BJD
British Journal of Dermatology
CASE REPORT
A case of tumour necrosis factor-a inhibitor- and rituximabinduced plantar pustular psoriasis that completely resolved with tocilizumab P. Jayasekera, R. Parslew and A. Al-Sharqi Department of Dermatology, Royal Liverpool and Broadgreen Hospitals NHS Trust, Liverpool, U.K.
Summary Correspondence Prativa Jayasekera. E-mail: [email protected]
Accepted for publication 21 May 2014
Funding sources None.
Rituximab, a chimeric B-cell-depleting monoclonal antibody, is a well-established therapy for rheumatoid arthritis. It is emerging that classical psoriatic lesions and plantar pustular psoriasis (PPP) are cutaneous side-effects of this drug. Antitumour necrosis factor (anti-TNF) therapies have multiple documented side-effects including PPP and psoriasis. We report a patient who has rheumatoid arthritis, who failed on anti-TNF therapies and then was commenced on rituximab. Subsequently she developed localized PPP. Due to deterioration of her joint disease she was switched to the interleukin-6 blocker tocilizumab, and the PPP resolved.
Conflicts of interest None declared. DOI 10.1111/bjd.13146
What’s already known about this topic?
• •
Antitumour necrosis factor (anti-TNF) treatments have a variety of documented side-effects such as psoriasiform eruptions, eczematous reactions, leucocytoclastic vasculitis, granuloma annulare, acneiform eruptions and viral and bacterial infections. It is now emerging that rituximab can also cause cutaneous side-effects such as psoriasis and plantar pustular psoriasis (PPP).
What does this study add?
• •
We report a patient who had anti-TNF therapy and then rituximab, who subsequently developed PPP, which cleared with tocilizumab. This series of events has never been reported before and indicates that there is a need for further studies to look at the pathways involved in the development of PPP.
The treatment of autoimmune inflammatory diseases such as rheumatoid arthritis and psoriasis has been revolutionized by the use of biological agents, especially tumour necrosis factor (TNF)-a inhibitors. Unfortunately there is not always a complete response with single TNF-a inhibitors and therefore many patients are switched from one to another. More recently, tocilizumab, a humanized monoclonal antibody against interleukin (IL)-6, has been licensed for patients with moderate-to-severe rheumatoid arthritis, in those who have
failed one or more disease-modifying antirheumatic medications (DMARDs) or TNF-a inhibitors.1 Although TNF-a inhibitors are used to treat moderate-tosevere psoriasis, there have been reports of paradoxical effects where psoriasis has been worsened, or even induced, by the TNF-a inhibitor.2 The exact mechanism of the aetiology of both of these unusual phenomena is unclear, but interestingly more than half of psoriatic presentations secondary to TNF-a inhibitors were of the palmar pustular type.3
British Journal of Dermatology (2014) 171, pp1546–1549
© 2014 British Association of Dermatologists
1546
Tocilizumab for drug-induced plantar pustular psoriasis, P. Jayasekera et al. 1547
The same is true for rituximab, with a few case reports where patients have developed psoriasis after treatment with anti-TNF treatment and rituximab, and indeed with rituximab alone.4
Case report An 80-year-old woman was diagnosed with rheumatoid arthritis 23 years earlier. She had been treated with multiple DMARDs including methotrexate, sulfasalazine, gold, penicillamine, azathioprine and ciclosporin. Her past medical history included hypertension, colonic angiodysplasia and right femoral hernia. In 2007, after failing the aforementioned DMARDs, she was started on adalimumab 40 mg fortnightly, which was stopped after one dose as she developed a diffuse rash. Subsequently she was started on etanercept 50 mg weekly, which she remained on for 5 months, and this was then stopped due to multiple infections. Since then she was started on rituximab, which she was stable on for 3 years. Two years after starting rituximab she developed right plantar pustular psoriasis (PPP), which initially responded to daily clobetasol propionate 005% ointment. Fourteen months later she was re-referred with a flare-up and then was treated again with daily clobetasol propionate 005% ointment. On subsequent clinic reviews she was given daily mometasone 01% ointment under occlusion and continued to deteriorate, and was then started on acitretin 25 mg daily. Unfortunately she was unable to tolerate acitretin due to flushing and sweating and this was stopped shortly afterwards. At that time her rheumatoid arthritis treatment was switched to tocilizumab. It was noticed incidentally that her PPP was improving, despite her being on no specific treatment, and the PPP actually resolved after four infusions of tocilizumab. In October 2013 she had an operation on the right foot to correct toe deformities, and due to the immunosuppressive risk of tocilizumab she was advised by the orthopaedic team to stop the infusions at least 30 days before the operation. Her last infusion was in September 2013, and 4 weeks after the infusion the PPP returned. Within 48 h of her last infu-
Fig 1. Pustules on the right heel. © 2014 British Association of Dermatologists
Fig 2. Pustules on the right sole.
