Eosinophilic Fasciitis in a 78-Year-Old Man Following Pembrolizumab Treatment for Bladder Cancer

Introduction

Anti-PD-1 (programmed cell death 1) immune checkpoint inhibitors (ICI), such as pembrolizumab, nivolumab, cemiplimab (FDA approved), and camrelizumab (approved in China), have been used for over a decade in the management of certain forms of advanced solid tumors and hematologic malignancies [1]. These monoclonal antibodies block the interaction between the inhibitory molecule PD-1 expressed on the surface of T cells and its ligand PD-L1 on cancer cells [2]. The rationale for their use in cancer is that anti-PD-1 antibodies block inhibitory immune checkpoints, thereby potentiating the T cell effector activity, particularly that of CD8+ T cells, and enhancing their anti-tumor properties [2]. Other immune checkpoint inhibitors used in cancer management target either PD-L1 on tumor cells (eg, atezolizumab, avelumab, and durvalumab), CTLA-4 (cytotoxic T-lymphocyte-associated protein 4; eg, ipilimumab and tremelimumab) on T cells, or LAG-3 on T cells (eg, relatlimab) [3].

The widespread use of ICIs has led to increased recognition of various rheumatic and non-rheumatic immune-related adverse events (irAEs) [1]. The most common non-rheumatic irAEs are hypothyroidism, pneumonitis, hepatitis, and colitis [1]. Rheumatic irAEs such as inflammatory polyarthritis, polymyalgia-rheumatica-like disease, sicca syndrome, and myositis are the most common ICI-induced rheumatic conditions [4,5]. Within the group of rheumatic irAEs, inflammatory arthritis is seen in about 3.0% to 7.5% of patients [6]. Eosinophilic fasciitis (EF) is a rare fibrosing connective tissue disease that typically presents with bilateral painful swelling and hardening of the skin and underlying soft tissues [7]. This disease was first described by Shulman in 1974, and it has been linked with the use of certain medications, toxins, physical exertion, infections, and autoimmune and hematologic disorders [7–10]. Interestingly, while EF does not appear to be associated with secondary cancer, it is estimated that about 10% of EF cases are paraneoplastic, more commonly encountered in patients with hematologic malignancies [11].

ICI-induced EF is an emerging rheumatic irAE, and this case report describes the clinical presentation and management of a 78-year-old man with a history of bladder cancer who developed eosinophilic fasciitis after 6 months of treatment with an ICI.

Case Report

A 78-year-old man with a history of hypothyroidism and bladder cancer presented with pain and diffuse hardening of the skin in his extremities and back. His bladder cancer was diagnosed in 2018, treated initially with intravesical BCG, gemcitabine, and docetaxel. Due to disease recurrence in 2022, treatment was changed to a protocol that included intravesical gemcitabine and cabazitaxel, and pembrolizumab infusions. He received a total of 3 mg/kg (400 mg) of pembrolizumab on weeks 0, 6, 12, 23, and 26. This treatment was planned for 2 years but was stopped after he developed anasarca that was diagnosed as capillary-leakage syndrome.

While hospitalized for capillary-leakage syndrome, he underwent an extensive laboratory workup. This included normal ferritin, brain natriuretic peptide, liver function tests, basic metabolic profile, creatine kinase, myoglobin, urine, and plasma osmolality; negative SSA(Ro), SSB(La), antineutrophil cytoplasmic antibodies, antinuclear antibody, normal levels of C3, C4, C1 inhibitor functional assay, and immunoglobulins. Cytokine panel revealed mild to moderate elevation of IL-5, IL-6, IL-10 and soluble IL-2R. Complete blood count (CBC) was unrevealing except for moderate elevation of white blood count with eosinophilia and mild drop in hemoglobin. Serum protein electrophoresis, urine immunofixation electrophoresis, and flow cytometry studies were unremarkable. He had low albumin, and his erythrocyte sedimentation rate (ESR) and C-reactive protein were elevated (Table 1).

He was noted to have erythematous patchy rashes with thin plaques coalescing across his back, and a skin biopsy showed superficial perivascular dermatitis with eosinophils. Dermatology suspected that his rash was drug-induced in the setting of capillary-leakage syndrome secondary to immune hyperactivation. Pembrolizumab was discontinued, and he was treated with intravenous immunoglobulin (IVIG) 2 g/kg in 2 divided doses over 2 days, furosemide, and 3 days of intravenous methylprednisolone 1 mg/kg, followed by oral prednisone 60 mg daily that was tapered over 3 months. Following resolution of his peripheral edema and completion of prednisone taper for capillary leak syndrome, he noticed progressive itching, tingling, and painful hardening and tightening of the skin in both his legs and forearms. He presented to the rheumatologist about 5 months after he noticed these symptoms. He had no joint pain or swelling, history of Raynaud’s disease, hematologic malignancy, past radiation therapy, burns, or end-stage renal disease. His physical examination was notable for areas of skin hardening with induration and tenderness in his back, forearms, and legs, with sparing of his arms, hands, feet, and thighs (Figures 1–3). He had some restriction of movement across his elbows. There was no telangiectasia, sclerodactyly, or digital ulcers, and his capillaroscopy exam was normal.

A full-thickness skin biopsy revealed fibrosis of subcutaneous tissue and deep fascia with multifocal collections of lymphocytes and plasma cells; changes suggestive of eosinophilic fasciitis (Figure 4). He was started on prednisone 60 mg daily with a gradual taper. He was considered steroid-unresponsive after 3 months, as he continued to have new areas of skin hardening on his back and lower abdomen, pain, and tingling in the hard areas on his legs and forearm. Mycophenolate mofetil was introduced and titrated to 1.5 grams twice daily. Given the lack of improvement in his symptoms after 3 months, hydroxychloroquine and benralizumab were added. He noticed significant softening of his skin and normalization of previously elevated inflammatory markers at his follow-up several months later.

