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Subacute lupus erythematosus during treatment with golimumab for seronegative rheumatoid arthritis AMG Brunasso, W Aberer and C Massone Lupus 2014 23: 201 originally published online 19 December 2013 DOI: 10.1177/0961203313517153 The online version of this article can be found at: http://lup.sagepub.com/content/23/2/201
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CASE REPORT
Subacute lupus erythematosus during treatment with golimumab for seronegative rheumatoid arthritis AMG Brunasso, W Aberer and C Massone Department of Dermatology, Medical University of Graz, Graz, Austria
We report on a 52-year-old woman with a history of severe seronegative rheumatoid arthritis. Several conventional therapies and biological therapy with etanercept and infliximab had been unsuccessful. In 2010 she was given golimumab subcutaneously at a monthly dose of 50 mg. She had a negative ANA titre. After 16 months of uninterrupted therapy and sustained response, she developed skin lesions on the upper trunk, back and upper extremities, which worsened on exposure to the sun. The skin biopsy was compatible with subacute lupus erythematosus. Laboratory findings included an ANA titre 1:640, negative anti-Ro/SSA and anti-DNA antibodies. Topical corticosteroid therapy proved inadequate. The patient’s condition improved only after discontinuation of golimumab. The causal relationship between subacute cutaneous lupus erythematosus and golimumab is not dose-related and occurs with some delay (a typical feature of immunological adverse reactions). The association is likely, but not confirmed (because re-challenge was not performed). However, a clear improvement was noted after withdrawal. Based on this case, we hypothesized the aetiological role of golimumab-associated immunogenicity. TNF-a antagonist-induced lupus-like syndrome (TAILS) is a well-known side effect of this class of substances. The British Society of Rheumatology recommends discontinuation of the causal anti-TNF-a treatment in patients with TAILS. Lupus (2014) 23, 201–203. Key words: Golimumab; TNF-a; lupus erythematosus; rheumatoid arthritis; autoimmunity; infliximab; etanercept; adalimumab
Case report A 52-year-old woman was referred to a local dermatologist because of skin lesions after sun exposure. She had a six-year history of severe seronegative rheumatoid arthritis associated with joint swelling. She had responded poorly to several therapies, including methotrexate, leflunomide and cortisone. Screening tests performed in December 2008, including ANA and anti-DNA antibodies, were negative. The patient was given etanercept for 12 weeks and subsequently infliximab for 10 months, but did not respond well to these. Golimumab at a dose of 50 mg subcutaneously (s.c.) monthly with negative ANA titres was started in May 2010. After 16 months of Correspondence to: Alexandra Maria Giovanna Brunasso, Department of Dermatology, Medical University of Graz, Auenbruggerplatz 8, A-8036 Graz, Austria. Email: [email protected] Received 8 August 2013; accepted 13 November 2013
uninterrupted treatment and sustained response, she developed persistent erythematous violaceous macules, papules associated with telangiectasia, and diffuse erythema on the upper trunk, back and upper extremities. The skin lesions were aggravated by sun exposure (Figure 1) and persisted for four weeks. A skin biopsy showed interface dermatitis with necrotic keratinocytes, indicative of subacute lupus erythematosus (Figure 2). Topical mometasone furoate cream (applied twice daily) was started. Three weeks later the patient was referred to our outpatient clinic for clinical and pathological correlation. She was still receiving golimumab and topical mometasone furoate cream once daily, but was not taking any other drug. At this time we found pale and poorly defined erythematous macules on the arms, back and de´collete´. She had no mucosal lesions or arthralgia. The general physical examination was unremarkable. Relevant laboratory findings included an ANA titre of 1:640 (nucleolar pattern), negative antiRo/SSA and anti-DNA antibodies. The following
! The Author(s), 2013. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav
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10.1177/0961203313517153
Subacute lupus triggered by golimumab therapy AMG Brunasso et al.