sion in December 2013 the PPP completely resolved, which may indicate a possible therapeutic role of tocilizumab in controlling the PPP. Figures 1 and 2 illustrate the PPP shortly after the patient stopped tocilizumab, and Figures 3 and 4 are medical photographs after restarting tocilizumab.
Fig 3. Improvement of right-sole pustules after restarting tocilizumab. British Journal of Dermatology (2014) 171, pp1546–1549
1548 Tocilizumab for drug-induced plantar pustular psoriasis, P. Jayasekera et al.
Fig 4. Improvement of right-heel pustules after restarting tocilizumab.
Discussion TNF-a, IL-6, IL-8, IL-12, IL-17, IL-18 and interferon (IFN)-c have all been implicated in the pathogenesis of psoriasis. One theory for why the paradoxical reaction occurs is TNF-a playing an important role in the regulation of IFN-a production and inhibition of plasmacytoid dendritic cell (PDC) maturation. It is believed that inhibition of TNF-a could lead to increased production of IFN-a by PDCs, which may then trigger psoriasis.3 The mechanism by which rituximab, a chimeric B-celldepleting monoclonal antibody, can worsen or cause psoriasis is unclear, but it may be due to a number of reasons: the disruption of regulatory B cells on T cells, increased susceptibility to infections resulting in plaque development, or T-cell reactivity against the murine component of the chimeric molecule.4–6 Another popular theory is that rituximab can induce autoimmune phenomena, one of the manifestations of which could be immune-related skin lesions such as psoriasis.7 A literature search revealed two cases of PPP induced by TNF-a inhibitors, with complete resolution with tocilizumab,8,9 and one case of PPP after use of rituximab, which improved with topical coal tar/salicylic acid and steroid.10 Il-6 is produced by keratinocytes, fibroblasts and vascular endothelial cells. It has been found that IL-6 is expressed in high levels in psoriatic skin and the plasma and serum of patients with psoriasis.11 There is a suggestion that IL-6 may
British Journal of Dermatology (2014) 171, pp1546–1549
contribute to the epidermal hyperplasia present in psoriatic epithelium and may affect the function of dermal inflammatory cells. This theory is based on the fact that in psoriatic skin, abnormal keratinocytes produce IL-6, transforming growth factor-a and IL-1a, which stimulate the growth of cultured keratinocytes.12 In psoriatic lesions IL-6 may inhibit effector T-cell suppression via regulatory T cells, which then increases T-cell trafficking. IL-6 then induces phosphorylation of signal transducer and activator of transcription 3 in these T cells, which leads to T helper 17 differentiation and production of the cytokines IL-17, IL-22, IL-6 and TNF-a, which are involved in inflammation.13 The aetiology of PPP is unclear; however, it is felt that PPP is a genetic entity that is separate from psoriasis, as PPP has no association with PSORS1, the main locus for psoriasis vulgaris and guttate psoriasis. Also it has been found that TNF238 and TNF-308 polymorphisms, which are associated with psoriasis vulgaris and psoriatic arthritis, are not associated with PPP, which further compounds the theory that PPP and psoriasis are distinct entities.14 In summary, we present a case of PPP that developed following the treatment of rheumatoid arthritis with rituximab, and cleared completely with the use