Discussion

A variety of sclerosing skin conditions, ranging from limited/diffuse systemic sclerosis to scleroderma mimics such as eosinophilic fasciitis (EF), have been reported in patients without pre-existing sclerosing skin conditions treated with ICIs [12,13]. According to a retrospective study from the Dana-Faber Cancer Institute, these sclerosing skin irAEs are extremely rare, with only 1 observed case of EF out of 4487 patients treated with ICIs from 2013 to 2019 [14]. EF should always be considered as a differential diagnosis in patients presenting with hardening of the skin, particularly in those treated with pembrolizumab or other anti-PD-1 drugs [13,15–19]. EF is an immune-mediated condition that can mimic other scleroderma-like conditions, such as systemic sclerosis and diffuse morphea. Its clinical presentation includes myalgia, symmetrical painful hardening of the skin, swelling, and stiffness, often sparing the hands and feet [13,15–19]. According to a recent review article by Macklin et al, EF is a more common complication of ICI treatment than morphea or systemic sclerosis [20]. Apart from the complication of capillary leak syndrome before developing EF, our patient’s clinical presentation is like other cases of pembrolizumab-induced EF as reported by authors like Chan et al and Zampeli et al [16,18].

The exact pathophysiology of anti-PD-1-induced EF is unknown, although an immune-mediated process that targets the fascia is believed to be a driving force [21]. It is hypothesized that it may be related to prolonged activation of CD8+ T cells, including those with anti-cancer and autoimmune properties [16]. There is a relatively high incidence of cutaneous irAEs among patients treated with checkpoint inhibitors who developed a high peripheral blood eosinophil count, and it is thought that EF may be the result of the eosinophilic anti-tumor activity of ICI in these patients [16,22]. It is unclear which patients are at higher risk of developing ICI-related toxicity. There is no clear relationship with the cumulative dose of pembrolizumab (or other anti-PD-1 agents) and irAEs since the dose varies among treatment protocols, and the interval between the initial treatment with an anti-PD1 agent and subsequent EF also varies widely [15,16]. For example, Khoja et al described a patient who developed symptoms after completing an 18-month course of pembrolizumab, while Kobak et al published a case of EF in a patient who developed EF after the first infusion [15,17].

While there is no specific laboratory abnormality that is diagnostic for EF, the most frequently observed is peripheral blood eosinophilia, which is usually transient and may be absent at the time of diagnosis [16]. In addition, an elevated sedimentation rate and hypergammaglobulinemia have also been described [1]. Magnetic resonance imaging (MRI) and 18FDG-PET/CT are imaging modalities that are most often employed for evaluating patients with sclerosing skin conditions [15,19]. MRI in EF shows hyperintensity of the muscular fascia, while 18FDG-PET/CT shows increased tracer uptake in the fascia [15,19]. Histologic findings in immune checkpoint inhibitor (ICI)-induced EF are like those in non-ICI EF and include fibrosis of the dermis, with associated mononuclear, eosinophilic, and lymphocytic infiltration of the fascia [1,13,19].

There are no guidelines on the appropriate treatment for EF, in most cases related to anti-PD-1; the consensus is that pembrolizumab (or other anti-PD-1) should be discontinued either temporarily or completely when it is suspected to be the underlying cause [13,16]. However, there were mild cases of EF that resolved spontaneously and did not require any interruption in the anti-PD1 management [17]. Corticosteroids are usually the first line of treatment and were effective in most patients [23]; however, patients with refractory disease required alternative treatments with 1 or a combination of methotrexate, mycophenolate mofetil, hydroxychloroquine, cyclosporine, sirolimus, IVIG, abatacept, omalizumab, or infliximab [13,16]. In our practice, we have had more success with the use of mycophenolate over methotrexate; hence, it is usually our first choice after glucocorticoids. Recent reports show that there may be a place for anti-interleukin-5(R) such as mepolizumab and benralizumab in patients with EF, based on the role of IL-5 in eosinophil activation, proliferation, and survival [24]. Deep-tissue biopsy in EF shows eosinophils in about 50% of patients, although this is more commonly seen in early disease [25]. Adjuvant forms of treatment for EF include the use of psoralen and ultraviolet A (PUVA) [25]. Since there are no standard biomarkers for measuring disease activity in EF, improvement is often monitored clinically based on skin thickening and associated complications such as contractures and tendon retractions [24]. Inflammatory markers (ESR, CRP), CK, aldolase, and eosinophil count may be checked if they were elevated at the onset of the disease [26]. Peripheral eosinophilia, which is present in some patients at the onset of disease, does not correlate with disease severity and usually disappears once steroid therapy is started [25].

Overall, EF has a relatively favorable prognosis, with most patients experiencing significant improvement with therapy, although some still exhibit residual skin hardening [25]. While there are no prospective studies on the cancer outcome in patients who developed irAEs necessitating the use of high-dose steroids or other forms of immunosuppressive treatment, the literature suggests that high doses of corticosteroids can reduce the beneficial anti-tumor properties of ICI [27].

Conclusions

This case report supports the need to have a high index of suspicion and investigate for eosinophilic fasciitis in cancer patients treated with anti-PD-1 medications such as pembrolizumab who present with symmetric, painful hardening of the skin.