The rapid onset of multiple squamous cell ... - Wiley Online Library

Australasian Journal of Dermatology (2012) 53, 57–60

doi: 10.1111/j.1440-0960.2011.00853.x

CASE SERIES

The rapid onset of multiple squamous cell carcinomas in two patients commenced on ustekinumab as treatment of psoriasis ajd_853

57..60

Lauren Young and D Czarnecki Department of Dermatology, Austin Repatriation Medical Centre, Melbourne, Victoria, Australia

ABSTRACT We report the cases of two patients who developed eruptive cutaneous squamous cell carcinomas (SCC) soon after commencement of ustekinumab, as treatment of moderate to severe plaque type psoriasis. Ustekinumab is a human monoclonal antibody with a novel mechanism, selectively targeting the shared p40 subunit of interleukin-12 (IL-12) and IL-23. Its efficacy has been well documented in three large phase-III trials (PHOENIX I, PHEONIX 2, ACCEPT). Safety data on this new biological agent continue to grow. To date, no link between ustekinumab and cutaneous carcinogenesis has been demonstrated and, to our knowledge, these cases are the first of their kind. Importantly, both these patients had independent risk factors for developing non-melanoma skin cancers; however, the specific time correlation with the administration of ustekinumab is of note. Our report suggests that ustekinumab may allow the development of cutaneous carcinomata in predisposed individuals. Key words: biological agent, cutaneous malignancy, phototherapy, psoriasis, squamous cell carcinoma, ustekinumab.

INTRODUCTION Psoriasis is a chronic inflammatory dermatosis affecting 2–3% of people worldwide.1 It may significantly impair these patients’ emotional, social and physical quality of life.2 In patients with extensive psoriasis, a satisfactory treatment response to traditional topical and systemic therapies may

Correspondence: Dr Lauren Young, Department of Dermatology, Austin Repatriation Medical Centre, Heidelberg, Vic. 3053, Australia. Email: [email protected] Lauren Young, MBBS. D Czarnecki, FACD. Submitted 28 July 2011; accepted 30 October 2011.

be difficult to achieve. The effectiveness of new biological agents to treat unremitting disease provides clinicians with more options in improving their patients’ quality of life. Reasonably lengthy follow-up data are now available for the older anti-tissue necrosis factor-alpha biological agents in other indications. For ustekinumab, safety data are now available for up to 4 years.3 No reports similar to those contained herein appear to be documented.

CASE SERIES The first patient reported is a 69-year-old man with a 45-year history of chronic plaque psoriasis. Apart from topical therapy, he has received narrow-band ultraviolet-B therapy (NBUVB), psoralen plus ultraviolet-A therapy (PUVA), methotrexate, acitretin, etanercept and ustekinumab (see Table 1). It is noteworthy that this patient developed over 50 nodular lesions on his lower limbs after 3 months of treatment with etanercept in 2006. Nine lesions were excised, of which two were found to be SCC, and seven found to be keratoacanthomas (KA). The etanercept was ceased, and many other lesions that had been clinically suspicious for SCC or KA regressed spontaneously. Ustekinumab was commenced in May 2010. In September 2010 three rapidly growing tumors emerged on his lower limbs (see Fig. 1). Histology revealed all three lesions to be well differentiated SCC. Ustekinumab was immediately ceased and, as of September 2011, no further tumors have emerged. He is now, once again, taking methotrexate. The second patient, a 63-year-old man, has previously received treatment with NBUVB, PUVA, methotrexate,

Abbreviations: BCC IL KA NBUVB NMSC PUVA SCC TNF-a

© 2012 The Authors Australasian Journal of Dermatology © 2012 The Australasian College of Dermatologists

basal cell carcinoma interleukin keratoacanthoma narrow-band ultraviolet-B therapy non-melanoma skin cancer psoralen plus ultraviolet-A therapy squamous cell carcinoma tissue necrosis factor-alpha

58 Table 1

L Young and D Czarnecki Patients’ characteristics and previous treatment of psoriasis

Age (years) Weight (kg) Ancestry Fitzpatrick skin type Occupation Past history of other cutaneous malignancy

Cutaneous malignancies whilst on ustekinumab Family history of cutaneous malignancy Actinic damage Previous treatment Phototherapy

Methotrexate Acitretin Cyclosporin

Infliximab Etanercept

Patient 1

Patient 2

68 old 75 British III Paint maker This patient developed an eruption of nodular lesions on the lower limbs while receiving etanercept previously. Two SCC and seven KA were excised. Many other clinical KA and SCC regressed after the cessation of the etanercept. Three well-differentiated SCC

63 85 British III Office worker Nil

Nil

Nil

Extensive field areas of actinic keratoses present clinically

Few to no actinic keratoses present clinically

NBUVB PUVA 1996–2001 (with some breaks in therapy) Total of over 500 treatments over many years at various sites Total dose not known Dose: 20 mg weekly Duration: 1987–1996, 2007–2010 Dose: 75 mg daily Duration: 1996–1998 Nil, due to patient’s and treating dermatologist’s preference to avoid cyclosporine’s potential toxicities, particularly its increased risk of carcinogenesis Nil, due to patient preference Dose: 50 mg weekly in two divided doses Duration: 3 months during 2006.

