. The development of antinuclear antibodies (ANA) in anti-TNF-treated patients has been frequently reported. The aim of this study was to investigate the incidence of ANA and anti-double stranded DNA (anti-dsDNA) antibodies in psoriatic patients receiving IFX. Incidence of new ANA and anti-ds-DNA was 16.2% and 8.1% respectively. No case of anti-TNF induced Lupus was observed during the follow-up. Drug Dev Res 75 : S61–S63, 2014. © 2014 Wiley Periodicals, Inc. Key words: psoriasis; anti-TNF; anti-nuclear-antibodies; disease activity
INTRODUCTION
Psoriasis is a chronic inflammatory skin disease affecting up to 2.5% of population. Epidermal hyperproliferation and dermal inflammation produce the typical thickened, erythematous, scaly plaques and patches. Approximately 30% of psoriatic patients exhibit joint involvement. Almost 25% of patients with plaque-type psoriasis require systemic therapy, phototherapy or both, but lack of efficacy over time, risk of cumulative toxicity and contraindications limit their favorable long-term outcome. Given the role of tumor necrosis factor (TNF) in the pathogenesis of psoriasis, in the last decade anti-TNF therapies have emerged as © 2014 Wiley Periodicals, Inc.
Funding/support information: Authors did not receive any funding for this work. Conflict of interest: MSC served as a consultant for Pfizer, Janssen-Cilag, and Merck Sharp & Dohme. *Correspondence to: Francesca Romana Spinelli, Dipartimento di Medicina Interna e Specialità Mediche, Reumatologia, Sapienza Università di Roma, viale del Policlinico 155, 00161 Rome, Italy. E-mail: [email protected] Published online in Wiley Online Library (wileyonlinelibrary .com). DOI: 10.1002/ddr.21198
S62
CHIMENTI ET AL.
second line systemic treatment [Papoutsaki et al., 2013]. Several studies have demonstrated the efficacy of Infliximab (IFX) as induction and maintenance therapy in the treatment of moderate to severe plaque psoriasis. The development of antinuclear antibodies (ANA) in anti-TNF-treated patients has been frequently reported [Poulalhon et al., 2007]. Aim of this study was to investigate incidence of ANA and antidouble stranded DNA (anti-dsDNA) antibodies in psoriatic patients receiving IFX. MATERIALS AND METHODS
We enrolled patients with plaque type psoriasis lasting from at least 6 months with a Psoriasis Area and Severity Index score (PASI) >12 who had failed systemic treatments for inefficacy or safety. All the patients signed an informed consent before entering the study. IFX was administrated intravenously at 5 mg/kg at baseline, after 2 and 6 weeks and every 8 weeks thereafter. ANA were investigated by indirect immunofluorescence assay (IIFA) on HEp-2 cells (Bio-Rad Laboratories, Hercules, CA) on sera diluted 1:40 in PBS and IgG, IgA and IgM isotype antidsDNA by IIFA on Crithidia luciliae (Bio-Rad) on sera diluted 1:10 in PBS at baseline, after 6 and 22 weeks; fluorescence intensity was scored semiquantitatively from 1+ to 4+ relative to the controls intensity. Disease activity was assessed by PASI and Health Assessment Questionnaire (HAQ). Safety was assessed by recording observed and reported adverse events and IFX infusion discontinuation. In particular,
TABLE 1. Incidence of Anti-nuclear Antibodies (ANA+) and Anti-double-Stranded DNA Antibodies (Anti-dsDNA) During Infliximab Treatment Patients (n = 37)
Baseline
Week 6
Week 22
ANA positive, n (%) Anti-dsDNA positive, n (%)
8 (21.6) 0 (0)
8 (21.6)* 3 (8.1)
12 (32.4) 3 (8.1)
*Two ANA positive patients at T0 became negative at T6.
