Drug-Associated Dermatomyositis Following Ipilimumab Therapy: A Novel Immune-Mediated Adverse Event Associated With Cytotoxic T-Lymphocyte Antigen 4 Blockade

Importance  Ipilimumab, a human monoclonal antibody targeted against cytotoxic T-lymphocyte antigen 4, has shown promise in the treatment of metastatic melanoma. However, given its mechanism of action, immune-related adverse effects have been reported with this therapy. Despite increasing reports of immune-related adverse effects related to ipilimumab therapy, dermatomyositis associated with this agent has not previously been reported.

Observations  We describe a woman undergoing treatment with ipilimumab for metastatic melanoma who developed classic cutaneous findings of dermatomyositis along with proximal muscle weakness and elevated muscle enzymes.

Conclusions and Relevance  This case adds to the expanding literature regarding immune-related adverse events associated with ipilimumab. To our knowledge, drug-induced dermatomyositis from ipilimumab has not previously been reported. Physicians should be aware of these potential immune-related adverse events and consider drug-associated dermatomyositis in the differential diagnosis in patients receiving ipilimumab who present with a cutaneous eruption or muscle weakness.

Despite recent therapeutic advances, metastatic melanoma has a poor median patient survival and limited treatment options.¹ In 2011, ipilimumab, a human monoclonal antibody targeted against cytotoxic T-lymphocyte antigen 4 (CTLA-4), was approved for use in patients with unresectable or metastatic melanoma. Cytotoxic T-lymphocyte antigen 4 normally serves to transduce a negative costimulation signal when bound to ligand B7 on antigen-presenting cells. When expressed on activated T cells, CTLA-4 counteracts costimulatory signaling through CD28, thus limiting anticancer immunity. Blockade of CTLA-4 releases this negative regulatory checkpoint and can facilitate an effective immune-mediated antitumor response.² Phase 3 clinical trials of ipilimumab have demonstrated an improvement in overall survival in patients with unresectable stage III or IV melanoma.³

Ipilimumab has been associated with multiple immune-related adverse events (irAEs), reflecting its immunomodulatory mechanism of action. A retrospective review of safety data from 14 phase 1 to 3 trials of ipilimumab administered at various doses demonstrated that irAEs of any grade occurred in 64.2% of patients.⁴ A substantial majority of irAEs were graded as mild to moderate, with death due to irAEs occurring in less than 1% of patients. Immune-related adverse events were thought to be dose related and most frequently affected the skin and gastrointestinal tract. The liver and endocrine glands were less often involved, and neurologic manifestations were rare. Less than 1% of patients experienced pancreatitis, uveitis, autoimmune nephritis, pneumonitis, myasthenia gravis, and other irAEs. Furthermore, in a pooled analysis of 325 patients with advanced melanoma treated with CTLA-4 blockade, grade III and IV irAEs occurred in 25.2% of patients, typically affecting the gastrointestinal tract (12%), liver (7%), skin (3%), and endocrine system (3%).⁵

Typically, irAEs present within the first 3 months of ipilimumab therapy.⁶ Dermatologic irAEs occurred in 65% of patients and were classically of mild to moderate severity, often presenting with a morbilliform cutaneous eruption with associated pruritus.⁴ Rarely, patients present with severe or fatal dermatologic irAEs, including Stevens-Johnson syndrome or toxic epidermal necrolysis.² An expanding number of irAEs attributed to ipilimumab have been described in recent literature, with a growing body of reports associating CTLA-4 blockade with conditions including polymyalgia rheumatica and giant cell arteritis syndrome, antibody-induced lupus nephritis, and enterocolitis.^7-9

We report a case of dermatomyositis developing in a patient being treated with ipilimumab for metastatic melanoma. To our knowledge, dermatomyositis is a previously unreported irAE associated with this immunomodulatory therapy. Because this is a single case report, no institutional review board approval was required. The patient provided written consent to have her case reported.

