Scleroderma Secondary to Pembrolizumab: A Case Report and Review of 19 Cases of Anti-PD-1-Induced Scleroderma Open Access

Immune checkpoint inhibitors (ICIs) are increasingly being used to treat various malignancies. They can potentially cause various dermatological side effects, including vitiligo, morbilliform rash, urticaria, dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis [1, 2]. Scleroderma has also rarely been reported with anti-PD-1 agents such as pembrolizumab and nivolumab [3] and may present with skin tightening and hardening at any point during or after immunotherapy. There are various factors and predictors that are involved in the treatment response and toxicity of immunotherapy, of which there is a need for better comprehension [4]. These include reliable predictors of response to ICIs, which would be vital to modulate their therapeutic responses [4], and better understanding of the role of potential biomarkers [5‒7].

A 54-year-old Caucasian woman was referred by her oncologist to the dermatology clinic with a 2-month history of diffuse, painful, and itchy skin tightening, which started on her distal extremities then gradually also affected her trunk and abdomen. There was no history to suggest Raynaud’s phenomenon, difficulty with swallowing or gastrooesophageal reflux, and no history of previous skin problems or autoimmune disease. She had a history of an extra-skeletal osteosarcoma of her left leg when she was 45 years old, which was fully excised and treated with radiotherapy.

She was diagnosed with triple negative (oestrogen receptor, progesterone receptor, HER2 receptor negative) right breast carcinoma in September 2019 and initially received a neoadjuvant treatment regimen of carboplatin-paclitaxel-pembrolizumab, started in December 2019. She was originally planned to receive a total of 4 cycles (carboplatin and paclitaxel administered on days 1, 8, and 15; and pembrolizumab administered on day 21 of each cycle), however, only received three cycles due to severe adverse effects, including lethargy, nausea, vomiting, diarrhoea, headaches, dizziness and paraesthesia in both lower limbs. She underwent right wide local excision with axillary clearance in March 2020, followed by 3 weeks of radiotherapy to the right breast and right axillary lymph nodes. This was followed by a further 13 cycles of 200 mg pembrolizumab every 3 weeks, started in July 2020.

The patient was doing well on pembrolizumab, however, following cycle 9 she developed an erythematous rash with hardness of skin and swelling over her right breast at the site of her previous radiotherapy. This was deemed to be due to radiation recall and was treated with hydrocortisone cream with good effect. The pembrolizumab was continued with no further skin issues and treatment was completed in April 2021, after 13 cycles.

Three months after her final cycle of pembrolizumab, the patient experienced persistent pruritus with skin erythema which initially affected her extremities, but later also the trunk, and was associated with gradually worsening skin induration and discomfort. Low dose oral prednisolone and betamethasone valerate cream were prescribed by her oncologists with minimal effect. In view of this, the patient was referred to the dermatology clinic.

Examination revealed diffuse skin sclerosis with induration, thickening, and erythema in the affected areas (Fig. 1, 2). There were no obvious telangiectasia apart from on the right chest in the same area that was treated previously with radiotherapy. The digits were unaffected with no signs of swelling, ischaemia, or calcinosis. The clinical impression was of scleroderma secondary to pembrolizumab. Investigations including a complete blood count, anti-nuclear antibody (ANA), rheumatoid factor IgM, total extractable nuclear antigen, ANCA, anti-citrullinated peptide, RNA polymerase III antibody, anti-Scl 70, anti-centromere, anti-RO 52, and anti-ribonucleoprotein antibodies were all unremarkable.

Skin biopsies from the left forearm and the right side of upper abdomen, respectively, revealed a thickened dermis with hyalinised sclerotic collagen fibre bundles that extended into the subcutis in thick bands. Mild thickening of the blood vessel walls could also be appreciated (Fig. 3). A Hale’s colloidal iron stain revealed very focal deposition of scanty mucin between the collagen fibres. These histological features were in keeping with a diagnosis of scleroderma.

Given that the patient had already responded unfavourably to topical and oral corticosteroids, oral psoralen-UVA (PUVA) therapy was added with, however, only minimal improvement after 2 months. PUVA was therefore stopped and methotrexate was prescribed instead (initially 5 mg weekly then increased gradually over 3 months to 15 mg weekly). The patient reported gradual improvement of her pain and erythema, however, significant skin stiffness persisted. The latter was managed further with physiotherapy. The skin fibrosis generally improved, but remained noticeable, especially over her right upper limb. The patient is currently still receiving methotrexate. The patient’s timeline of diagnoses and treatment is outlined (shown in Fig. 4). She has also remained well from an oncological point of view and her most recent PET scan was unremarkable.