emergence of sign and symptoms drug-induced lupus was evaluated at each visit. RESULTS
We enrolled 37 consecutive psoriatic patients: 21 male and 16 female with a mean age of 47.6 (range 29–65) years and mean disease duration of 19.8 (range 4–37) years. Table 1 shows the incidence of ANA and anti-dsDNA after 6 and 22 week of follow-up. IFX administration induced only IgM isotype anti-dsDNA. We did not observe any case of drug-induced lupus. We did not find any difference in mean PASI and HAQ scores between patients who developed ANA and those who did not. DISCUSSION
Emergence of antinuclear antibodies during antiTNF therapy is a well-documented phenomenon: ANA has been detected in up to 95% and anti-dsDNA in up to 45% of patients treated with IFX for inflammatory arthritides [Alessandri et al., 2007]. Mechanisms involved in ANA induction by anti-TNF include dysregulation of apoptosis, apoptotic body removal by C-reactive protein and serum amyloid P. Moreover, TNF antagonists are proposed to induce autoantibodies production by inhibiting cytotoxic T-lymphocytes response [Lora et al., 2013]. Table 2 summarizes literature data on ANA and anti-dsDNA emergence in psoriatic patients treated with IFX. In our cohort, incidence of new ANA and anti-dsDNA after 22 weeks was 16.2% and 8.1% respectively. The occurrence of anti-nuclear antibodies has been rarely associated to drug-induced lupus; accordingly, none of our patients developed sign or symptoms associated to antibodies emergence. In agreement with previous data, our results confirm that IFX-induced ANA and anti-dsDNA do not affect drug’s efficacy and safety. This phenomenon seems to be related to antibodies isotype: only IgG anti-dsDNA play a pathogenic role while IFX induce mostly IgM antibodies [Saraceno et al., 2012].
TABLE 2. Emergence of Anti-Nuclear Antibodies (ANA) and Anti-Double-Stranded DNA Antibodies (Anti-dsDNA) During Infliximab Treatment ANA (%)
Anti-dsDNA (%)
Author
n°
Follow-up
Baseline
Follow-up
Baseline
Follow-up
Lora et al., 2013 Saraceno et al., 2012 Hoffmann et al., 2011 Poulalhon et al., 2007
27 69 29 28
12 months 26 months 34 months 22 weeks
22 8.7 65.5* 10.7
63 48 89* 72
7 0 ne 0
48 5 ne 60.7
*Increase in ANA+ patients and increased ANA titter during follow-up. ne, not evaluated.
Drug Dev. Res.
ANAs WITH INFLIXIMAB IN PSORIASIS
ACKNOWLEDGMENT
Editorial assistance was provided by Mary Hines on behalf of HPS—Health Publishing and Services Srl and funded by Pfizer Italia.
S63
Lora V, Bonaguri C, Gisondi P, Sandei F, Battistelli L, Russo A, Melegari A, Trenti T, Lippi G, Girolomoni G. 2013. Autoantibody induction and adipokine levels in patients with psoriasis treated with infliximab. Immunol Res 56:382–389. Papoutsaki M, Osório F, Morais P, Torres T, Magina S, Chimenti S, Costanzo A. 2013. Infliximab in psoriasis and psoriatic arthritis. Biodrugs 27 (Suppl. 1):13–23.
Alessandri C, Scrivo R, Spinelli FR, Ceccarelli F, Magrini L, Priori R, Valesini G. 2007. Autoantibody production in anti-TNF-alphatreated patients. Ann N Y Acad Sci 1110:319–329.
Poulalhon N, Begon E, Lebbé C, Lioté F, Lahfa M, Bengoufa D, Morel P, Dubertret L, Bachelez H. 2007. 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 156:329–336.
Hoffmann JH, Hartmann M, Enk AH, Hadaschik EN. 2011. Autoantibodies in psoriasis as predictors for loss of response and anti-infliximab antibody induction. Br J Dermatol 165:1355– 1358.
Saraceno R, Specchio F, Torres T, Nisticò SP, Rizza S, Chimenti S. 2012. The role of antinuclear autoantibodies in patients with psoriasis treated with anti-tumor necrosis factor-alpha agents: a retrospective long-term study. J Am Acad Dermatol 66:180–182.
REFERENCES
Drug Dev. Res.
