Case and Review Received: June 21, 2013 Accepted after revision: March 15, 2014 Published online: June 12, 2014
Dermatology 2014;228:311–313 DOI: 10.1159/000362266
Tocilizumab-Induced Psoriasiform Rash in Rheumatoid Arthritis Natalia Palmou-Fontana a Juan Antonio Sánchez Gaviño b Dennis McGonagle e Eva García-Martinez c Luis Iñiguez de Onzoño Martín d a Rheumatology Division, b Dermatology Division and c Pharmacology Division, Hospital General de Almansa, and d Pathology Division, Hospital Universitario de Albacete, Almansa, Spain; e Department of Rheumatology, University of Leeds, Leeds, UK
Abstract Tocilizumab (TCZ) is a humanized monoclonal antibody against the interleukin-6 (IL-6) receptor and has been approved for the treatment of rheumatoid arthritis (RA) patients who have had an inadequate response to previous biological therapies. Psoriasiform skin lesions, especially palmoplantar pustulosis lesions, are well described following anti-tumour necrosis factor therapy. We describe a 79-year-old woman with rheumatoid factor-positive, anti-citrullinated protein antibody-positive erosive RA, who developed a psoriasiform palmoplantar pustulosis reaction following treatment with TCZ therapy (IL-6 receptor). The rash showed histological features compatible with psoriasis and disappeared following discontinuation © 2014 S. Karger AG, Basel of TCZ.
All listed authors meet the ICMJE authorship criteria. Written informed consent was obtained from the patient for publication of this case report and accompanying images.
Introduction
Tocilizumab (TCZ) is a humanized monoclonal antibody directed against the interleukin-6 (IL-6) receptor and is licensed for the treatment of moderate to severe rheumatoid arthritis (RA) in adults who have inadequately responded or have been intolerant to previous therapy with one or more disease-modifying antirheumatic drugs (DMARDs) or tumour necrosis factor (TNF) antagonists. In patients with RA who had inadequate responses to conventional DMARDs or TNF, TCZ demonstrated rapid and sustained efficacy [1]. Different adverse events associated with TCZ have been reported, including rash, pruritus and urticaria. In RA, several rare skin manifestations including TCZinduced erythroderma showing eosinophil infiltration [2], drug eruption [3] and acute generalized exanthematous pustulosis have been reported [4]. Rarely the induction of psoriasis or psoriasiform exanthemata during TCZ treatment has been reported in RA. To the best of our knowledge, psoriasiform rashes have not been described in auto-antibody-positive RA. Here we describe a case of psoriasis onset during TCZ treatment in a patient with RA.
© 2014 S. Karger AG, Basel 1018–8665/14/2284–0311$39.50/0 E-Mail [email protected] www.karger.com/drm
Case Report
A 79-year-old woman with a 20-year history of rheumatoid factor-positive, anticitrullinated protein antibody (ACPA)positive RA presented with active disease with a Disease Activity Score of 5.73. Her rheumatoid factor titre was 200 and she was strongly ACPA-positive. She was antinuclear antibody-negative and her C-reactive protein was 38 mg/l. She had previously failed to respond to several DMARDs including gold sodium thiomalate, hydroxychloroquine, leflunomide, azathioprine and methotrexate, either due to drug inefficacy or toxicity including hepatitis or gastric intolerance. She also failed to respond to two TNF inhibitors, namely etanercept and adalimumab, because of allergic skin reaction with pruritus and urticaria that rapidly disappeared following therapy cessation. TCZ 8 mg/kg infusion as DMARD monotherapy with prednisone 10 mg/day was then tried. She responded well with a reduction in her Disease Activity Score to 2.94 and her rheumatoid factor titre fell to 63. After the sixth TCZ infusion, the patient developed a painful pustular psoriasiform eruption at the back of both legs (fig. 1b), in the intergluteal cleft (fig. 1a),
Natalia Palmou-Fontana, MD Rheumatology Division, Hospital General de Almansa Carretera de la Circunvalación s/n ES–02640 Almansa (Spain) E-Mail npalmouu @ gmail.com
Downloaded by: North Dakota State University 134.129.120.3 - 5/22/2015 2:14:17 PM
Key Words Rheumatoid arthritis · Psoriasiform skin rash · Tocilizumab · Anti-citrullinated protein antibody · Rheumatoid factor
Color version available online
a
c
b
Fig. 1. a At the level of the intergluteal cleft lesions were shown as erythematous plaques which reminded of inverse psoriasis. b Behind the knees: erythematous plaques, with bruising, some of annular appearance, with vesiculopustular elements on an erythematous base with peripheral ecchymosis. c On the soles of the feet: erythematous plaques, with bruising, some of annular appearance, with vesiculopustular elements on an erythematous base with peripheral ecchymosis.
