Via Research Recognition Day 2024 VCOM-Carolinas

Clinical Case-Based Reports

A CASE REPORT ON PUSTULAR HYPERSENSITIVITY: COMBINATION OF SYMPONI ARIA AND PROLIA Christopher Jue, OMS-III; Wayne Davis, MD. Edward Via College of Osteopathic Medicine, Spartanburg, SC.

Abstract # Goes here

Abstract

Clinical Case

Discussion

Pustular Hypersensitivity is a Type IVd reaction. These reactions are mediated by T cells and granulocyte-monocyte colony stimulating factor. Type IV Hypersensitivity Reactions are commonly seen with contact dermatitis and drug hypersensitivity 6 . Although many drugs can cause adverse reactions, biologic drugs are highly immunogenic proteins that focus on the immune system and are administered parenterally 5 . While adverse skin reactions to denosumab and golimumab have been discussed alone, their combination has yet to be published. Denosumab is a monoclonal antibody with a high affinity for RANKL. This drug’s primary use is for treatment of osteoporosis by preventing osteoclast formation. The most common adverse effects of the drugs include back pain, pain in the extremity, hypercholesterolemia, musculoskeletal pain, and cystitis. Although less common, serious skin infections and dermatitis are also seen with this monoclonal antibody 11 . One case explains a 65-year-old woman who noticed systemic urticaria, eyelid angioedema, and a pruriginous lesion at the injection site 8 . Another case mentioned cutaneous lichenoid drug eruptions from denosumab in a lymphohistiocytic reaction pattern 9 . Several research studies show that it is possible to use desensitization to combat the adverse skin reactions associated with denosumab. The desensitization protocol of denosumab was tested using IgE levels 7 . Golimumab is a monoclonal antibody that primarily acts as a Tumor Necrosis Factor (TNF)- α inhibitor 13 . Golimumab is currently FDA approved to treat resistant rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and polyarticular juvenile idiopathic arthritis 12 . Golimumab has shown to cause a delayed T-cell mediated response 13 . One patient receiving golimumab for ulcerative colitis (UC) was described to have a persistent erythema multiforme reaction. Erythema multiforme is a type of hypersensitivity reaction. The delayed skin reaction occurred eighteen months after the start of successful treatment for UC. Sections A and B of Figure 1 below show a gross image of the skin reaction. The imaging displays an annular lesion with a pink central zone and peripheral erythema. The histology in part C shows lymphocytic infiltrates with vacuolar changes and dyskeratosis of basal epidermal cells. Part D is a CD8+ stain further confirming a delayed Type IV Hypersensitivity reaction 2 . ● The antibiotic and steroid resistant rash was determined to be pustular hypersensitivity due to a combination of the monoclonal antibodies. ● Additional symptoms included dizziness, fever, sore and swollen throat, and an ear infection. ● Once the offending immunologic medications were removed, symptoms gradually improved. ● This case focuses on the recognition of less common and more severe adverse skin reactions associated with monoclonal antibodies. Introduction ● Skin reactions to monoclonal antibodies are commonly reported adverse effects. ● Although most reactions are localized injection site inflammation, monoclonal antibodies have also shown to cause more severe, systemic rashes 1 . ● This is a case of a 71-year-old Caucasian female with osteoporosis and rheumatoid arthritis being treated with denosumab and golimumab. ● While on these medications, the patient saw a rash that began on her bilateral lower extremities that eventually became bullous and spread throughout the entire body.

A 71 year old Caucasian female presented to the clinic with a blistering rash on both of her lower extremities that has recently spread to her feet, arms, palms, and scalp. The rash began four months ago and has worsened over the last six weeks. She also mentioned throat soreness and swollen glands around the neck. The patient has a history of several drug allergies. The patient has Rheumatoid Arthritis and Osteoporosis being treated with Symponi Aria (golimumab) and Prolia (denosumab). The Rheumatologist who prescribed both immunologics was adamant that the reaction was Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome. Patient was referred to dermatologist and a punch biopsy was performed. Dermatologist prescribed doxycycline and clobetasol, and the patient was instructed to discontinue Prolia and Symponi Aria. She returned to the office the following week complaining of dizziness of two days duration. Neck soreness was still noted with edema on the anterior neck near the thyroid. The rash spread to all extremities and the abdomen. Patient was instructed to continue doxycycline and clobetasol. The patient returned three days later after a firm, red sore developed overnight on her groin. This sore was identified as a recurrent allergic drug reaction, and the patient was prescribed mupirocin ointment. Dermatologist were able to drain the cyst in the groin region and treat with oral prednisone. Punch biopsy of the rash showed spongiotic and pustular dermatitis with eosinophils. Diagnosis of pustular hypersensitivity reaction was made. During the peak of rash severity, the patient noted right ear pain that had persisted for two weeks. The patient’s ear pain improved after treatment with amoxicillin, but the body rash persisted. Patient met with a rheumatologist who determined the cause of the rash was the combination of Prolia and Symponi Aria immunologics. It was later reported that the Rheumatologist administered both infusions at the same time on Friday evening because he was rushed for time. The co-administration was done against protocols and was approved by the infusion technician. Rash is reported more times with Prolia and was found to be the offender. Prolia may have potentiated Simponi Aria treatment and caused pustular hypersensitivity. After discontinuing biologic medications for three months, the patient’s rash disappeared, and her symptoms improved.

Adverse skin reactions to denosumab and golimumab have been researched separately. This study explores the possible pustular hypersensitivity that occurred when both monoclonal antibodies were used in combination. Denosumab has been shown to cause dermatitis in some patients 4 . The dermatitis in this patient could have been worsened with the use of golimumab, the (TNF)- α inhibitor. One common adverse effect of (TNF)- α inhibitors, specifically golimumab, is potential for opportunistic infections 11 . (TNF)- α is a pro-inflammatory cytokine. If this cytokine is damaged, potential for infections and inflammation would increase. These warnings include infection reactivation, malignancy, hypersensitivities, and cytopenias 3 . This combination may have led to the more systemic, delayed dermatitis seen with the patient. The systemic symptoms such as fever, anterior neck soreness and swelling, and localized cyst also raise concern that the infection was more severe than the common localized skin reaction that is seen from denosumab alone. The biopsy showing spongiotic and pustular dermatitis also confirmed the Type IV Hypersensitivity Reaction. This study is the first to show the adverse reaction between denosumab and golimumab.

Conclusion

● The intention of this case is to identify a rare adverse skin reaction between two monoclonal antibodies. ● The first monoclonal antibody was generated in 1975, which makes these drugs a relatively new area of study for researchers 10 . Research on immunologic drug benefits is increasingly surfacing. ● As use of biologic medications continues, more data of adverse reactions will become available. Developing a comprehensive list of adverse effects of each immunologic drug will be essential in the coming years. ● Once this goal is achieved, monoclonal antibodies will be better understood and can be used for more specific purposes.

Acknowledgements

The author of this poster would like to acknowledge and thank Dr. Wayne Davis for his assistance and guidance in developing this case report.

References

Figure 1 (top left) displays an adverse skin reaction associated with Golimumab along with pathology of lymphocytic infiltrates. Figures 2-4 show the patient’s systemic skin reactions due to combination treatment of golimumab and denosumab.

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