of tocilizumab. We believe that IL-6 could represent an important pathway in the pathogenesis of PPP. Furthermore, recent experimental studies using exome sequencing have identified two missense variants that could underlie anti-TNF-induced PPP. We therefore postulate that anti-IL6 therapies may be more beneficial for the treatment of PPP than nonspecific treatments such as anti-TNF agents and rituximab. Genetic polymorphisms have previously been described associated with psoriasis and other autoimmune conditions; however, more studies need to be carried out investigating the pathways involved in PPP, including anti-TNF-induced PPP.15
References 1 National Institute for Health and Care Excellence. Tocilizumab for the treatment of rheumatoid arthritis (rapid review of technology appraisal guidance 198). Available at: http://www.nice.org.uk/ guidance/TA247 (last accessed 27 October 2014). 2 Kawazoe Y, Sugita S, Yamada Y et al. Psoriasis triggered by infliximab in a patient with Behcßet’s disease. Jpn J Ophthalmol 2013; 57:95–7. 3 de Gannes GC, Ghoreishi M, Pope J et al. Psoriasis and pustular dermatitis triggered by TNF-a in patients with rheumatologic conditions. Arch Dermatol 2007; 143:223–31. 4 Thomas L, Canoui-Poitrine F, Gottenberg JE et al. Incidence of new-onset and flare of pre-existing psoriasis during rituximab. J Rheumatol 2012; 39:893–8. 5 Dass S, Vital EM, Emery P. Development of psoriasis after B cell depletion with rituximab. Arthritis Rheum 2007; 56:2715–18. 6 Olivieri I, D’Angelo S, Leccese P et al. Worsening of psoriasis with rituximab therapy. Clin Exp Rheumatol 2010; 28:926. 7 Markatseli TE, Kaltsonoudis ES, Voulgari PV et al. Induction of psoriatic skin lesions in a patient with rheumatoid arthritis treated with rituximab. Clin Exp Rheumatol 2009; 27:996–8.
© 2014 British Association of Dermatologists
Tocilizumab for drug-induced plantar pustular psoriasis, P. Jayasekera et al. 1549 8 Rueda-Gotor J, Gonzalez-Gay M, Alonso R et al. Successful effect of tocilizumab in anti-TNF-a-induced palmoplantar pustulosis in rheumatoid arthritis. Joint Bone Spine 2012; 79:510–13. 9 Younis S, Rimar D, Slobodin G, Rosner I. Tumor necrosis factorassociated palmoplantar pustular psoriasis treated with interleukin 6 blocker. J Rheumatol 2012; 39:2055–6. 10 Hardcastle SA, Williamson L. Atypical psoriasis following rituximab for rheumatoid arthritis. J Rheumatol 2012; 39:1303–4. 11 Ameglio F, Bonifati C, Pietravallle M, Fazio M. Interleukin-6 and tumour necrosis factor levels decrease in the suction blister fluids of psoriatic patients during effective therapy. Dermatology 1994; 189:359–63.
© 2014 British Association of Dermatologists
12 Galadari I, Sheriff M. Estimation of interleukin-6 level in psoriasis patients. Eur Ann Allergy Clin Immunol 2005; 37:63–5. 13 Goodman W, Levine A, Massari J et al. IL-6 signalling in psoriasis prevents immune suppression by regulatory T cells. J Immunol 2009; 18:3170–6. 14 de Waal AC, van de Kerkhof PCM. Pustulosis palmoplantaris is a disease distinct from psoriasis. J Dermatolog Treat 2011; 22:102–5. 15 Ellingford J, Black G, Bhaskar S et al. Exome sequencing and network analysis identifies two candidate mutations in patients with anti-tumour necrosis factor therapy-induced palmoplantar pustulosis. Presented at the British Society of Investigative Dermatology Meeting, Newcastle, U.K., 7–9 April 2014.