Color version available online
behind the knees (fig. 1b) and on the soles of her feet (fig. 1c). She remained well otherwise and her acute phase reactants remained within the normal range. She was reviewed by a dermatologist, who noted multiple erythematous plaques with annular erythematous peripheral ecchymosis with multiple pustular lesions. At this stage she had developed hyperkeratosis, which was especially severe in the heels and the intergluteal cleft. A punch biopsy from a lesion on her left leg showed a psoriasiform hyperplasia extending to the under surface of the stratum corneum and focal parakeratosis (fig. 2). The alterations observed in the epidermis were regular acanthosis with mounds of parakeratosis containing neutrophils (vertically and laterally delimited), which is consistent with psoriasis. However, the papillary dermis showed predominantly perivascular inflammatory cells with prominent eosinophils and few lymphocytes, which is not typical of psoriasis. The observed histological pattern is one of several histopathological features reported in the literature with TCZ including inflammatory cell infiltration ranging from vasculitis to the presence of abundant eosinophils. Consequently TCZ was discontinued and topical corticosteroids were prescribed. In the following weeks the patient improved significantly but her arthritis flared. She was subsequently prescribed another anti-TNF, namely certolizumab, and had a good clinical response without recrudescence of her rash. Discussion
312
a
b
Fig. 2. a Perivascular inflammatory cell infiltration and focal parakeratosis. b Mixed in-
flammatory infiltrate with eosinophils, lymphocytes and histiocytes.
severe ankylosing spondylitis associated with Crohn’s disease. Another case report described success of TCZ in anti-TNF-αinduced palmoplantar pustulosis in RA [7]. Specifically, 2 cases of adalimumab-induced palmoplantar pustular psoriasis in RA had complete resolution of rash and arthropathy following TCZ therapy [8]. Induction or worsening of psoriasis has been more commonly described as a para-
Dermatology 2014;228:311–313 DOI: 10.1159/000362266
doxical side effect in some patients receiving TNF inhibitors [9, 10]. Treatment of paradoxical psoriasis often requires withdrawal of the inducing drug and switching to a different biological agent. Puig et al. [11] described a psoriatic arthritis patient treated with ustekinumab. An array of postTCZ cutaneous reactions such as delayed skin eruption, lupus-like syndrome, cutaneous vasculitis, palmoplantar pustulosis,
Palmou-Fontana et al.
Downloaded by: North Dakota State University 134.129.120.3 - 5/22/2015 2:14:17 PM
This case report describes the development of a psoriasiform rash in a patient with ACPA-positive RA that was controlled by TCZ. A previous case report by Wendling et al. [5] reported de novo psoriasis in a patient with seronegative RA raising the possibility that this was a new development of psoriasis in a psoriatic arthritis case [2, 4, 5]. To the best of our knowledge this is the first case report of TCZ psoriasis in an auto-antibody-positive RA case. The literature with respect to the effects of TCZ in arthritis cases is limited but indicates efficacy in some settings with improvement of pre-existing psoriasis or antiTNF-induced psoriasis. Brulhart et al. [6] described the complete resolution of skin psoriasis in a patient treated with TCZ for
psoriasis vulgaris, atopic dermatitis, lichenoid rash and purpuric capillaritis have been reported [12]. The response to a second or third anti-TNF in these patients was mixed. The underlying pathomechanisms of induction of psoriasis or psoriasiform exanthemata by TNF inhibitors remain elusive but there is reason to assume that induction of such adverse events has more than one pathophysiology including the emergence of a dominant type 1 interferon response. With specific reference to TCZ-induced psoriasis a number of cases have been re-
ported. One of the patients [13] has still disease and the other has RA [4], with exacerbation of pre-existing psoriasis within 2 weeks after the first infusion of TCZ, while 1 patient developed de novo psoriasis [5]. Several studies have shown elevated levels of IL-6 in psoriasis with a putative role in both inflammation and keratinocyte hyperplasia [14, 15]. Likewise, STAT3, which is induced by IL-6, is associated with psoriatic phenotypes in mouse models [16]. Therefore, the onset of a psoriasiform rash during IL-6 blockade is somewhat surpris-
ing but likely represents the extreme heterogeneity within psoriasis phenotypes. In conclusion, we reported the development of a psoriasiform rash in a patient undergoing TCZ therapy for RA.
