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Table of Contents
CASE REPORT
Year : 2019  |  Volume : 37  |  Issue : 3  |  Page : 157-161

Cyclosporine but not acitretin for psoriasis exacerbation and general Myalgia induced by Pembrolizumab in a patient with advanced esophageal cancer


Department of Dermatology, Chang Gung Memorial Hospital, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

Date of Submission21-Mar-2018
Date of Acceptance24-Dec-2018
Date of Web Publication23-May-2019

Correspondence Address:
Chih-Hung Lee
Department of Dermatology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, No. 123, Ta-Pei Road, Niao-Sung District, Kaohsiung 83301
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ds.ds_45_18

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  Abstract 


Pembrolizumab is a checkpoint inhibitor to treat cancers by boosting overall immunity with T-cell disinhibition. However, this nonselectively enhanced immunity could trigger de novo or aggravate autoimmune diseases. Only a few reports showed exacerbation of psoriasis after pembrolizumab. We reported a psoriatic patient with esophageal cancer experiencing exacerbation of psoriasis and general myalgia soon after pembrolizumab induction. These adverse effects failed initially to acitretin but responded successfully and durably to cyclosporine subsequently, suggesting immune targeting regimen could be a treatment choice for pembrolizumab-induced psoriasis. We briefly reviewed and discussed the limited numbers of reports regarding this scenario.

Keywords: Anti-programmed cell death protein-1, cyclosporine, pembrolizumab, psoriasis exacerbation, recurrent esophageal cancer


How to cite this article:
Tseng YJ, Lee CH. Cyclosporine but not acitretin for psoriasis exacerbation and general Myalgia induced by Pembrolizumab in a patient with advanced esophageal cancer. Dermatol Sin 2019;37:157-61

How to cite this URL:
Tseng YJ, Lee CH. Cyclosporine but not acitretin for psoriasis exacerbation and general Myalgia induced by Pembrolizumab in a patient with advanced esophageal cancer. Dermatol Sin [serial online] 2019 [cited 2019 Dec 16];37:157-61. Available from: http://www.dermsinica.org/text.asp?2019/37/3/157/258941




  Introduction Top


Pembrolizumab belongs to a subclass of immune checkpoint inhibitor that blocks the action of programmed cell death protein-1 (PD-1).[1] For its ability to lift the brakes of immune responses and to enhance anti-tumor responses, pembrolizumab is indicated in patients with several cancers, including unresectable or metastatic melanoma, nonsmall cell lung cancer, head-and-neck squamous cell carcinoma, urothelial carcinoma, gastric cancer, and microsatellite instability-high cancer by food and drug administration of the U. S. Pembrolizumab suppresses tumor formation by inhibiting negative regulatory function of immune systems and activating T-cell activity against tumor cells.[2] Due to its general enhancement of immune responses, pembrolizumab has been reported to induce certain immune-related cutaneous adverse effects, including lichenoid skin reactions, eczema, and vitiligo in patients without preexisting autoimmune diseases.[3] However, all clinical trials of checkpoint inhibitors to date excluded patients with preexisting psoriasis or autoimmune disorders.[4] A multi-centered study enrolled 52 patients with preexisting autoimmune disorders (AD) and found 38% of patients suffered from the flare of immune-related adverse effects (irAE) after receiving anti-PD1 therapy.[5] However, only limited reports showed the patients with preexisting psoriasis deteriorated after treatment with pembrolizumab. Herein, we reported a patient with preexisting psoriasis vulgaris receiving pembrolizumab experienced the acute exacerbation of psoriasis accompanied with intense myalgia, both of which are responsive to cyclosporine.


  Case Report Top


A 59-year-old male has suffered from esophageal squamous cell carcinoma, T3N2M0, stage IIIB, in the past 2 years. Initially, he underwent six times of concurrent chemoradiotherapy with platinum and 5-fluorouracil (5-FU) with partial remission. However, the tumor recurred several months later and the salvage esophagectomy was performed. After the surgery, he received three times of adjuvant concurrent chemoradiotherapy with Taxotere, cisplatin, and 5-FU, which ended last year (2015) with a complete clinical remission. For his skin, he also has chronic plaque-type psoriasis vulgaris for over 10 years with stable control by oral acitretin 25 mg/day and topical steroids.