Emergence of Antinuclear Antibodies in Psoriatic Patients Treated with Infliximab: Personal Experience and Literature Review
DDR
DRUG DEVELOPMENT RESEARCH 75 : S61–S63 (2014)
Maria Sole Chimenti,1 Francesca Romana Spinelli,2* Alessandro Giunta,3 Francesco Martinelli,2 Rosita Saraceno,3 Fabrizio Conti,2 Roberto Perricone,1 and Guido Valesini2 1 Dipartimento di “Medicina dei Sistemi”—Reumatologia, Allergologia e Immunologia Clinica, Università di Rome “Tor Vergata”, 00163 Rome, Italy 2 Dipartimento di Medicina Interna e Specialità Mediche—Reumatologia, Sapienza Università di Roma, 00161 Rome, Italy 3 Dipartimento di “Medicina dei Sistemi”—Dermatologia, Università di Roma “Tor Vergata,” 00163 Rome, Italy
Strategy, Management and Health Policy Enabling Technology, Genomics, Proteomics
Preclinical Research
Preclinical Development Toxicology, Formulation Drug Delivery, Pharmacokinetics
Clinical Development Phases I-III Regulatory, Quality, Manufacturing
Postmarketing Phase IV
ABSTRACT Psoriasis is a chronic inflammatory skin disease affecting up to 2.5% of the population, with joint involvement in approximately 30% of patients. Given the role of tumor necrosis factor (TNF) in the pathogenesis of psoriasis, anti-TNF therapies have been developed; several studies have demonstrated the efficacy of infliximab (IFX) as induction and maintenance therapy in the treatment of moderate to severe plaque psoriasis. The development of antinuclear antibodies (ANA) in anti-TNF-treated patients has been frequently reported. The aim of this study was to investigate the incidence of ANA and anti-double stranded DNA (anti-dsDNA) antibodies in psoriatic patients receiving IFX. Incidence of new ANA and anti-ds-DNA was 16.2% and 8.1% respectively. No case of anti-TNF induced Lupus was observed during the follow-up. Drug Dev Res 75 : S61–S63, 2014. © 2014 Wiley Periodicals, Inc. Key words: psoriasis; anti-TNF; anti-nuclear-antibodies; disease activity
INTRODUCTION
Psoriasis is a chronic inflammatory skin disease affecting up to 2.5% of population. Epidermal hyperproliferation and dermal inflammation produce the typical thickened, erythematous, scaly plaques and patches. Approximately 30% of psoriatic patients exhibit joint involvement. Almost 25% of patients with plaque-type psoriasis require systemic therapy, phototherapy or both, but lack of efficacy over time, risk of cumulative toxicity and contraindications limit their favorable long-term outcome. Given the role of tumor necrosis factor (TNF) in the pathogenesis of psoriasis, in the last decade anti-TNF therapies have emerged as © 2014 Wiley Periodicals, Inc.
Funding/support information: Authors did not receive any funding for this work. Conflict of interest: MSC served as a consultant for Pfizer, Janssen-Cilag, and Merck Sharp & Dohme. *Correspondence to: Francesca Romana Spinelli, Dipartimento di Medicina Interna e Specialità Mediche, Reumatologia, Sapienza Università di Roma, viale del Policlinico 155, 00161 Rome, Italy. E-mail: [email protected] Published online in Wiley Online Library (wileyonlinelibrary .com). DOI: 10.1002/ddr.21198
S62
CHIMENTI ET AL.
second line systemic treatment [Papoutsaki et al., 2013]. Several studies have demonstrated the efficacy of Infliximab (IFX) as induction and maintenance therapy in the treatment of moderate to severe plaque psoriasis. The development of antinuclear antibodies (ANA) in anti-TNF-treated patients has been frequently reported [Poulalhon et al., 2007]. Aim of this study was to investigate incidence of ANA and antidouble stranded DNA (anti-dsDNA) antibodies in psoriatic patients receiving IFX. MATERIALS AND METHODS
We enrolled patients with plaque type psoriasis lasting from at least 6 months with a Psoriasis Area and Severity Index score (PASI) >12 who had failed systemic treatments for inefficacy or safety. All the patients signed an informed consent before entering the study. IFX was administrated intravenously at 5 mg/kg at baseline, after 2 and 6 weeks and every 8 weeks thereafter. ANA were investigated by indirect immunofluorescence assay (IIFA) on HEp-2 cells (Bio-Rad Laboratories, Hercules, CA) on sera diluted 1:40 in PBS and IgG, IgA and IgM isotype antidsDNA by IIFA on Crithidia luciliae (Bio-Rad) on sera diluted 1:10 in PBS at baseline, after 6 and 22 weeks; fluorescence intensity was scored semiquantitatively from 1+ to 4+ relative to the controls intensity. Disease activity was assessed by PASI and Health Assessment Questionnaire (HAQ). Safety was assessed by recording observed and reported adverse events and IFX infusion discontinuation. In particular,
TABLE 1. Incidence of Anti-nuclear Antibodies (ANA+) and Anti-double-Stranded DNA Antibodies (Anti-dsDNA) During Infliximab Treatment Patients (n = 37)
Baseline
Week 6
Week 22
ANA positive, n (%) Anti-dsDNA positive, n (%)
8 (21.6) 0 (0)
8 (21.6)* 3 (8.1)
12 (32.4) 3 (8.1)
*Two ANA positive patients at T0 became negative at T6.