NBUVB PUVA Total of over 500 treatments over many years at various sites Total dose not known Dose: 20–30 mg weekly Duration: approximately 10 years Dose: 75 mg daily Duration: 2 years Nil, due to patient’s and treating dermatologist’s preference to avoid cyclosporine’s potential toxicities, particularly its increased risk of carcinogenesis Nil, due to patient preference Dose: PBS schedule Duration: 18 months of intermittent therapy from 2006–2008. Ceased due to the availability of longer courses of subsidised therapy with efalizumab. Recommenced in May 2011, after cessation of ustekinumab, as etanercept had been efficacious previously. Dose: PBS schedule Duration: 6 months of treatment in 2009. Ceased due to market withdrawal. 6 months of treatment. Ceased in April 2010 due to difficulties with patient compliance. Dose: 45 mg Duration: commenced in May 2010, with doses at weeks 0, 4 and 16. Ceased due to eruptive squamous cell carcinomas. Baseline PASI: 26

Ceased due to the development of multiple SCC and KA. Efalizumab

Nil

Adalimumab

Nil

Ustekinumab

Dose: 45 mg Duration: commenced in May 2010, with doses at weeks 0, 4 and 16. Ceased due to eruptive squamous cell carcinomas. Baseline PASI: 22

Ten well-differentiated SCC

KA, keratoacanthoma; NBUVB (narrow band ultraviolet-B), PASI (psoriasis area and severity index). PBS, pharmaceutical benefits scheme; PUVA (psoralen and ultraviolet-A); SCC, squamous cell carcinoma.

acitretin, etanercept, efalizumab, adalimumab and ustekinumab (see Table 1). Ustekinumab was commenced in May 2010. After the first two doses of ustekinumab, he developed several rapidly growing tumors on the buttocks and upper thighs. Five histologically confirmed SCC were excised. Despite the risk of further skin cancers, with a medical recommendation to cease ustekinumab, the patient requested that ustekinumab be continued because it had cleared his psoriasis. Five further well-differentiated SCC

were subsequently excised. The patient ceased ustekinumab after its third dose and recommenced etanercept. No further SCC have emerged, as at early September 2011.

DISCUSSION Ustekinumab is the first market-approved member of a new biological therapy family targeting interleukin (IL)-12 and IL-23. These heterodimeric cytokines are secreted by


Eruptive SCC with ustekinumab

Figure 1 Patient one’s lower limb, with multiple squamous cell carcinomas apparent after commencing ustekinumab. Also note pre-existing actinic damage and evidence of chronic venous stasis.

Table 2 Number of patients and period of follow up for phase 3 trials using ustekinumab

PHOENIX 13,4 PHOENIX 23,4 ACCEPT3,4

Number of patients

Weeks of follow up

766 1230 903

152 208 64

antigen presenting cells. They are involved in innate and adaptive immune responses and contribute to natural killer cell activation and CD4+ T-cell differentiation and activation.4 The disordered regulation of IL-12 and IL-23 has been associated with immune-mediated disease processes including psoriasis.5 The expression of both cytokines is increased in the plaques of psoriasis, and genetic polymorphisms in the gene encoding the shared p40 subunit common to these cytokines have been demonstrated in patients with psoriasis.6 Ustekinumab may interrupt the disordered regulation of these cytokines. The efficacy of ustekinumab has been demonstrated in three large phase III clinical trials.3,5 Safety data up to 4 years have recently become available, encompassing data collected for 619 patients for a full 4-year period, with a larger group of 2414 patients followed for 6 months or more3 (see Table 2). Commonly reported adverse events (>0.5 per 100 patient years [PY]) for 4 years include nasopharyngitis, upper respiratory tract infection, headache, arthralgia, back pain and influenza.3 Placebocontrolled safety data exist only up to 20 weeks. Rates of serious infection were less common in combined ustekinumab groups than in placebo groups, with no cumulative toxicity demonstrated over time.3 There was some evidence of dose-response, with a slightly higher incidence of serious infection in patients receiving 90 mg of ustekinumab, as opposed to those receiving 45 mg. The incidence of malignancy, other than non-melanoma skin cancer