202
for four weeks) and photoprotection were continued. Seven weeks after golimumab had been discontinued, the patient was free of cutaneous lesions, but her joint symptoms reappeared. Methotrexate 15 mg weekly plus prednisone 12.5 mg/day were started. The ANA titre had reduced to 1:320 at three months and 1:160 at six months after withdrawal. This level was retained at the last control investigation in December 2012, when the patient was free of skin symptoms even after unprotected sun exposure in the summer.
Discussion
Figure 1 Erythematous-violaceous macules and papules associated with telangiectasia and diffuse erythema on the back. The site of the biopsy is marked on the right middle back.
Figure 2 Superficial and deep, perivascular and interstitial lymphohistiocytic infiltrate with interface dermatitis and necrotic keratinocytes (hematoxylin and eosin; original magnification 100).
were normal: erythrocyte sedimentation rate, CRP, creatinine, urinalysis, complement levels and blood cell count. Anti-histone antibody testing was not performed. As drug-induced subacute cutaneous lupus erythematosus (SCLE) was established, the treatment with golimumab was discontinued while the mometasone furoate cream (applied once daily
This is the first reported case of new onset of SCLE during treatment with golimumab. A possible causal relationship between golimumab and the onset of SCLE is supported by the temporal relationship between initiation of the drug and the onset of the cutaneous lesions, the negative autoimmune status of our patient at baseline, the serological conversion of ANA titres, the improvement of cutaneous manifestations after withdrawal, the reduction of ANA titres after drug suspension, the absence of other potential trigger factors and the healing of SCLE at 19 months after withdrawal despite unprotected sun exposure. An alternative explanation for the skin lesions associated with chronic seronegative rheumatoid arthritis would be systemic lupus erythematosus (SLE), but our patient fulfilled just three SLE criteria of the American College of Rheumatology (ACR). Even seven years after the initial diagnosis of chronic polyarthritis, the patient fulfilled too few ACR criteria for SLE.1 In the present case, the causal relationship between SCLE and golimumab was not doserelated and occurred in delayed fashion, a typical feature of immunological adverse reactions.2,3 The association may be considered likely (seven points on the Naranjo scale)4 but not confirmed because re-challenge was not performed. However, a clear improvement was observed after withdrawal.2,3 The time to the onset of lupus symptoms (cutaneous or systemic) after anti-TNF-a treatment has been reported to range between 10 days and 54 months (mean 11.6 months for cutaneous lupus lesions); our findings concurred with these data.5,6 The majority of reports concerned with TNF-a antagonist-induced lupus-like syndrome (TAILS) are focused on patients receiving either etanercept or infliximab.5–7 To date, only one patient was
Lupus Downloaded from lup.sagepub.com at University of Hong Kong Libraries on November 13, 2014
Subacute lupus triggered by golimumab therapy AMG Brunasso et al.
203
reported to experience an exacerbation of SCLE after golimumab.8 As regards the grade of certainty, it was considered unlikely that the event was related to golimumab because the condition did not improve after discontinuation of golimumab. Besides, other drugs such as nisoldipine or diltiazem provide a plausible explanation for the skin symptoms, which improved after discontinuation of diltiazem.2,3,5–8 Our patient had an ANA titre of 1:640 (nucleolar pattern), negative anti-Ro/SSA and anti-DNA antibodies. Anti-histone antibodies are usually reported to be positive in patients with druginduced lupus (DILS). However, they are less commonly observed in individuals with TAILS. Specifically, only 17–57% of patients with TAILS had positive anti-histone antibodies compared with the positive detection rate of 95% in patients with DILS due to other medications. Tested antiextractable nuclear antigen antibodies include anti-Smith, anti-SSA/Ro, anti-SSB/La and antiRNP. Between 42% and 53% of patients test positive for at least one of these autoantibodies. In a review of 72 patients with TAILS, 12% reported the presence of anti-Ro/La, 10% anti-Smith and 7% anti-RNP antibodies.9,10 As confirmed in our patient, DILS and TAILS cannot be distinguished from conventional (non-drug-induced) SLE by clinical features alone.11 The pathogenesis of TAILS has not been clearly established yet. Several hypotheses have been proposed to explain the onset of immunogenicity and TAILS, including the accumulation of apoptotic cells, activation of polyclonal B lymphocytes and inhibition of the cytotoxic T-lymphocyte response.12 The British Society of Rheumatology recommends discontinuation of the causative anti-TNFa treatment in patients with TAILS.13
Conflict of interest The authors have no conflict of interest.