7 Younis S, et al: Tumor necrosis factor-associated palmoplantar pustular psoriasis treated with interleukin 6 blocker. J Rheumatol 2012; 39:2055–2056. 8 Rueda-Gotor J, et al: Successful effect of tocilizumab in anti-TNF-alpha-induced palmoplantar pustulosis in rheumatoid arthritis. Joint Bone Spine 2012;79:510–513. 9 Joyau C, et al: Anti-tumour necrosis factor alpha therapy and increased risk of de novo psoriasis: is it really a paradoxical side effect? Clin Exp Rheumatol 2012;30:700–706. 10 Harrison MJ, et al: Rates of new-onset psoriasis in patients with rheumatoid arthritis receiving anti-tumour necrosis factor alpha therapy: results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis 2009;68:209–215. 11 Puig L, et al: Ustekinumab treatment of TNF antagonist-induced paradoxical psoriasis flare in a patient with psoriatic arthritis: case report and review. Dermatology 2012; 225:14–17.
12 Ogata A, Kumanogoh A, Tanaka T: Pathological role of interleukin-6 in psoriatic arthritis. Arthritis 2012;2012:713618. 13 Laurent S, et al: Onset of psoriasis following treatment with tocilizumab. Br J Dermatol 2010;163:1364–1365. 14 Neuner P, et al: Increased IL-6 production by monocytes and keratinocytes in patients with psoriasis. J Invest Dermatol 1991;97:27–33. 15 Grossman RM, et al: Interleukin 6 is expressed in high levels in psoriatic skin and stimulates proliferation of cultured human keratinocytes. Proc Natl Acad Sci USA 1989; 86:6367–6371. 16 Miyoshi K, et al: Stat3 as a therapeutic target for the treatment of psoriasis: a clinical feasibility study with STA-21, a Stat3 inhibitor. J Invest Dermatol 2011;131:108–117.
Disclosure Statement
This work was not supported by any funding from any source. The authors declare no conflicts of interest in preparing this article.
1 GUIPCAR 2007. http://www.ser.es/practica Clinica/GUIPCAR_2007/Menu0_Principal. php. 2 Nakamura M, Tokura Y: Tocilizumab-induced erythroderma. Eur J Dermatol 2009;19: 273–274. 3 Yoshiki R, Nakamura M, Tokura Y: Drug eruption induced by IL-6 receptor inhibitor tocilizumab. J Eur Acad Dermatol Venereol 2009;24:495–496. 4 Izquierdo JH, et al: Acute generalized exanthematous pustulosis due to tocilizumab in a rheumatoid arthritis patient. Case Rep Rheumatol 2012;2012:517424. 5 Wendling D, et al: Psoriasis onset with tocilizumab treatment for rheumatoid arthritis. J Rheumatol 2012;39:657. 6 Brulhart L, et al: Tocilizumab in a patient with ankylosing spondylitis and Crohn’s disease refractory to TNF antagonists. Joint Bone Spine 2010;77:625–626.