British Journal of Dermatology (2014) 171, pp1546–1549
British Journal of Dermatology
CASE REPORT
A case of tumour necrosis factor-a inhibitor- and rituximabinduced plantar pustular psoriasis that completely resolved with tocilizumab P. Jayasekera, R. Parslew and A. Al-Sharqi Department of Dermatology, Royal Liverpool and Broadgreen Hospitals NHS Trust, Liverpool, U.K.
Summary Correspondence Prativa Jayasekera. E-mail: [email protected]
Accepted for publication 21 May 2014
Funding sources None.
Rituximab, a chimeric B-cell-depleting monoclonal antibody, is a well-established therapy for rheumatoid arthritis. It is emerging that classical psoriatic lesions and plantar pustular psoriasis (PPP) are cutaneous side-effects of this drug. Antitumour necrosis factor (anti-TNF) therapies have multiple documented side-effects including PPP and psoriasis. We report a patient who has rheumatoid arthritis, who failed on anti-TNF therapies and then was commenced on rituximab. Subsequently she developed localized PPP. Due to deterioration of her joint disease she was switched to the interleukin-6 blocker tocilizumab, and the PPP resolved.
Conflicts of interest None declared. DOI 10.1111/bjd.13146
What’s already known about this topic?
• •
Antitumour necrosis factor (anti-TNF) treatments have a variety of documented side-effects such as psoriasiform eruptions, eczematous reactions, leucocytoclastic vasculitis, granuloma annulare, acneiform eruptions and viral and bacterial infections. It is now emerging that rituximab can also cause cutaneous side-effects such as psoriasis and plantar pustular psoriasis (PPP).
What does this study add?
• •
We report a patient who had anti-TNF therapy and then rituximab, who subsequently developed PPP, which cleared with tocilizumab. This series of events has never been reported before and indicates that there is a need for further studies to look at the pathways involved in the development of PPP.
The treatment of autoimmune inflammatory diseases such as rheumatoid arthritis and psoriasis has been revolutionized by the use of biological agents, especially tumour necrosis factor (TNF)-a inhibitors. Unfortunately there is not always a complete response with single TNF-a inhibitors and therefore many patients are switched from one to another. More recently, tocilizumab, a humanized monoclonal antibody against interleukin (IL)-6, has been licensed for patients with moderate-to-severe rheumatoid arthritis, in those who have
failed one or more disease-modifying antirheumatic medications (DMARDs) or TNF-a inhibitors.1 Although TNF-a inhibitors are used to treat moderate-tosevere psoriasis, there have been reports of paradoxical effects where psoriasis has been worsened, or even induced, by the TNF-a inhibitor.2 The exact mechanism of the aetiology of both of these unusual phenomena is unclear, but interestingly more than half of psoriatic presentations secondary to TNF-a inhibitors were of the palmar pustular type.3
British Journal of Dermatology (2014) 171, pp1546–1549
© 2014 British Association of Dermatologists
1546
Tocilizumab for drug-induced plantar pustular psoriasis, P. Jayasekera et al. 1547
The same is true for rituximab, with a few case reports where patients have developed psoriasis after treatment with anti-TNF treatment and rituximab, and indeed with rituximab alone.4
Case report An 80-year-old woman was diagnosed with rheumatoid arthritis 23 years earlier. She had been treated with multiple DMARDs including methotrexate, sulfasalazine, gold, penicillamine, azathioprine and ciclosporin. Her past medical history included hypertension, colonic angiodysplasia and right femoral hernia. In 2007, after failing the aforementioned DMARDs, she was started on adalimumab 40 mg fortnightly, which was stopped after one dose as she developed a diffuse rash. Subsequently she was started on etanercept 50 mg weekly, which she remained on for 5 months, and this was then stopped due to multiple infections. Since then she was started on rituximab, which she was stable on for 3 years. Two years after starting rituximab she developed right plantar pustular psoriasis (PPP), which initially responded to daily clobetasol propionate 005% ointment. Fourteen months later she was re-referred with a flare-up and then was treated again with daily clobetasol propionate 005% ointment. On subsequent clinic reviews she was given daily mometasone 01% ointment under occlusion and continued to deteriorate, and was then started on acitretin 25 mg daily. Unfortunately she was unable to tolerate acitretin due to flushing and sweating and this was stopped shortly afterwards. At that time her rheumatoid arthritis treatment was switched to tocilizumab. It was noticed incidentally that her PPP was improving, despite her being on no specific treatment, and the PPP actually resolved after four infusions of tocilizumab. In October 2013 she had an operation on the right foot to correct toe deformities, and due to the immunosuppressive risk of tocilizumab she was advised by the orthopaedic team to stop the infusions at least 30 days before the operation. Her last infusion was in September 2013, and 4 weeks after the infusion the PPP returned. Within 48 h of her last infu-
Fig 1. Pustules on the right heel. © 2014 British Association of Dermatologists
Fig 2. Pustules on the right sole.