emergence of sign and symptoms drug-induced lupus was evaluated at each visit. RESULTS
We enrolled 37 consecutive psoriatic patients: 21 male and 16 female with a mean age of 47.6 (range 29–65) years and mean disease duration of 19.8 (range 4–37) years. Table 1 shows the incidence of ANA and anti-dsDNA after 6 and 22 week of follow-up. IFX administration induced only IgM isotype anti-dsDNA. We did not observe any case of drug-induced lupus. We did not find any difference in mean PASI and HAQ scores between patients who developed ANA and those who did not. DISCUSSION
Emergence of antinuclear antibodies during antiTNF therapy is a well-documented phenomenon: ANA has been detected in up to 95% and anti-dsDNA in up to 45% of patients treated with IFX for inflammatory arthritides [Alessandri et al., 2007]. Mechanisms involved in ANA induction by anti-TNF include dysregulation of apoptosis, apoptotic body removal by C-reactive protein and serum amyloid P. Moreover, TNF antagonists are proposed to induce autoantibodies production by inhibiting cytotoxic T-lymphocytes response [Lora et al., 2013]. Table 2 summarizes literature data on ANA and anti-dsDNA emergence in psoriatic patients treated with IFX. In our cohort, incidence of new ANA and anti-dsDNA after 22 weeks was 16.2% and 8.1% respectively. The occurrence of anti-nuclear antibodies has been rarely associated to drug-induced lupus; accordingly, none of our patients developed sign or symptoms associated to antibodies emergence. In agreement with previous data, our results confirm that IFX-induced ANA and anti-dsDNA do not affect drug’s efficacy and safety. This phenomenon seems to be related to antibodies isotype: only IgG anti-dsDNA play a pathogenic role while IFX induce mostly IgM antibodies [Saraceno et al., 2012].
TABLE 2. Emergence of Anti-Nuclear Antibodies (ANA) and Anti-Double-Stranded DNA Antibodies (Anti-dsDNA) During Infliximab Treatment ANA (%)
Anti-dsDNA (%)
Author
n°
Follow-up
Baseline
Follow-up
Baseline
Follow-up
Lora et al., 2013 Saraceno et al., 2012 Hoffmann et al., 2011 Poulalhon et al., 2007
27 69 29 28
12 months 26 months 34 months 22 weeks
22 8.7 65.5* 10.7
63 48 89* 72
7 0 ne 0
48 5 ne 60.7
*Increase in ANA+ patients and increased ANA titter during follow-up. ne, not evaluated.
Drug Dev. Res.
ANAs WITH INFLIXIMAB IN PSORIASIS
ACKNOWLEDGMENT
Editorial assistance was provided by Mary Hines on behalf of HPS—Health Publishing and Services Srl and funded by Pfizer Italia.
S63
Lora V, Bonaguri C, Gisondi P, Sandei F, Battistelli L, Russo A, Melegari A, Trenti T, Lippi G, Girolomoni G. 2013. Autoantibody induction and adipokine levels in patients with psoriasis treated with infliximab. Immunol Res 56:382–389. Papoutsaki M, Osório F, Morais P, Torres T, Magina S, Chimenti S, Costanzo A. 2013. Infliximab in psoriasis and psoriatic arthritis. Biodrugs 27 (Suppl. 1):13–23.
Alessandri C, Scrivo R, Spinelli FR, Ceccarelli F, Magrini L, Priori R, Valesini G. 2007. Autoantibody production in anti-TNF-alphatreated patients. Ann N Y Acad Sci 1110:319–329.
Poulalhon N, Begon E, Lebbé C, Lioté F, Lahfa M, Bengoufa D, Morel P, Dubertret L, Bachelez H. 2007. 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 156:329–336.
Hoffmann JH, Hartmann M, Enk AH, Hadaschik EN. 2011. Autoantibodies in psoriasis as predictors for loss of response and anti-infliximab antibody induction. Br J Dermatol 165:1355– 1358.
Saraceno R, Specchio F, Torres T, Nisticò SP, Rizza S, Chimenti S. 2012. The role of antinuclear autoantibodies in patients with psoriasis treated with anti-tumor necrosis factor-alpha agents: a retrospective long-term study. J Am Acad Dermatol 66:180–182.
REFERENCES
Drug Dev. Res.