Tocilizumab-Induced Psoriasiform Rash in Rheumatoid Arthritis
Dermatology 2014;228:311–313 DOI: 10.1159/000362266
313
Downloaded by: North Dakota State University 134.129.120.3 - 5/22/2015 2:14:17 PM
References
Dermatology 2014;228:311–313 DOI: 10.1159/000362266
Tocilizumab-Induced Psoriasiform Rash in Rheumatoid Arthritis Natalia Palmou-Fontana a Juan Antonio Sánchez Gaviño b Dennis McGonagle e Eva García-Martinez c Luis Iñiguez de Onzoño Martín d a Rheumatology Division, b Dermatology Division and c Pharmacology Division, Hospital General de Almansa, and d Pathology Division, Hospital Universitario de Albacete, Almansa, Spain; e Department of Rheumatology, University of Leeds, Leeds, UK
Abstract Tocilizumab (TCZ) is a humanized monoclonal antibody against the interleukin-6 (IL-6) receptor and has been approved for the treatment of rheumatoid arthritis (RA) patients who have had an inadequate response to previous biological therapies. Psoriasiform skin lesions, especially palmoplantar pustulosis lesions, are well described following anti-tumour necrosis factor therapy. We describe a 79-year-old woman with rheumatoid factor-positive, anti-citrullinated protein antibody-positive erosive RA, who developed a psoriasiform palmoplantar pustulosis reaction following treatment with TCZ therapy (IL-6 receptor). The rash showed histological features compatible with psoriasis and disappeared following discontinuation © 2014 S. Karger AG, Basel of TCZ.
All listed authors meet the ICMJE authorship criteria. Written informed consent was obtained from the patient for publication of this case report and accompanying images.
Introduction
Tocilizumab (TCZ) is a humanized monoclonal antibody directed against the interleukin-6 (IL-6) receptor and is licensed for the treatment of moderate to severe rheumatoid arthritis (RA) in adults who have inadequately responded or have been intolerant to previous therapy with one or more disease-modifying antirheumatic drugs (DMARDs) or tumour necrosis factor (TNF) antagonists. In patients with RA who had inadequate responses to conventional DMARDs or TNF, TCZ demonstrated rapid and sustained efficacy [1]. Different adverse events associated with TCZ have been reported, including rash, pruritus and urticaria. In RA, several rare skin manifestations including TCZinduced erythroderma showing eosinophil infiltration [2], drug eruption [3] and acute generalized exanthematous pustulosis have been reported [4]. Rarely the induction of psoriasis or psoriasiform exanthemata during TCZ treatment has been reported in RA. To the best of our knowledge, psoriasiform rashes have not been described in auto-antibody-positive RA. Here we describe a case of psoriasis onset during TCZ treatment in a patient with RA.
© 2014 S. Karger AG, Basel 1018–8665/14/2284–0311$39.50/0 E-Mail [email protected] www.karger.com/drm
Case Report
A 79-year-old woman with a 20-year history of rheumatoid factor-positive, anticitrullinated protein antibody (ACPA)positive RA presented with active disease with a Disease Activity Score of 5.73. Her rheumatoid factor titre was 200 and she was strongly ACPA-positive. She was antinuclear antibody-negative and her C-reactive protein was 38 mg/l. She had previously failed to respond to several DMARDs including gold sodium thiomalate, hydroxychloroquine, leflunomide, azathioprine and methotrexate, either due to drug inefficacy or toxicity including hepatitis or gastric intolerance. She also failed to respond to two TNF inhibitors, namely etanercept and adalimumab, because of allergic skin reaction with pruritus and urticaria that rapidly disappeared following therapy cessation. TCZ 8 mg/kg infusion as DMARD monotherapy with prednisone 10 mg/day was then tried. She responded well with a reduction in her Disease Activity Score to 2.94 and her rheumatoid factor titre fell to 63. After the sixth TCZ infusion, the patient developed a painful pustular psoriasiform eruption at the back of both legs (fig. 1b), in the intergluteal cleft (fig. 1a),
Natalia Palmou-Fontana, MD Rheumatology Division, Hospital General de Almansa Carretera de la Circunvalación s/n ES–02640 Almansa (Spain) E-Mail npalmouu @ gmail.com
Downloaded by: North Dakota State University 134.129.120.3 - 5/22/2015 2:14:17 PM
Key Words Rheumatoid arthritis · Psoriasiform skin rash · Tocilizumab · Anti-citrullinated protein antibody · Rheumatoid factor
Color version available online
a
c
b
Fig. 1. a At the level of the intergluteal cleft lesions were shown as erythematous plaques which reminded of inverse psoriasis. b Behind the knees: erythematous plaques, with bruising, some of annular appearance, with vesiculopustular elements on an erythematous base with peripheral ecchymosis. c On the soles of the feet: erythematous plaques, with bruising, some of annular appearance, with vesiculopustular elements on an erythematous base with peripheral ecchymosis.