sion in December 2013 the PPP completely resolved, which may indicate a possible therapeutic role of tocilizumab in controlling the PPP. Figures 1 and 2 illustrate the PPP shortly after the patient stopped tocilizumab, and Figures 3 and 4 are medical photographs after restarting tocilizumab.
Fig 3. Improvement of right-sole pustules after restarting tocilizumab. British Journal of Dermatology (2014) 171, pp1546–1549
1548 Tocilizumab for drug-induced plantar pustular psoriasis, P. Jayasekera et al.
Fig 4. Improvement of right-heel pustules after restarting tocilizumab.
Discussion TNF-a, IL-6, IL-8, IL-12, IL-17, IL-18 and interferon (IFN)-c have all been implicated in the pathogenesis of psoriasis. One theory for why the paradoxical reaction occurs is TNF-a playing an important role in the regulation of IFN-a production and inhibition of plasmacytoid dendritic cell (PDC) maturation. It is believed that inhibition of TNF-a could lead to increased production of IFN-a by PDCs, which may then trigger psoriasis.3 The mechanism by which rituximab, a chimeric B-celldepleting monoclonal antibody, can worsen or cause psoriasis is unclear, but it may be due to a number of reasons: the disruption of regulatory B cells on T cells, increased susceptibility to infections resulting in plaque development, or T-cell reactivity against the murine component of the chimeric molecule.4–6 Another popular theory is that rituximab can induce autoimmune phenomena, one of the manifestations of which could be immune-related skin lesions such as psoriasis.7 A literature search revealed two cases of PPP induced by TNF-a inhibitors, with complete resolution with tocilizumab,8,9 and one case of PPP after use of rituximab, which improved with topical coal tar/salicylic acid and steroid.10 Il-6 is produced by keratinocytes, fibroblasts and vascular endothelial cells. It has been found that IL-6 is expressed in high levels in psoriatic skin and the plasma and serum of patients with psoriasis.11 There is a suggestion that IL-6 may
British Journal of Dermatology (2014) 171, pp1546–1549
contribute to the epidermal hyperplasia present in psoriatic epithelium and may affect the function of dermal inflammatory cells. This theory is based on the fact that in psoriatic skin, abnormal keratinocytes produce IL-6, transforming growth factor-a and IL-1a, which stimulate the growth of cultured keratinocytes.12 In psoriatic lesions IL-6 may inhibit effector T-cell suppression via regulatory T cells, which then increases T-cell trafficking. IL-6 then induces phosphorylation of signal transducer and activator of transcription 3 in these T cells, which leads to T helper 17 differentiation and production of the cytokines IL-17, IL-22, IL-6 and TNF-a, which are involved in inflammation.13 The aetiology of PPP is unclear; however, it is felt that PPP is a genetic entity that is separate from psoriasis, as PPP has no association with PSORS1, the main locus for psoriasis vulgaris and guttate psoriasis. Also it has been found that TNF238 and TNF-308 polymorphisms, which are associated with psoriasis vulgaris and psoriatic arthritis, are not associated with PPP, which further compounds the theory that PPP and psoriasis are distinct entities.14 In summary, we present a case of PPP that developed following the treatment of rheumatoid arthritis with rituximab, and cleared completely with the use of tocilizumab. We believe