References 1 Guidelines for referral and management of systemic lupus erythematosus in adults. American College of Rheumatology Ad Hoc Committee on Systemic Lupus Erythematosus Guidelines. Arthritis Rheum 1999; 42: 1785–1796. 2 Edwards IR, Aronson JK. Adverse drug reactions: Definitions, diagnosis, and management. Lancet 2000; 356: 1255–1259. 3 Nebeker JR, Barach P, Samore MH. Clarifying adverse drug events: a clinician’s guide to terminology, documentation, and reporting. Ann Intern Med 2004; 140: 795–801. 4 Naranjo Algorithm, 16 June 2003. Available at: http://qmweb. dads.state.tx.us/MedSim/Naranjo.htm (accessed 16 October 2013). 5 Williams VL, Cohen PR. TNF alpha antagonist-induced lupus-like syndrome: Report and review of the literature with implications for treatment with alternative TNF alpha antagonists. Int J Dermatol 2011; 50: 619–625. 6 De Bandt M, Sibilia J, Le Loe¨t X, et al. Systemic lupus erythematosus induced by anti-tumour necrosis factor alpha therapy: A French national survey. Arthritis Res Ther 2005; 7: R545–R551. 7 Costa MF, Said NR, Zimmermann B. Drug-induced lupus due to anti-tumor necrosis factor alpha agents. Semin Arthritis Rheum 2008; 37: 381–387. 8 Wilkerson E, Hazey MA, Bahrami S, Callen JP. Golimumabexacerbated subacute cutaneous lupus erythematosus. Arch Dermatol 2012; 148: 1186–1190. 9 Ramos-Casals M, Roberto-Perez-Alvarez, Diaz-Lagares C, Cuadrado MJ, Khamashta MA; BIOGEAS Study Group. Autoimmune diseases induced by biological agents: A doubleedged sword? Autoimmun Rev 2010; 9: 188–1893. 10 Williams VL, Cohen PR. TNF alpha antagonist-induced lupus-like syndrome: Report and review of the literature with implications for treatment with alternative TNF alpha antagonists. Int J Dermatol 2011; 50: 619–625. 11 Lowe G, Henderson CL, Grau RH, Hansen CB, Sontheimer RD. A systematic review of drug-induced subacute cutaneous lupus erythematosus. Br J Dermatol 2011; 164: 465–472. 12 Brunasso AM, Puntoni M, Salvini C, Delfino, et al. Tolerability and safety of biological therapies for psoriasis in daily clinical practice: A study of 103 Italian patients. Acta Derm Venereol 2011; 91: 44–49. 13 Ledingham J, Deighton C; British Society for Rheumatology Standards, Guidelines and Audit Working Group. Update on the British Society for Rheumatology guidelines for prescribing TNFalpha blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001). Rheumatology (Oxford) 2005; 44: 157–163.
Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors.
Lupus Downloaded from lup.sagepub.com at University of Hong Kong Libraries on November 13, 2014
http://lup.sagepub.com/
Subacute lupus erythematosus during treatment with golimumab for seronegative rheumatoid arthritis AMG Brunasso, W Aberer and C Massone Lupus 2014 23: 201 originally published online 19 December 2013 DOI: 10.1177/0961203313517153 The online version of this article can be found at: http://lup.sagepub.com/content/23/2/201
Published by: http://www.sagepublications.com
Additional services and information for Lupus can be found at: Email Alerts: http://lup.sagepub.com/cgi/alerts Subscriptions: http://lup.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
>> Version of Record - Jan 13, 2014 OnlineFirst Version of Record - Dec 19, 2013 What is This?
