Abstract
Background: Immunotherapy using immune checkpoint inhibitors is not devoid of immune-related adverse events (irAEs) including rheumatological conditions. Case Report: We report a rare case of a 47-year-old woman with metastatic melanoma who developed systemic scleroderma after initiating nivolumab. The patient displayed inflammatory arthralgias, morning stiffness, and classical cutaneous manifestations of the disease. Clinical evaluations also revealed carpal tunnel syndrome, cardiac involvement, and dyspnea. RNA-Polymerase III antibodies were positive. Nivolumab, an anti-PD-1 antibody, was considered as a potential trigger for this condition. Conclusion: To our knowledge, this is the first case of nivolumab-induced systemic scleroderma in the context of melanoma described in the literature that fulfills the classification criteria of the disease. This case underscores the need for increased awareness of immune-related adverse events in patients receiving immune checkpoint inhibitors, emphasizing timely intervention and further research.
- Systemic scleroderma
- nivolumab
- checkpoint inhibitors
- melanoma
- immunotherapy
- paraneoplastic
- immune-related adverse events
Systemic scleroderma is a rare autoimmune disease affecting connective tissue and microvessels. It is characterized by cutaneous fibrosis and vascular obliteration phenomena, with the most well-known being Raynaud’s phenomenon (1).
Immunotherapy using immune checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and program cell death/program cell death ligand 1 (PD/PD-L1) pathways has been used for approximately a decade in cancer treatments, particularly melanoma and lung cancers (2). While they have become essential in management owing to their effects on overall survival, they are not devoid of immune-related adverse events (irAEs). The most commonly reported side effects are gastrointestinal and endocrinological. Rheumatic irAEs are also increasingly documented in the literature, including clinical presentations resembling commonly known rheumatic conditions like polymyalgia rheumatica, rheumatoid arthritis, myositis, and even connective tissue diseases such as scleroderma-like disorders (3).
In this case report, we present the case of a 47-year-old patient who developed typical systemic scleroderma shortly after initiating nivolumab treatment.
Case Report
A 47-year-old woman followed for metastatic melanoma of the right shoulder with right axillary lymph node involvement presented with inflammatory arthralgias of the wrists and hands in September 2022, after her third cycle of nivolumab (approximately 2 months after treatment initiation). She experienced nocturnal awakenings at 1 AM with significant morning stiffness lasting approximately 30 min, which improved throughout the day. These pains were non-migratory. Associated with these symptoms were finger paresthesias and a sensation of ocular and oral dryness. Raynaud’s phenomenon was not present.
Upon initial clinical examination in December 2022, she exhibited bilateral and symmetrical arthralgias of the wrists, metacarpophalangeal and proximal interphalangeal joints, with a positive squeeze test, no apparent synovitis or marked joint stiffness, and carpal tunnel syndrome. Laboratory tests showed anti-nuclear antibodies at 1/640 without specificity, negative anti-citrullinated peptides antibodies and rheumatoid factors, and no signs of inflammation. Creatine phosphokinase levels were normal. A complete blood count revealed no anomalies, including no eosinophilia, and liver and kidney function tests were unremarkable. Thyroid-stimulating hormone and cortisol levels were within normal limits. Serological tests for hepatitis B and C, human immunodeficiency virus, cytomegalovirus, and Ebstein-Barr virus were negative. X-rays of painful articulations were unremarkable. Treatment with non-steroidal anti-inflammatory drugs was initiated, with only partial pain relief.
By January 2023, the cutaneous involvement had evolved: the fingers appeared sausage-like, there was cutaneous sclerosis of the proximal phalanges, likely nail bed hemorrhage in one finger, a few telangiectasias on the trunk, Raynaud’s phenomenon in the fingers, and limited oral opening. Gastroesophageal reflux had developed. Arthralgias and carpal tunnel syndrome persisted. Anti-nuclear antibody levels were over 1/1,280, with positive anti-ribonucleic acid (RNA) polymerase III antibodies. Serum protein electrophoresis and complement exploration (C3, C4, CH50) were normal. Electromyography of the upper limbs confirmed median nerve canal involvement. Ultrasound of the hands and wrists showed no synovitis. Thoracoabdominopelvic computed tomography (CT) scan was normal.