Color version available online
behind the knees (fig. 1b) and on the soles of her feet (fig. 1c). She remained well otherwise and her acute phase reactants remained within the normal range. She was reviewed by a dermatologist, who noted multiple erythematous plaques with annular erythematous peripheral ecchymosis with multiple pustular lesions. At this stage she had developed hyperkeratosis, which was especially severe in the heels and the intergluteal cleft. A punch biopsy from a lesion on her left leg showed a psoriasiform hyperplasia extending to the under surface of the stratum corneum and focal parakeratosis (fig. 2). The alterations observed in the epidermis were regular acanthosis with mounds of parakeratosis containing neutrophils (vertically and laterally delimited), which is consistent with psoriasis. However, the papillary dermis showed predominantly perivascular inflammatory cells with prominent eosinophils and few lymphocytes, which is not typical of psoriasis. The observed histological pattern is one of several histopathological features reported in the literature with TCZ including inflammatory cell infiltration ranging from vasculitis to the presence of abundant eosinophils. Consequently TCZ was discontinued and topical corticosteroids were prescribed. In the following weeks the patient improved significantly but her arthritis flared. She was subsequently prescribed another anti-TNF, namely certolizumab, and had a good clinical response without recrudescence of her rash. Discussion
312
a
b
Fig. 2. a Perivascular inflammatory cell infiltration and focal parakeratosis. b Mixed in-
flammatory infiltrate with eosinophils, lymphocytes and histiocytes.
severe ankylosing spondylitis associated with Crohn’s disease. Another case report described success of TCZ in anti-TNF-αinduced palmoplantar pustulosis in RA [7]. Specifically, 2 cases of adalimumab-induced palmoplantar pustular psoriasis in RA had complete resolution of rash and arthropathy following TCZ therapy [8]. Induction or worsening of psoriasis has been more commonly described as a para-
Dermatology 2014;228:311–313 DOI: 10.1159/000362266
doxical side effect in some patients receiving TNF inhibitors [9, 10]. Treatment of paradoxical psoriasis often requires withdrawal of the inducing drug and switching to a different biological agent. Puig et al. [11] described a psoriatic arthritis patient treated with ustekinumab. An array of postTCZ cutaneous reactions such as delayed skin eruption, lupus-like syndrome, cutaneous vasculitis, palmoplantar pustulosis,
Palmou-Fontana et al.
Downloaded by: North Dakota State University 134.129.120.3 - 5/22/2015 2:14:17 PM
This case report describes the development of a psoriasiform rash in a patient with ACPA-positive RA that was controlled by TCZ. A previous case report by Wendling et al. [5] reported de novo psoriasis in a patient with seronegative RA raising the possibility that this was a new development of psoriasis in a psoriatic arthritis case [2, 4, 5]. To the best of our knowledge this is the first case report of TCZ psoriasis in an auto-antibody-positive RA case. The literature with respect to the effects of TCZ in arthritis cases is limited but indicates efficacy in some settings with improvement of pre-existing psoriasis or antiTNF-induced psoriasis. Brulhart et al. [6] described the complete resolution of skin psoriasis in a patient treated with TCZ for
psoriasis vulgaris, atopic dermatitis, lichenoid rash and purpuric capillaritis have been reported [12]. The response to a second or third anti-TNF in these patients was mixed. The underlying pathomechanisms of induction of psoriasis or psoriasiform exanthemata by TNF inhibitors remain elusive but there is reason to assume that induction of such adverse events has more than one pathophysiology including the emergence of a dominant type 1 interferon response. With specific reference to TCZ-induced psoriasis a number of cases have been re-
ported. One of the patients [13] has still disease and the other has RA [4], with exacerbation of pre-existing psoriasis within 2 weeks after the first infusion of TCZ, while 1 patient developed de novo psoriasis [5]. Several studies have shown elevated levels of IL-6 in psoriasis with a putative role in both inflammation and keratinocyte hyperplasia [14, 15]. Likewise, STAT3, which is induced by IL-6, is associated with psoriatic phenotypes in mouse models [16]. Therefore, the onset of a psoriasiform rash during IL-6 blockade is somewhat surpris-
ing but likely represents the extreme heterogeneity within psoriasis phenotypes. In conclusion, we reported the development of a psoriasiform rash in a patient undergoing TCZ therapy for RA.