Downloaded from lup.sagepub.com at University of Hong Kong Libraries on November 13, 2014
Lupus (2014) 23, 201–203 http://lup.sagepub.com
CASE REPORT
Subacute lupus erythematosus during treatment with golimumab for seronegative rheumatoid arthritis AMG Brunasso, W Aberer and C Massone Department of Dermatology, Medical University of Graz, Graz, Austria
We report on a 52-year-old woman with a history of severe seronegative rheumatoid arthritis. Several conventional therapies and biological therapy with etanercept and infliximab had been unsuccessful. In 2010 she was given golimumab subcutaneously at a monthly dose of 50 mg. She had a negative ANA titre. After 16 months of uninterrupted therapy and sustained response, she developed skin lesions on the upper trunk, back and upper extremities, which worsened on exposure to the sun. The skin biopsy was compatible with subacute lupus erythematosus. Laboratory findings included an ANA titre 1:640, negative anti-Ro/SSA and anti-DNA antibodies. Topical corticosteroid therapy proved inadequate. The patient’s condition improved only after discontinuation of golimumab. The causal relationship between subacute cutaneous lupus erythematosus and golimumab is not dose-related and occurs with some delay (a typical feature of immunological adverse reactions). The association is likely, but not confirmed (because re-challenge was not performed). However, a clear improvement was noted after withdrawal. Based on this case, we hypothesized the aetiological role of golimumab-associated immunogenicity. TNF-a antagonist-induced lupus-like syndrome (TAILS) is a well-known side effect of this class of substances. The British Society of Rheumatology recommends discontinuation of the causal anti-TNF-a treatment in patients with TAILS. Lupus (2014) 23, 201–203. Key words: Golimumab; TNF-a; lupus erythematosus; rheumatoid arthritis; autoimmunity; infliximab; etanercept; adalimumab
Case report A 52-year-old woman was referred to a local dermatologist because of skin lesions after sun exposure. She had a six-year history of severe seronegative rheumatoid arthritis associated with joint swelling. She had responded poorly to several therapies, including methotrexate, leflunomide and cortisone. Screening tests performed in December 2008, including ANA and anti-DNA antibodies, were negative. The patient was given etanercept for 12 weeks and subsequently infliximab for 10 months, but did not respond well to these. Golimumab at a dose of 50 mg subcutaneously (s.c.) monthly with negative ANA titres was started in May 2010. After 16 months of Correspondence to: Alexandra Maria Giovanna Brunasso, Department of Dermatology, Medical University of Graz, Auenbruggerplatz 8, A-8036 Graz, Austria. Email: [email protected] Received 8 August 2013; accepted 13 November 2013
uninterrupted treatment and sustained response, she developed persistent erythematous violaceous macules, papules associated with telangiectasia, and diffuse erythema on the upper trunk, back and upper extremities. The skin lesions were aggravated by sun exposure (Figure 1) and persisted for four weeks. A skin biopsy showed interface dermatitis with necrotic keratinocytes, indicative of subacute lupus erythematosus (Figure 2). Topical mometasone furoate cream (applied twice daily) was started. Three weeks later the patient was referred to our outpatient clinic for clinical and pathological correlation. She was still receiving golimumab and topical mometasone furoate cream once daily, but was not taking any other drug. At this time we found pale and poorly defined erythematous macules on the arms, back and de´collete´. She had no mucosal lesions or arthralgia. The general physical examination was unremarkable. Relevant laboratory findings included an ANA titre of 1:640 (nucleolar pattern), negative antiRo/SSA and anti-DNA antibodies. The following
! The Author(s), 2013. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav
Downloaded from lup.sagepub.com at University of Hong Kong Libraries on November 13, 2014
10.1177/0961203313517153
Subacute lupus triggered by golimumab therapy AMG Brunasso et al.