In February 2023, New York Heart Association Class III dyspnea emerged, associated with subtle basal crackles and myalgias with sensations of lower limb weakness. Creatine phosphokinase levels were normal. Dot-myositis and anti-β-hydroxy β-methylglutaryl coenzyme A reductase (HMG-CoA) antibody tests were negative. The transthoracic cardiac ultrasound did not indicate pulmonary arterial hypertension. Electrocardiography and electromyography were normal. Capillaroscopy revealed severe vascular rarefaction in all fingers with an area of neovascularization in the 4th ray of the left hand, including two bushy capillaries without clear identification of megacapillaries. Pulmonary function tests revealed no ventilatory disorders, but diffusion was within normal limits, with a diffusion capacity (DLCO) at 69% and the diffusing capacity divided by the alveolar volume (DLCO/VA) at 77%. A follow-up thoracoabdominopelvic CT scan was consistent with the previous findings.
Finally, the patient fulfilled the classification criteria of systemic scleroderma (1). All differential diagnoses were excluded, and we hypothesized nivolumab-induced systemic scleroderma.
Discontinuation of nivolumab, coupled with low-dose oral corticosteroid treatment and local corticosteroid injection in the carpal canals, significantly improved musculoskeletal symptoms.
Discussion
The clinical presentation of immune checkpoint inhibitor-induced systemic scleroderma in general appears to differ from the typical descriptions of this condition: the sex ratio is balanced, onset occurs around the age of 50, and cutaneous sclerosis often begins in the extremities, although it may occasionally start on the trunk. The presence of Raynaud’s phenomenon, nail bed hemorrhages, and ulcers is inconsistent, and there is a notable seronegativity of antibodies (4). To our knowledge, only 4 cases of nivolumab-induced scleroderma-like disorders in the context of melanoma are described in the literature and here, it’s the first case described that fulfills the classification criteria.
Nivolumab is an anti-PD-1 antibody. Its role is to block the PD-1 receptor located on T lymphocytes, preventing the receptor from binding to its ligand PD-L1 on tumor cells. This interaction leads to reactivation of the T lymphocyte response against cancer cells, facilitating their destruction (2).
The presence of soluble forms of PD-1 (s-PD1) has recently been described in several cancers. These forms are believed to act as antagonists to the PD-1 receptor. In patients with systemic scleroderma, levels of s-PD1 have been positively correlated with more extensive and severe cutaneous sclerosis, indicating a more severe disease activity (5). Moreover, PD-1 inhibition by s-PD1 or an anti-PD-1 antibody could lead to the release of soluble forms of PD-L1 and PD-L2 by tumor cells, potentially contributing to the development of systemic scleroderma, as demonstrated in mouse models (6). Finally, the study by Terrier et al. supports the hypothesis of a significant role of PD-1 blockade in the pathophysiology of scleroderma by demonstrating an increased risk of developing this syndrome in patients treated with nivolumab and pembrolizumab but not with atezolizumab or durvalumab, which block PD-L1 localized on antigen-presenting cells (7).
Paraneoplastic scleroderma can be baffling too. Although patients developing systemic sclerosis are more likely to develop cancer in the long term, the simultaneous occurrence of both conditions within a short time frame remains perplexing. In this context, the onset of symptoms is also delayed compared to classic systemic scleroderma, and caution is warranted in the presence of anti-RNA polymerase III, proved to be linked to cancer (8). An overexpression of the antigen of these antibodies has been demonstrated in the tissues of patients with some cancers. In melanoma, this type of mechanism could be partially responsible of systemic scleroderma development (9). Furthermore, in this case, initiating immunotherapy by nivolumab could have revealed and exacerbated the symptoms, resulting on the one hand in an acceleration in the progression of this autoimmune condition, but on the other hand reflecting a sign of good antitumoral response, as described for vitiligo (10).
Finally, in practice, it remains challenging to distinguish between classical systemic scleroderma, immunotherapy-induced scleroderma, or paraneoplastic scleroderma.
Conclusion
To our knowledge, this is the first reported case of systemic scleroderma induced by nivolumab that fulfills classification criteria and exhibits typical manifestations of the disease. The emergence of immune checkpoint inhibitors in the management of cancers, such as melanoma, lung cancer, and renal cancer underscores the need for increased publications focusing on irAEs due to the poor prognosis of these conditions in terms of quality of life and mortality, requiring early intervention.
Footnotes
Authors’ Contributions
Thibaud Loupret, Romain Boisseau, and Jean-Guillaume Lopez participated in the drafting, writing, and editing of the manuscript. Philippe Bertin and Pascale Vergne-Salle have supervised the study.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this article.
- Received January 14, 2024.
- Revision received February 20, 2024.
- Accepted February 21, 2024.
- Copyright © 2024 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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