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Characterization of arthralgia induced by PD-1 antibody treatment in patients with metastasized cutaneous malignancies

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Abstract

Background

PD-1 antibodies (PD1ab) are increasingly used in metastatic melanoma and other malignancies. Arthralgia is an underestimated side effect of PD-1 antibody treatment with unknown cause. Our aim was to characterize PD1ab-induced arthralgia.

Patients and methods

We retrospectively included patients with metastatic cutaneous malignancies treated with pembrolizumab or nivolumab ± ipilimumab at the National Center for Tumor Diseases (Heidelberg) between 01/2013 and 09/2016. Arthralgia was characterized by laboratory diagnostics, imaging, and if indicated, rheumatologic consultation.

Results

26 of 195 patients (13.3%) developed arthralgia. The median onset of symptoms was 100 days (7–780 days). Most frequently, arthralgia involved large joints (shoulders, knees) in a predominantly symmetrical pattern. Only two patients were seropositive for rheumatoid factor and/or anti-citrullinated protein antibodies. Ten patients developed the clinical picture of arthritis, with seven of them showing synovitis in MRI or PET/CT. Five patients showed inflammation in joints pre-damaged by osteoarthritis. In 11 patients arthralgia could not be specified. The majority of patients was satisfactorily treated with non-steroidal anti-inflammatory drugs (NSAIDs), 23.1% required additional low-dose corticosteroids and only 7.6% of our patients received further immunosuppressive treatment. Patients with arthralgia showed a better treatment response and improved PFS and OS.

Conclusion

Arthralgia is frequent during PD1ab treatment. The clinical picture varies between synovitis of predominantly large joints, progressive osteoarthritis and arthralgia without evident joint damage. Vast majority of cases can be satisfactorily managed by NSAID and/or low-dose corticosteroids.

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Abbreviations

ACPA:

Anti-citrullinated protein antibodies

ANA:

Antinuclear antibodies

CR:

Complete response

CT:

Computed tomography

CTC-AE:

Common terminology criteria for adverse events

FDG-PET:

Fludeoxyglucose positron emission tomography

irAE:

Immune-related adverse event

MRI:

Magnetic resonance imaging

NCT:

National Center for Tumor Diseases, Heidelberg

NSAID:

Non-steroidal antirheumatic drug

OA:

Osteoarthritis

PD:

Progressive disease

PD1ab:

PD-1 antibody

PFS:

Progression-free survival

PR:

Partial response

RA:

Rheumatoid arthritis

RF:

Rheumatoid factor

SD:

Stable disease

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Acknowledgements

We thank our pain nurses for systematic pain assessment. We thank all patients and their families for supporting our clinical research.

Author information

Authors and Affiliations

  1. Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany

    Kristina Buder-Bakhaya, Carsten Schulz, Alexander Enk & Jessica C. Hassel

  2. Division of Rheumatology, Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany

    Karolina Benesova & Hanns-Martin Lorenz

  3. Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center, Heidelberg, Germany

    Hoda Anwar & Antonia Dimitrakopoulou-Strauss

  4. Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg, Germany

    Tim F. Weber

Authors
  1. Kristina Buder-Bakhaya
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  2. Karolina Benesova
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  3. Carsten Schulz
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  4. Hoda Anwar
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  5. Antonia Dimitrakopoulou-Strauss
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  6. Tim F. Weber
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  7. Alexander Enk
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  8. Hanns-Martin Lorenz
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  9. Jessica C. Hassel
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Contributions

Study conception and design was done by Kristina Buder-Bakhaya, Karolina Benesova, Hanns-Martin Lorenz, and Jessica C. Hassel. Kristina Buder-Bakhaya, Karolina Benesova, Carsten Schulz, Hoda Anwar, Antonia Dimitrakopoulou-Strauss, Tim F. Weber, Hanns-Martin Lorenz, and Jessica C. Hassel are responsible for the integrity of acquired data. Statistical analysis was performed by Kristina Buder-Bakhaya and Jessica C. Hassel. Kristina Buder-Bakhaya and Karolina Benesova prepared the manuscript. All authors made substantial contributions to data analysis and interpretation, manuscript editing, review and approval.

Corresponding author

Correspondence to Kristina Buder-Bakhaya.

Ethics declarations

Ethical approval

Retrospective analyses of clinical data were approved by the institutional review board of the Medical Faculty of the University Hospital Heidelberg (no. S-069/2010). The ethical committee had agreed to the retrospective analysis of routinely collected clinical data without prior informed consent of patients.

Informed consent

Informed consent of patients for publication of imaging data was obtained.

Funding

No relevant funding.

Conflict of interest

K Buder-Bakhaya received honoraria and travel reimbursements from TEVA Pharmaceutical Industries GmbH, MSD Sharp & Dome GmbH Oncology (MSD), and Roche Pharma AG (Roche). K. Benesova received payment for lectures from Roche and Abbvie Germany GmbH & Co, KG (Abbvie), travel expenses and/or conference fees from Abbvie, Pfizer Pharma GmbH (Pfizer) and Bristol-Myers Squibb (BMS). H.-M. Lorenz received consultancy fees, honoraria for lectures, support for scientific projects or travel reimbursements from Abbvie, MSD, BMS, Pfizer, Roche, Celgene GmbH, Baxter Germany GmbH, Swedish Orphan Biovitrum GmbH, Biogen GmbH, Medac GmbH, GlaxoSmithKline GmbH & Co. KG (GSK), Chugai Pharma Europe Ltd., Novartis Pharma GmbH (Novartis), UCB Pharma GmbH, Janssen-Cilag GmbH, AstraZeneca GmbH, Lilly Germany GmbH, Actelion Pharmaceuticals Germany GmbH, Bayer Vital GmbH, Shire Germany GmbH, and Octapharm GmbH. A. Enk received consultancy fees and honoraria for lectures from Biotest AG, Galderma Laboratorium GmbH, Janssen-Cilag GmbH, AbbVie, BMS, MSD, and Roche. J.C. Hassel received consultancy fees from Amgen GmbH, and MSD, payment for lectures from BMS, MSD, Roche, GSK, Novartis, and Pfizer and travel reimbursements from BMS, MSD, Amgen, and GSK. All other authors declare that they have no conflicts of interest.

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Buder-Bakhaya, K., Benesova, K., Schulz, C. et al. Characterization of arthralgia induced by PD-1 antibody treatment in patients with metastasized cutaneous malignancies. Cancer Immunol Immunother 67, 175–182 (2018). https://doi.org/10.1007/s00262-017-2069-9

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  • DOI: https://doi.org/10.1007/s00262-017-2069-9

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