He received regular follow-up in oncology clinic for his esophageal cancer until 1 month ago, when the annual positron emission tomography with computed tomography (CT) revealed new tumor growth over left adrenal gland. After discussing with the oncologist, he decided to receive palliative immunotherapy using out-of-pocket pembrolizumab at a dose of 100 mg (2 mg/kg) via intravenous infusion, taking consideration that his performance status was good and the laboratory data reported only mild normocytic anemia (hemoglobin 11.6 g/dL), mildly elevated alkaline phosphate (103 U/L, normal limit: 28–94 U/L), the normal coagulation function, and renal function.

Three days after receiving the first dose of pembrolizumab, he developed painful and generalized erythematous confluent scaly plaques and patches, swelling at distal limbs, and focal erosions over four extremities, abdomen, and back. Severe painful acrodermatitis continua of Hallopeau-like lesions developed at all distal phalanx, causing huge burden both physically and psychologically. The Psoriasis Area Severity Index (PASI) score was 29.9 when he visited our clinic. He also developed severe arthralgia and myalgia over distal extremities [Figure 1]. Neither fever nor oral ulcers were accompanied. No significant new medication or culprit drugs except pembrolizumab were noticed. Under the initial impression of psoriasis exacerbation, skin biopsy was performed on the erythematous plaque at his left lower leg. Histopathology revealed psoriasiform acanthosis of the epidermis, mounds of parakeratosis with neutrophils infiltrate, and moderate lymphocytic infiltrate at upper dermis, all of which indicated the diagnosis of psoriasis vulgaris [Figure 1]. Microscopically, drug eruption can be ruled out because that there was neither basal vacuolated degeneration nor epidermal dyskeratosis.
Figure 1: Diffuse erythematous scaly papuloplaques on trunk and extremities. There were swollen joints at distal limbs (the left lower part and the middle part). Histopathology revealed psoriasiform acanthosis, mounds of parakeratosis, Munro's microabscess, and dense dermal lymphocytic infiltration (the right part, H and E, ×100/×200/×400 from the top)

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For his previous history of favorable response to acitretin, we used oral acitretin 50 mg/day and potent topical steroid (Dermovate® ointment) 10 days after pembrolizumab infusion. However, he developed progressive and severe pruritus with erythema 1 week after oral acitretin, and he could not tolerate those symptoms. Therefore, we replaced acitretin to cyclosporine 200 mg/day. The symptoms started to improve several days after the treatment of cyclosporine. His skin lesions continued to improve 2 months later, and the PASI score decreased to less than 5. He continued to use cyclosporine for the following 5 months to maintain the therapeutic effects of psoriasis until his serum creatinine level elevated from 1.23 mg/dL to 2.01 mg/dL during the cyclosporine treatment. Owing to the experience of exacerbation of psoriasis, the patient declined any further use of pembrolizumab. He did not receive any further treatment thereafter until a new tumor developed at the posterior pharyngeal wall by regular CT. He received radiotherapy for the tumor control. As for the left adrenal tumor, the follow-up CT revealed a progressive regression 2 months after immunotherapy and in fact, its size was stable after 6 months of follow-up till now.


  Discussion Top


In patients with head-and-neck squamous cell carcinoma (HNSCC), pembrolizumab is indicated for patients with recurrent or metastatic HNSCC, who has progressive disease or fails to the conventional platinum-containing chemotherapy. As a prototypic drug for the immune checkpoint inhibitor, although anti-PD1 is generally considered to be safer than anti-cytotoxic T-lymphocyte-associated protein-4, which is another checkpoint inhibitor for managing advanced malignancies, the adverse effects of anti-PD-1 are still reported in various clinical settings.[3] However, recent data from clinical trials always excluded patients with preexisting autoimmune diseases. Only limited reports demonstrated patients with preexisting autoimmune diseases deteriorating after treatment with pembrolizumab.[4],[5],[6] Moreover in real-world practices, various irAE effects, such as vitiligo, bullous pemphigoid, autoimmune diabetes, and autoimmune thyroid diseases, occurred even in patients without underlying autoimmune diseases after using anti-PD1.[5],[7],[8],[9]

Regardless of the underlying diseases, eczema, lichenoid reaction, and vitiligo are the three most common cutaneous irAE after using immunotherapy, accounting for 25% of patients in the first 10 months.[3] For patients with preexisting autoimmune diseases, the first reported one is a 75-year-old man, with a history of stable-controlled myasthenia gravis (MG), received pembrolizumab 2 mg/kg every 3 weeks due to metastatic BRAF-negative melanoma. After two doses of pembrolizumab, symptoms of MG worsened with progressive diplopia, ptosis, and respiratory distress. Despite the cessation of anti-PD1 and serial rescue treatments such as plasma exchange, intravenous immunoglobulin, and rituximab, the patient passed away 1 month later due to infection.[4] Another study in 2017 enrolled 52 patients receiving anti-PD1 with underlying various AD, such as rheumatic arthritis, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, and psoriasis. Among them, 38% of the patients had flares of preexisting AD at a median interval of 38 days after the initiation of anti-PD1 antibody, and most of the AD subtypes are rheumatologic and dermatologic (52% and 38%, respectively).[5]

