Antineutrophil cytoplasmatic antibody (ANCA)–associated vasculitis (AAV) is characterized by multisystem organ involvement with necrotizing granulomatous inflammation and vasculitis.1 ANCA antibodies are considered both specific and pathogenic for this group of autoimmune diseases.2 Hence, B-cell depletion by anti-CD20 therapy has shown substantial benefit and is now considered the standard of care.3 Some patients, however, do not respond to conventional therapy and require additional treatment options.
Long-lived plasma cells are not affected by usual immunosuppressive therapies and have been shown to maintain ANCA production, thereby leading to ongoing autoimmune inflammation.4 Daratumumab (Darzalex; Janssen Biotech) is a monoclonal antibody that binds to CD38, which is highly expressed on long-lived plasma cells and overexpressed on multiple myeloma cells. Targeting CD38 with daratumumab has been shown to benefit patients with multiple myeloma.5 Daratumumab has also been used to treat patients with systemic lupus erythematosus.6 We report the case of a patient with AAV and severe pulmonary and cutaneous involvement who received conventional therapy that failed and who then recovered following daratumumab therapy.
This case took place in 2022 at the Saarland University Medical Center, Homburg, Germany. The male patient was in his late 20s and initially presented with a cutaneous ulceration on his right foot and upper lobe predominant, centrilobular consolidations. Positive anti–proteinase 3 (PR3) ANCA titers were documented. Histological examination of a tissue sample obtained from his foot revealed granulomatosis with polyangiitis (GPA). Kidney involvement was not apparent during the entire course of his disease. Despite intensive immunosuppression, including both rituximab (3 applications at 375 mg/m2) and cyclophosphamide (3 intravenous applications at 750 mg/m2 followed by 4 mg/kg/d of continuous oral therapy) induction regimens, therapeutic plasma exchange (11 treatments at 60 mL/kg of albumin replacement by means of filter separation), 6 pulses of methylprednisolone (1000 mg each), prednisolone maintenance (1 mg/kg/d), and avacopan (30 mg twice daily), clinical disease activity progressed unimpeded. Sixty-seven days after hospital admission, he finally required extracorporeal membrane oxygenation (ECMO) due to bronchoscopy-proven diffuse alveolar hemorrhage. Because of the continuing presence of positive PR3 ANCAs in this situation, we administered daratumumab in the light of its effectiveness for patients with systemic lupus erythematosus.
Daratumumab was administered according to protocols approved for multiple myeloma.5 The patient’s representative provided written informed consent for the off-label use of daratumumab. The procedure was performed according to the Good Clinical Practice guidelines. A commercial sponsor was not involved. Due to the retrospective nature of this analysis and anonymized clinical data, ethical approval was waived by the institutional review board of Saarland University Medical School.
Daratumumab (16 mg/kg infusions once a week) was initiated 3 days after the patient started ECMO therapy. Figure 1 shows the evolution of his pulmonary and cutaneous disease manifestations after adding daratumumab to oral cyclophosphamide, prednisolone, and avacopan. Figure 2 shows an overview of his treatment, his respiratory support, and ANCA titer from the time of hospital admission to hospital discharge. Eleven days after the patient received daratumumab, his ANCA titer became negative for the first time throughout his entire treatment course. With continuation of daratumumab, oral cyclophosphamide, and prednisolone tapering, he could successfully be weaned from ECMO and respiratory support. On September 6, 2022, hospital day 120 and 50 days after starting daratumumab, the patient was sent home without supplemental oxygen and with a healing wound on his foot; cyclophosphamide and avacopan were discontinued. Daratumumab (16 mg/kg infusions every 4 weeks) and prednisolone (last with 10 mg/d) were continued. As of January 2023, the patient remained in remission.
In AAV, the ANCAs are believed to contribute to the pathogenesis of the disease.2 If those autoantibodies are produced by long-lived plasma cells, the immunosuppressive therapies for AAV that are usually administered may be ineffective. A limitation of this case report is that the patient could have improved due to the cumulative intensive immunosuppressive therapy that he received and not specifically because of treatment with daratumumab. Nonetheless, the clinical course and apparent response to daratumumab suggest that therapies targeting CD38 should be further studied for patients with severe refractory pulmonary and cutaneous AAV.
Accepted for Publication: January 4, 2023.
Published Online: April 10, 2023. doi:10.1001/jamainternmed.2023.0152
Corresponding Author: Torben M. Rixecker, MD, Department of Internal Medicine 5 (Pneumology, Allergology, and Intensive Care Medicine), Saarland University Medical School, Kirrberger Str 100, 66421 Homburg, Germany (torben.rixecker@uks.eu).
Author Contributions: Dr Rixecker had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Rixecker, Thurner, Bittenbring.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Rixecker, Bittenbring.
Critical revision of the manuscript for important intellectual content: All authors.
Administrative, technical, or material support: Rixecker, Lepper, Espig, Brill, Thurner.
Supervision: Lepper, Thurner, Bittenbring.
Conflict of Interest Disclosures: Dr Thurner reported receiving grants from the Wilhelm Sander Foundation, BioNanoMed, AbbVie, Janssen, and EUSSA-Pharm and participating in advisory boards for Takeda, AstraZeneca, Merck, and EUSA Pharma outside the submitted work; in addition, Dr Thurner, together with others, holds a patent for progranulin antibodies as a marker for autoimmune diseases filed by the Saarland University. Dr Bittenbring reported receiving personal fees from AstraZeneca and MSD outside the submitted work. No other disclosures were reported.
Data Sharing Statement: See the Supplement.
Additional Contributions: The authors are grateful to the patient for agreeing to publish his case. We thank Robert Bals, MD, PhD, Guy Danziger, MD, and Carsten Zeiner, MD, from the Department of Pneumology and Intensive Care Medicine, Saarland University Medical School, for reviewing the manuscript. We thank Anna-Maria Jung, MD, from the Department of Pediatrics, Saarland University Medical School, for technical assistance. None of these individuals were financially compensated for their contributions.