202
for four weeks) and photoprotection were continued. Seven weeks after golimumab had been discontinued, the patient was free of cutaneous lesions, but her joint symptoms reappeared. Methotrexate 15 mg weekly plus prednisone 12.5 mg/day were started. The ANA titre had reduced to 1:320 at three months and 1:160 at six months after withdrawal. This level was retained at the last control investigation in December 2012, when the patient was free of skin symptoms even after unprotected sun exposure in the summer.
Discussion
Figure 1 Erythematous-violaceous macules and papules associated with telangiectasia and diffuse erythema on the back. The site of the biopsy is marked on the right middle back.
Figure 2 Superficial and deep, perivascular and interstitial lymphohistiocytic infiltrate with interface dermatitis and necrotic keratinocytes (hematoxylin and eosin; original magnification 100).
were normal: erythrocyte sedimentation rate, CRP, creatinine, urinalysis, complement levels and blood cell count. Anti-histone antibody testing was not performed. As drug-induced subacute cutaneous lupus erythematosus (SCLE) was established, the treatment with golimumab was discontinued while the mometasone furoate cream (applied once daily
This is the first reported case of new onset of SCLE during treatment with golimumab. A possible causal relationship between golimumab and the onset of SCLE is supported by the temporal relationship between initiation of the drug and the onset of the cutaneous lesions, the negative autoimmune status of our patient at baseline, the serological conversion of ANA titres, the improvement of cutaneous manifestations after withdrawal, the reduction of ANA titres after drug suspension, the absence of other potential trigger factors and the healing of SCLE at 19 months after withdrawal despite unprotected sun exposure. An alternative explanation for the skin lesions associated with chronic seronegative rheumatoid arthritis would be systemic lupus erythematosus (SLE), but our patient fulfilled just three SLE criteria of the American College of Rheumatology (ACR). Even seven years after the initial diagnosis of chronic polyarthritis, the patient fulfilled too few ACR criteria for SLE.1 In the present case, the causal relationship between SCLE and golimumab was not doserelated and occurred in delayed fashion, a typical feature of immunological adverse reactions.2,3 The association may be considered likely (seven points on the Naranjo scale)4 but not confirmed because re-challenge was not performed. However, a clear improvement was observed after withdrawal.2,3 The time to the onset of lupus symptoms (cutaneous or systemic) after anti-TNF-a treatment has been reported to range between 10 days and 54 months (mean 11.6 months for cutaneous lupus lesions); our findings concurred with these data.5,6 The majority of reports concerned with TNF-a antagonist-induced lupus-like syndrome (TAILS) are focused on patients receiving either etanercept or infliximab.5–7 To date, only one patient was
Lupus Downloaded from lup.sagepub.com at University of Hong Kong Libraries on November 13, 2014
Subacute lupus triggered by golimumab therapy AMG Brunasso et al.