Psoriasis is a chronic inflammatory disorder mediated by T-lymphocytes, dendritic cells, and the complex immune responses. The mechanism of deterioration of psoriasis after using pembrolizumab may correlate with the hyperactive T-cell function induced by pembrolizumab. A recent study by Bonigen et al. included 21 patients with anti-PD1-induced psoriasis.[6] About 30% of patients requiring oral acitretin in additional to conventional topical medications; nearly 4.8% of patients were stable after phototherapy. 90.5% of the patients improved after the treatments, although none of them used cyclosporine for the exacerbated psoriasis.[6] The majority of the patients would go on with anti-PD1 therapy after rescuing management, whereas 19% of them had to stop the anti-PD1 treatment due to intolerance.[6]

Besides, there were limited numbers of case reports reported the skin manifestations in psoriatic patients receiving anti-PD-1, and we summarized these case reports from 2016 to 2017 in [Table 1]. Twenty-eight patients received anti-PD1 with an average age of 65.9 years old and the underlying advanced malignancies including lung cancer, urothelial carcinoma, and squamous cell carcinoma. Before anti-PD1 therapy, 19 patients had a history of psoriasis; two patients had a family history of psoriasis without personal skin lesions; seven patients did not have psoriasis history at the beginning of anti-PD1 therapy. The interval between the initiation of anti-PD1/PDL1 to the flare of psoriasis ranged significantly, from several days to several months. The most common type of anti-PD1/PDL1-induced flare of psoriasis is the plaque type, followed by guttate psoriasis, palmoplantar psoriasis, psoriatic arthritis, and erythroderma. Among the 28 patients, 26 (93%) patients were improved after conventional psoriasis treatment, including topical steroid, narrow-band ultraviolet B phototherapy, oral acitretin, and oral MTX. Twenty-four patients (85.7%) of the patients could continue the immunotherapy with topical medications along with systemic acitretin (n = 8) and methotrexate (n = 1).
Table 1: Worsening of psoriasis vulgaris after anti-programmed cell death protein-1/programmed death-ligand 1

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In this case of PD-1 associated psoriasis, we introduced acitretin initially. However, due to the progressive pruritus, erythema, myalgia, and weakness by acitretin, we replaced it with cyclosporine. Most reported cases of PD-1 associated psoriasis showed a rather good response to acitretin; however, none of them received cyclosporin treatment. The reason why the patient of PD-1 associated psoriasis exacerbation had the discrepancy regarding to the treatment responses to acitretin is not clear; however, the concurrent worsening of the skin lesions with the intolerable myalgia and weakness, in this case, suggested a more systemic immune responses (i.e., irAE) rather than simple skin exacerbation in the previously reported cases. The impact of cyclosporine on the cancer progression is controversial. In an animal study, there was no increased risk of malignancies with cyclosporine at a dose of up to 8 mg/kg/day.[10],[11] Cyclosporine is widely used for the long-term immunosuppressant in transplant patients. However, only skin squamous cell carcinomas but not other internal malignancies were associated with the high dose and long-term use of cyclosporine.[12],[13] Phototherapy is not feasible for this patient because he lives in Penghu, far from the Main island of Taiwan, and he had difficulty visiting the medical facility frequently. Therefore, with appropriate monitoring, cyclosporine could be useful in managing immunotherapy-exacerbated psoriasis.

It was proposed that the severity of the flared psoriasis might be proportional to the tumor response to anti-PD-1.[14],[15] The role of dermatologist in the scenario is to help manage the exacerbation of cutaneous irAE to continue the anti-PD1 treatment.


