Eosinophilic Fasciitis Following Checkpoint Inhibitor Therapy: Four Cases and a Review of Literature

Abstract

Background: Checkpoint inhibitor therapy is widely known to cause a number of immune-related adverse events. One rare adverse effect that is emerging is eosinophilic fasciitis, a fibrosing disorder causing inflammatory infiltration of subcutaneous fascia. It is characterized clinically by edema and subsequent induration and tightening of the skin and subcutaneous tissues. The condition is rare, yet at our institutions we have seen four cases in the past 3 years. We describe our 4 cases and review 11 other cases reported in the literature.

Case presentation: We present four cases of eosinophilic fasciitis following treatment with programmed cell death protein 1 or programmed cell death-ligand 1 blockade. All patients had extremity involvement with characteristic skin changes ranging from peripheral edema to induration, tightening, and joint limitation. The patients had varying degrees of peripheral eosinophilia. In two of our patients, the diagnosis was made by full-thickness skin biopsy showing lymphocytic infiltration of the subcutaneous fascia, with CD4+ T cells predominating in one case and CD8+ T cells in the other. In the other two cases, the diagnosis was made on the basis of characteristic imaging findings in the context of clinical features consistent with the diagnosis. All four patients were treated with glucocorticoids with varying degrees of success; immunotherapy had to be discontinued in all four. Patients with advanced melanoma who experienced this adverse effect had either a partial response or a complete response to therapy.

Conclusion: Eosinophilic fasciitis can occur as a result of checkpoint inhibitor therapy. Although a tissue diagnosis is the gold standard, imaging studies may facilitate the diagnosis in the presence of consistent clinical features, but a degree of suspicion is key to recognizing the condition early. Therapy requires a collaborative approach by oncology, rheumatology, and dermatology; physical therapy is an important adjunct in treatment. For advanced melanoma, it may be a good prognostic indicator.

Implications for practice: It is important for clinicians to recognize that eosinophilic fasciitis is a potential immune-related adverse event (irAE) as a consequence of immune checkpoint inhibitor therapy. The presentation is quite stereotypical; the diagnosis can be made by imaging in the absence of a full-thickness skin biopsy. Early intervention is important to limit morbidity. This irAE may be a good prognostic sign among patients with melanoma.

Keywords: Checkpoint inhibitor; Eosinophilic fasciitis; Immune-related adverse event.

Figure 1

Spectrum of skin findings. (A): Patient 1. Groove sign along a superficial vessel, with swelling around the medial malleolus. (B): Patient 4. Puffiness of the hands and fingers with limited finger extension. (C): Patient 4. Pedal edema most obvious around the lateral malleolus.

Figure 2

Magnetic resonance imaging findings. (A): Patient 1. Axial section through the proximal leg shows fascial edema (arrows in STIR) and preserved muscle bulk in intermediate‐weighted FSE sequences. (B): Patient 3. Axial section through the mid‐forearm shows fascial edema (arrows in STIR) and preserved muscle bulk in intermediate‐weighted FSE sequences. Abbreviations: FSE, fast spin echo; STIR, short tau inversion recovery.

Figure 3

Full‐thickness skin biopsy from patient 1. (A): Hematoxylin and eosin staining at ×400 showing broad, hyalinized collagen bundles within the fascia with deposition of mucin and a lymphocytic and plasma cell infiltrate. (B–E): Immunostains demonstrating CD8+ T‐cell predominance (×200). Lymphocytes are primarily of the T‐cell subset as revealed by the extent of immunoreactivity for CD3 (B). The T cells comprise a mixture of CD4+ T cells (C) and CD8+ T cells (D), with some cells staining positive for granzyme (E).

Figure 4

Full‐thickness skin biopsy from patient 2. (A): Fibrosing stromal changes with predominant involvement of deep subcutaneous tissue and fascia is appreciated at low magnification (hematoxylin and eosin [H&E], ×10; square indicating area seen at higher magnification in (B)). (B): Inflammatory infiltrate composed of lymphocytes, plasma cells, and eosinophils is seen in perivascular and interstitial pattern on a background of sclerosis and fibrinoid degenerative changes (H&E, ×400). (C): CD20 immunostain highlights few B cells. (D): CD3 immunostain highlights the lymphocytic infiltrate that corresponds predominantly to T cells. (E): Most T cells are CD4+. CD4 also highlights occasional dendritic cells and histiocytes. (F): CD8+ T cells are also present. (C–F × 200)