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(NMSC), was not elevated, with a rate of 0.39 (95% confidence interval [CI] 0.19–0.72) per 100PY in the ustekinumab groups, and 0.44 (95% CI 0.14–1.03) per 100PY in the placebo group.3 With four years of data, 0.97 malignancies (95% CI 0.49–1.74) are documented per 100PY, with no evidence of dose-response.7 Major adverse cardiac events occurred at a rate of 0.44 (95% CI 0.14–1.03) per 100PY up to 4 years’ follow up, which is equivocal to the rate in the placebo group during the controlled period. The overall rate of NMSC was 0.61 (95% CI 0.43–0.83) per 100PY for the combined ustekinumab groups over 4 years, which is below that of 1.13 (95% CI 0.14–4.09) per 100PY for the placebo group during the controlled period, suggesting no cumulative effect.3 However, in the placebo-controlled period, the rates of NMSC were higher in the treatment arm than in the placebo arm, although this was not statistically significant. Of 1319 patients followed up to 2010, 41 developed NMSC, with 34 patients with basal cell carcinoma (BCC) and 10 cases of SCC reported, with an ensuing BCC : SCC ratio of 3 : 1.3 With 44 lesions reported in 41 patients it would seem that there were no cases of multiple eruptive lesions in individual patients, as for the two cases reported herein. Clinical trials are inherently contrasted to external reallife patient groups, secondary to inclusion and exclusion criteria that may be difficult to replicate. Patients included in these phase III trials had a mean age of 46 years. In terms of previous therapy, 66% of them had received ultraviolet light therapy, 57% had been treated with conventional systemic agents and 34% had been exposed to biological agents.3 Active tuberculosis, recent serious infection and malignancies represented exclusion criteria for the phase III studies.4,5 In real-life scenarios, clinicians often manage patients with increased age, an extensive previous treatment history and issues with previous malignancies or serious infections. Experience in these patient groups may be minimal at the time of a drug’s introduction to the market, with safety data for these scenarios obtained through clinical experience, and registries of relevant reportable events. The Therapeutic Goods Administration of Australia provided some detail on five cases of SCC emerging after the commencement of ustekinumab. The cases were reported between November 2010 and August 2011, and are exclusive of the two cases described herein. Unfortunately, minimal detail is available to contextualise these reports, but ustekinumab was recorded as a suspected cause for the SCC in all five cases, with causality deemed to be possible. There have been case reports of the rapid development of multiple KA and SCC after the initiation of other biological agents, namely the anti-tumor necrosis factor-alpha (TNFa) agents, including etanercept and infliximab.8–11 Large trials, though, fail to confirm any clear association between the anti-TNFa agents and cutaneous carcinogenesis.12,13 Of note, most of those patients who did develop NMSC while receiving etanercept or infliximab had a history of treatment with phototherapy. Experimental studies in animal models show that the inhibition of TNFa may actually be protective in impeding tumorigenesis.14,15


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L Young and D Czarnecki

Patients with psoriasis are recognised to carry a higher risk of cutaneous malignancy than the general population. This is felt to be largely secondary to the effects of immunosuppressive and phototherapy treatments used in the control of the disease.7 Cyclosporin, a conventional systemic treatment for psoriasis, has been shown to increase the risk of cutaneous and other, malignancies.16 PUVA has been clearly associated with photodamage and a persisting increased risk of cutaneous malignancy, particularly in patients subsequently exposed to cyclosporine.16 An increased risk of NMSC also exists, at least theoretically, with NBUVB.16 Both patients presented herein possess significant risk factors for cutaneous malignancy, particularly secondary to extended periods of therapy with PUVA. Additionally, patient one had developed eruptive SCC and KA while receiving etanercept in 2006. In both patients multiple lesions arose after two doses of ustekinumab and in both no lesions have arisen subsequent to the drug’s cessation. It is interesting that patient two had not developed malignancy during periods of therapy with different biological agents targeting either CD11a or TNFa. A potential specific mechanism for the tumors’ emergence after ustekinumab therapy can only be postulated. Specific aspects of the anti-IL-12-directed and IL-23-directed immunosuppression secondary to ustekinumab may directly affect innate defence mechanisms against tumorigenesis. The short duration, in both cases presented herein between starting ustekinumab and the onset of multiple SCC implies that perhaps ultraviolet radiation-induced subclinical tumors were present in these patients at the onset of therapy. The immunosuppressive effect of ustekinumab perhaps merely acted to unmask these.

CONCLUSION We thus report the rapid emergence of multiple SCC in two patients treated with ustekinumab for psoriasis. Both patients had pre-existing risk factors for NMSC, which may have contributed a predisposition to the tumors’ emergence. Ustekinumab represents an effective therapeutic option for extensive psoriatic disease and, to date, trials have not demonstrated an increased risk of NMSC in patients receiving this medication. Trial data, though, are reflective of patients without a history of malignancy, and also with a mean age of two decades’ less than the patients described in this series. It may be extrapolated that patients included in such trials have a lower baseline risk for NMSC than those whom clinicians sometimes hope to treat with agents such as ustekinumab. In patients with such risk factors, it may be judicious for clinicians to closely monitor patients for the emergence of NMSC at the commencement

of therapy with ustekinumab. With new biological agents becoming available, an early move to biological therapy may be warranted to lessen the risk of complications of excessive previous phototherapy, particularly PUVA, in patients requiring long-term control of their psoriasis.

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