  Conclusion Top


Pembrolizumab is an uprising drug for late-stage or unresectable cancer, and it may be the last hope for these end-stage patients at this point in current science. The cutaneous adverse effects mainly result from its enhancement of immune functions which leads to the exacerbation of previous immune-related diseases in susceptible patients. We reported a patient with metastatic esophageal cancer and stable status of psoriasis vulgaris, who experienced psoriasis exacerbation, and myalgia 3 days after a single dose of pembrolizumab. The symptoms worsened and were intolerable after acitretin treatment, but they improved soon after its replacement with cyclosporine. The exact mechanism, predicting factors for the onset and severity of irAE, and what appropriate treatment is in patients with psoriasis receiving pembrolizumab remain undefined. More data and clinical experiences are required to provide more compelling information for the patient receiving immunotherapy with anti-PD-1.[16]

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Kumar V, Chaudhary N, Garg M, Floudas CS, Soni P, Chandra AB, et al. Corrigendum: Current diagnosis and management of immune related adverse events (irAEs) induced by immune checkpoint inhibitor therapy. Front Pharmacol 2017;8:311.  Back to cited text no. 1
    
2.
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443-54.  Back to cited text no. 2
    
3.
Hwang SJ, Carlos G, Wakade D, Byth K, Kong BY, Chou S, et al. Cutaneous adverse events (AEs) of anti-programmed cell death (PD)-1 therapy in patients with metastatic melanoma: A single-institution cohort. J Am Acad Dermatol 2016;74:455-610.  Back to cited text no. 3
    
4.
Phadke SD, Ghabour R, Swick BL, Swenson A, Milhem M, Zakharia Y, et al. Pembrolizumab therapy triggering an exacerbation of preexisting autoimmune disease: A report of 2 patient cases. J Investig Med High Impact Case Rep 2016;4:2324709616674316.  Back to cited text no. 4
    
5.
Menzies AM, Johnson DB, Ramanujam S, Atkinson VG, Wong AN, Park JJ, et al. Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Ann Oncol 2017;28:368-76.  Back to cited text no. 5
    
6.
Bonigen J, Raynaud-Donzel C, Hureaux J, Kramkimel N, Blom A, Jeudy G, et al. Anti-PD1-induced psoriasis: A study of 21 patients. J Eur Acad Dermatol Venereol 2017;31:e254-7.  Back to cited text no. 6
    
7.
Hua C, Boussemart L, Mateus C, Routier E, Boutros C, Cazenave H, et al. Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol 2016;152:45-51.  Back to cited text no. 7
    
8.
Carlos G, Anforth R, Chou S, Clements A, Fernandez-Peñas P. A case of bullous pemphigoid in a patient with metastatic melanoma treated with pembrolizumab. Melanoma Res 2015;25:265-8.  Back to cited text no. 8
    
9.
Martin-Liberal J, Furness AJ, Joshi K, Peggs KS, Quezada SA, Larkin J, et al. Anti-programmed cell death-1 therapy and insulin-dependent diabetes: A case report. Cancer Immunol Immunother 2015;64:765-7.  Back to cited text no. 9
    
10.
Barle EL, Winkler GC, Ulrich P, Perino C, Kuster M, Probst A, et al. Cancer risk of immunosuppressants in manufacturing. Regul Toxicol Pharmacol 2014;70:122-4.  Back to cited text no. 10
    
11.
Attia P, Phan GQ, Maker AV, Robinson MR, Quezado MM, Yang JC, et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol 2005;23:6043-53.  Back to cited text no. 11
    
12.
Wimmer CD, Angele MK, Schwarz B, Pratschke S, Rentsch M, Khandoga A, et al. Impact of cyclosporine versus tacrolimus on the incidence of de novo malignancy following liver transplantation: A single center experience with 609 patients. Transpl Int 2013;26:999-1006.  Back to cited text no. 12
    
13.
Webster AC, Woodroffe RC, Taylor RS, Chapman JR, Craig JC. Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: Meta-analysis and meta-regression of randomised trial data. BMJ 2005;331:810.  Back to cited text no. 13
    
14.
Ku GY, Yuan J, Page DB, Schroeder SE, Panageas KS, Carvajal RD, et al. Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: Lymphocyte count after 2 doses correlates with survival. Cancer 2010;116:1767-75.  Back to cited text no. 14
    
15.
Sahuquillo-Torralba A, Ballester-Sánchez R, Pujol-Marco C, Botella-Estrada R. Pembrolizumab: A new drug that can induce exacerbations of psoriasis. Actas Dermosifiliogr 2016;107:264-6.  Back to cited text no. 15
    
16.
Voudouri D, Nikolaou V, Laschos K, Charpidou A, Soupos N, Triantafyllopoulou I, et al. Anti-PD1/PDL1 induced psoriasis. Curr Probl Cancer 2017;41:407-12.  Back to cited text no. 16
    


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This article has been cited by
1 Pembrolizumab
Reactions Weekly. 2019; 1777(1): 194
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