Scleroderma is an autoimmune multisystem connective tissue disorder characterized by skin fibrosis which may be limited or diffuse, causing skin tightening and hardening, and possibly fibrosis of other organ systems such as the lung and vascular involvement [8, 9]. Aetiopathogenesis is complex and is thought to include genetic and environmental factors [10]. Malignancy may play a role in scleroderma in two main ways. Scleroderma may be triggered through cytokines or hormones secreted by the tumour cells which lead to cytotoxic and autoantibody responses. In such cases, the scleroderma is termed paraneoplastic and this was a differential diagnosis in our case. Scleroderma may also develop secondary to immunotherapy-induced immune disruption [11].

It may be clinically difficult to differentiate with certainty between paraneoplastic scleroderma and ICI-induced scleroderma in an individual patient; however, the literature offers some possible clues which may help distinguish between the two. Raynaud’s phenomenon, organ involvement, nailfold capillary abnormality, and ANA and RNA polymerase III antibody positivity do not usually feature in drug-induced scleroderma [10, 12]. The timeline of events may also be indicative, in that paraneoplastic scleroderma usually predates the diagnosis of malignancy or both are diagnosed at around the same time [10]. In our case, scleroderma developed after the patient had already been treated with surgery, radiotherapy and finished a course of planned immunotherapy. She had no Raynaud’s phenomenon, no organ involvement elsewhere and her immunology screen (including RNA polymerase III antibody) was negative, making drug-induced scleroderma more likely.

ICIs are a recent breakthrough in oncology treatment of various malignancies via immune mediated responses against tumour growth [13]. ICIs are monoclonal antibodies and include cytotoxic T-lymphocyte-associated protein 4 (CLTA-4) inhibitors, programmed cell death-1 (PD-1) inhibitors, or programmed cell death ligand-1 (PD-L1) inhibitors [3]. Pembrolizumab is a selective immunoglobulin G4-kappa monoclonal antibody that inhibits PD-1. The use of pembrolizumab as immunotherapy was first approved in 2014 for the treatment of metastatic melanoma [1, 14], and later on for other malignancies such as non-small cell lung cancer [3], urothelial carcinoma [15] and triple-negative breast cancer such as in our case.

An emergent downside of these ICIs is immune-related adverse events (irAEs) which could involve the skin. Cutaneous adverse effects which have been reported with anti-PD-1 agents such as pembrolizumab and nivolumab include dermatoses such as vitiligo, morbilliform rash, urticaria, dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis [1, 2]. Scleroderma is another, but less reported, adverse effect of pembrolizumab and nivolumab [1]. These irAEs occur secondary to erroneous immune system activation against self-antigens. The severity and incidence of irAEs depend on various factors, which include the type of tumour and the type of ICI used, amongst others [5].

We performed an extensive literature review to collate all the reported cases of pembrolizumab- and nivolumab-induced scleroderma up to June 2022. PubMed and Google Scholar were used to search for cases, using the terms “scleroderma,” “pembrolizumab,” and “nivolumab.” In total, 12 other cases of pembrolizumab-induced scleroderma and 6 cases of nivolumab-induced scleroderma were found. These, together with our case, are summarized in Tables 1 and 2.

In our review, eight males and eleven females were affected, with their ages ranging from 33 years old to 81 years old. Skin changes of scleroderma developed at different stages of treatment, in some cases as early as after the first cycle of immunotherapy. Treatment options utilized included corticosteroids, methotrexate, hydroxychloroquine, cyclophosphamide, mycophenolate mofetil, immunoglobulins, and infliximab, with varying response. In most cases, the scleroderma stabilized within a few months of treatment (Tables 1, 2).

The underlying mechanism behind scleroderma secondary to PD-1 inhibitors is not yet fully understood. It is known that through the inhibition of PD-1, pembrolizumab, or nivolumab cause increased CD4 T-cell activity which in turn promotes a T-helper cell response [29]. Several authors have suggested that a profibrotic state is created via type 2 macrophage polarization which promotes fibroblast activation and excessive extracellular matrix production. This may in turn lead to an increase in dermal thickness. ICI-induced scleroderma appears to only occur with PD-1 antagonists and to our knowledge has not been reported with CTLA-4 or PD-L1 inhibitors [20].

Immunotherapy is a relatively new treatment in oncology and further research regarding different factors which play a role in immunotherapy response is still needed. However, so far, immunotherapy has shown great efficacy and potential in the treatment of various malignancies. This report aims to create awareness that pembrolizumab and nivolumab may rarely cause scleroderma. Clinical diagnosis and management of scleroderma in this setting may be challenging, and an accurate drug history and dermatological input are recommended in such cases. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000533373).

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. Ethical approval is not required for this study in accordance with local or national guidelines.

The authors have no conflicts of interest to declare.

There was no funding received for this article.

S.F., L.M., A.B., N.R., and M.J.B. contributed to the management and the reporting of the case, photography, and research involved for this case report.

All data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author.