203
reported to experience an exacerbation of SCLE after golimumab.8 As regards the grade of certainty, it was considered unlikely that the event was related to golimumab because the condition did not improve after discontinuation of golimumab. Besides, other drugs such as nisoldipine or diltiazem provide a plausible explanation for the skin symptoms, which improved after discontinuation of diltiazem.2,3,5–8 Our patient had an ANA titre of 1:640 (nucleolar pattern), negative anti-Ro/SSA and anti-DNA antibodies. Anti-histone antibodies are usually reported to be positive in patients with druginduced lupus (DILS). However, they are less commonly observed in individuals with TAILS. Specifically, only 17–57% of patients with TAILS had positive anti-histone antibodies compared with the positive detection rate of 95% in patients with DILS due to other medications. Tested antiextractable nuclear antigen antibodies include anti-Smith, anti-SSA/Ro, anti-SSB/La and antiRNP. Between 42% and 53% of patients test positive for at least one of these autoantibodies. In a review of 72 patients with TAILS, 12% reported the presence of anti-Ro/La, 10% anti-Smith and 7% anti-RNP antibodies.9,10 As confirmed in our patient, DILS and TAILS cannot be distinguished from conventional (non-drug-induced) SLE by clinical features alone.11 The pathogenesis of TAILS has not been clearly established yet. Several hypotheses have been proposed to explain the onset of immunogenicity and TAILS, including the accumulation of apoptotic cells, activation of polyclonal B lymphocytes and inhibition of the cytotoxic T-lymphocyte response.12 The British Society of Rheumatology recommends discontinuation of the causative anti-TNFa treatment in patients with TAILS.13
Conflict of interest The authors have no conflict of interest.
References 1 Guidelines for referral and management of systemic lupus erythematosus in adults. American College of Rheumatology Ad Hoc Committee on Systemic Lupus Erythematosus Guidelines. Arthritis Rheum 1999; 42: 1785–1796. 2 Edwards IR, Aronson JK. Adverse drug reactions: Definitions, diagnosis, and management. Lancet 2000; 356: 1255–1259. 3 Nebeker JR, Barach P, Samore MH. Clarifying adverse drug events: a clinician’s guide to terminology, documentation, and reporting. Ann Intern Med 2004; 140: 795–801. 4 Naranjo Algorithm, 16 June 2003. Available at: http://qmweb. dads.state.tx.us/MedSim/Naranjo.htm (accessed 16 October 2013). 5 Williams VL, Cohen PR. TNF alpha antagonist-induced lupus-like syndrome: Report and review of the literature with implications for treatment with alternative TNF alpha antagonists. Int J Dermatol 2011; 50: 619–625. 6 De Bandt M, Sibilia J, Le Loe¨t X, et al. Systemic lupus erythematosus induced by anti-tumour necrosis factor alpha therapy: A French national survey. Arthritis Res Ther 2005; 7: R545–R551. 7 Costa MF, Said NR, Zimmermann B. Drug-induced lupus due to anti-tumor necrosis factor alpha agents. Semin Arthritis Rheum 2008; 37: 381–387. 8 Wilkerson E, Hazey MA, Bahrami S, Callen JP. Golimumabexacerbated subacute cutaneous lupus erythematosus. Arch Dermatol 2012; 148: 1186–1190. 9 Ramos-Casals M, Roberto-Perez-Alvarez, Diaz-Lagares C, Cuadrado MJ, Khamashta MA; BIOGEAS Study Group. Autoimmune diseases induced by biological agents: A doubleedged sword? Autoimmun Rev 2010; 9: 188–1893. 10 Williams VL, Cohen PR. TNF alpha antagonist-induced lupus-like syndrome: Report and review of the literature with implications for treatment with alternative TNF alpha antagonists. Int J Dermatol 2011; 50: 619–625. 11 Lowe G, Henderson CL, Grau RH, Hansen CB, Sontheimer RD. A systematic review of drug-induced subacute cutaneous lupus erythematosus. Br J Dermatol 2011; 164: 465–472. 12 Brunasso AM, Puntoni M, Salvini C, Delfino, et al. Tolerability and safety of biological therapies for psoriasis in daily clinical practice: A study of 103 Italian patients. Acta Derm Venereol 2011; 91: 44–49. 13 Ledingham J, Deighton C; British Society for Rheumatology Standards, Guidelines and Audit Working Group. Update on the British Society for Rheumatology guidelines for prescribing TNFalpha blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001). Rheumatology (Oxford) 2005; 44: 157–163.
Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors.
Lupus Downloaded from lup.sagepub.com at University of Hong Kong Libraries on November 13, 2014
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