that IL-6 could represent an important pathway in the pathogenesis of PPP. Furthermore, recent experimental studies using exome sequencing have identified two missense variants that could underlie anti-TNF-induced PPP. We therefore postulate that anti-IL6 therapies may be more beneficial for the treatment of PPP than nonspecific treatments such as anti-TNF agents and rituximab. Genetic polymorphisms have previously been described associated with psoriasis and other autoimmune conditions; however, more studies need to be carried out investigating the pathways involved in PPP, including anti-TNF-induced PPP.15
References 1 National Institute for Health and Care Excellence. Tocilizumab for the treatment of rheumatoid arthritis (rapid review of technology appraisal guidance 198). Available at: http://www.nice.org.uk/ guidance/TA247 (last accessed 27 October 2014). 2 Kawazoe Y, Sugita S, Yamada Y et al. Psoriasis triggered by infliximab in a patient with Behcßet’s disease. Jpn J Ophthalmol 2013; 57:95–7. 3 de Gannes GC, Ghoreishi M, Pope J et al. Psoriasis and pustular dermatitis triggered by TNF-a in patients with rheumatologic conditions. Arch Dermatol 2007; 143:223–31. 4 Thomas L, Canoui-Poitrine F, Gottenberg JE et al. Incidence of new-onset and flare of pre-existing psoriasis during rituximab. J Rheumatol 2012; 39:893–8. 5 Dass S, Vital EM, Emery P. Development of psoriasis after B cell depletion with rituximab. Arthritis Rheum 2007; 56:2715–18. 6 Olivieri I, D’Angelo S, Leccese P et al. Worsening of psoriasis with rituximab therapy. Clin Exp Rheumatol 2010; 28:926. 7 Markatseli TE, Kaltsonoudis ES, Voulgari PV et al. Induction of psoriatic skin lesions in a patient with rheumatoid arthritis treated with rituximab. Clin Exp Rheumatol 2009; 27:996–8.
© 2014 British Association of Dermatologists
Tocilizumab for drug-induced plantar pustular psoriasis, P. Jayasekera et al. 1549 8 Rueda-Gotor J, Gonzalez-Gay M, Alonso R et al. Successful effect of tocilizumab in anti-TNF-a-induced palmoplantar pustulosis in rheumatoid arthritis. Joint Bone Spine 2012; 79:510–13. 9 Younis S, Rimar D, Slobodin G, Rosner I. Tumor necrosis factorassociated palmoplantar pustular psoriasis treated with interleukin 6 blocker. J Rheumatol 2012; 39:2055–6. 10 Hardcastle SA, Williamson L. Atypical psoriasis following rituximab for rheumatoid arthritis. J Rheumatol 2012; 39:1303–4. 11 Ameglio F, Bonifati C, Pietravallle M, Fazio M. Interleukin-6 and tumour necrosis factor levels decrease in the suction blister fluids of psoriatic patients during effective therapy. Dermatology 1994; 189:359–63.
© 2014 British Association of Dermatologists
12 Galadari I, Sheriff M. Estimation of interleukin-6 level in psoriasis patients. Eur Ann Allergy Clin Immunol 2005; 37:63–5. 13 Goodman W, Levine A, Massari J et al. IL-6 signalling in psoriasis prevents immune suppression by regulatory T cells. J Immunol 2009; 18:3170–6. 14 de Waal AC, van de Kerkhof PCM. Pustulosis palmoplantaris is a disease distinct from psoriasis. J Dermatolog Treat 2011; 22:102–5. 15 Ellingford J, Black G, Bhaskar S et al. Exome sequencing and network analysis identifies two candidate mutations in patients with anti-tumour necrosis factor therapy-induced palmoplantar pustulosis. Presented at the British Society of Investigative Dermatology Meeting, Newcastle, U.K., 7–9 April 2014.
British Journal of Dermatology (2014) 171, pp1546–1549