7 Younis S, et al: Tumor necrosis factor-associated palmoplantar pustular psoriasis treated with interleukin 6 blocker. J Rheumatol 2012; 39:2055–2056. 8 Rueda-Gotor J, et al: Successful effect of tocilizumab in anti-TNF-alpha-induced palmoplantar pustulosis in rheumatoid arthritis. Joint Bone Spine 2012;79:510–513. 9 Joyau C, et al: Anti-tumour necrosis factor alpha therapy and increased risk of de novo psoriasis: is it really a paradoxical side effect? Clin Exp Rheumatol 2012;30:700–706. 10 Harrison MJ, et al: Rates of new-onset psoriasis in patients with rheumatoid arthritis receiving anti-tumour necrosis factor alpha therapy: results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis 2009;68:209–215. 11 Puig L, et al: Ustekinumab treatment of TNF antagonist-induced paradoxical psoriasis flare in a patient with psoriatic arthritis: case report and review. Dermatology 2012; 225:14–17.
12 Ogata A, Kumanogoh A, Tanaka T: Pathological role of interleukin-6 in psoriatic arthritis. Arthritis 2012;2012:713618. 13 Laurent S, et al: Onset of psoriasis following treatment with tocilizumab. Br J Dermatol 2010;163:1364–1365. 14 Neuner P, et al: Increased IL-6 production by monocytes and keratinocytes in patients with psoriasis. J Invest Dermatol 1991;97:27–33. 15 Grossman RM, et al: Interleukin 6 is expressed in high levels in psoriatic skin and stimulates proliferation of cultured human keratinocytes. Proc Natl Acad Sci USA 1989; 86:6367–6371. 16 Miyoshi K, et al: Stat3 as a therapeutic target for the treatment of psoriasis: a clinical feasibility study with STA-21, a Stat3 inhibitor. J Invest Dermatol 2011;131:108–117.
Disclosure Statement
This work was not supported by any funding from any source. The authors declare no conflicts of interest in preparing this article.
1 GUIPCAR 2007. http://www.ser.es/practica Clinica/GUIPCAR_2007/Menu0_Principal. php. 2 Nakamura M, Tokura Y: Tocilizumab-induced erythroderma. Eur J Dermatol 2009;19: 273–274. 3 Yoshiki R, Nakamura M, Tokura Y: Drug eruption induced by IL-6 receptor inhibitor tocilizumab. J Eur Acad Dermatol Venereol 2009;24:495–496. 4 Izquierdo JH, et al: Acute generalized exanthematous pustulosis due to tocilizumab in a rheumatoid arthritis patient. Case Rep Rheumatol 2012;2012:517424. 5 Wendling D, et al: Psoriasis onset with tocilizumab treatment for rheumatoid arthritis. J Rheumatol 2012;39:657. 6 Brulhart L, et al: Tocilizumab in a patient with ankylosing spondylitis and Crohn’s disease refractory to TNF antagonists. Joint Bone Spine 2010;77:625–626.
Tocilizumab-Induced Psoriasiform Rash in Rheumatoid Arthritis
Dermatology 2014;228:311–313 DOI: 10.1159/000362266
313
Downloaded by: North Dakota State University 134.129.120.3 - 5/22/2015 2:14:17 PM
References