A woman in her 50s presented with stage IV B-RAF V600E mutant malignant melanoma with metastases of the liver, lungs, and peritoneum. Her primary site was unknown. She was started on a course of ipilimumab, 3 mg/kg, intravenously every 4 weeks. Within 2 weeks of the first dose, she developed an erythematous and pruritic eruption on the face, upper chest, posterior neck, upper back, and lateral thighs. With subsequent doses of ipilimumab, the eruption worsened, and she developed painful erythema along the proximal nailfolds, ragged cuticles, erythematous papules over the dorsal knuckles, and upper eyelid erythema. She also reported muscle weakness. The patient was treated with prednisone at an initial dose of 60 mg/d for a presumed grade III immune-related cutaneous reaction secondary to ipilimumab. Prednisone was tapered over 4 weeks with partial resolution of the eruption. Given the severity of her cutaneous eruption as well as the impressive tumor response noted on restaging computed tomography scans, ipilimumab was withheld following the third dose. Subsequent computed tomography scans showed no residual melanoma. The cutaneous eruption improved over several months.

Nearly 14 months after the third dose of ipilimumab, the patient presented with acute and progressive back pain. Results of radiographic imaging, followed by biopsy, revealed metastatic melanoma involving the T3 spine as well as presumed metastatic lesions in the right acetabular fossa, distal right femur, and multiple ribs. Given the patient’s previous dramatic response to ipilimumab and the published benefit of reinduction therapy in patients having an initial response,¹⁰ reinduction therapy with ipilimumab, 3 mg/kg, intravenously every 4 weeks was discussed with the patient. After the risks of recurrent toxicity were clarified, the patient opted to pursue treatment. After one dose of ipilimumab, the patient noted recurrence of the cutaneous eruption on her face, upper chest, posterior neck, upper back, lateral thighs, arms, dorsal hands, and nailfolds. Following the third dose of this course of ipilimumab, the patient also developed acute proximal muscle weakness involving the upper and lower extremities, along with worsening of her cutaneous eruption.

Evaluation by the dermatology department revealed a photodistributed erythematous to violaceous eruption. The patient had diffuse erythema of the forehead and midface, involving the nasolabial folds, as well as erythema and edema of the upper eyelids (Figure 1). She also had diffuse erythema of the upper chest (Figure 1) and upper back with flagellate erythema on the posterior neck. There were few flat-topped pink to erythematous papules over the knuckles on the dorsal hands (Figure 2) as well as prominent erythema at the nailfolds, which also revealed dilated capillary loops, capillary dropout, and ragged cuticles (Figure 3). Findings on clinical examination were consistent with a diagnosis of cutaneous dermatomyositis.

The patient’s musculoskeletal examination revealed grade 4/5 strength on resisted abduction of her shoulders bilaterally as well as limited flexion of both hips. Functionally, the patient had reduced her activity level due to weakness and early fatigue. She denied symptoms of Raynaud phenomenon, dysarthria, dysphagia, or dyspnea.

Laboratory test results revealed an elevated creatine kinase of 1088 U/L (normal, 30-135 U/L), which increased to 1854 U/L on the following day (to convert to microkatals per liter, multiply by 0.0167). The patient’s aldolase activity was also elevated at 23.0 U/L (normal, 0-7.7 U/L) (to convert to microkatals per liter, multiply by 0.0167). C-reactive protein was elevated at 28.6 mg/L (normal, 0-3 mg/L) (to convert to nanomoles per liter, multiply by 9.524). Antinuclear antibody titer was 1:640 with a speckled pattern. Jo-1 antibody was negative. The patient declined a skin biopsy. Findings on magnetic resonance imaging demonstrated mild short TI inversion recovery hyperintensity of the bilateral vastus lateralis and rectus femoris muscles. These imaging findings, along with the patient’s classic cutaneous examination, proximal muscle weakness, and elevated serum muscle enzymes, were consistent with a diagnosis of dermatomyositis. A scheduled fourth dose of ipilimumab was withheld.

The patient’s muscle weakness progressed rapidly over 3 days. Oral prednisone, 80 mg/d, was initiated but the patient’s condition continued to worsen, requiring the use of a wheelchair and hospitalization for intravenous methylprednisolone, 80 mg twice daily. A biopsy of the vastus lateralis muscle was performed, which demonstrated atrophy of type II muscle fibers but no evidence of inflammatory myositis. However, this biopsy was performed 6 days after the patient was initiated on systemic corticosteroids. Given improvement with intravenous methylprednisolone, the patient was discharged on oral prednisone, 1 mg/kg/d. Within 14 days of starting corticosteroid therapy, the patient’s serum creatine kinase and aldolase activity normalized, and her strength improved dramatically. Prednisone was tapered slowly over the following 8 weeks. Despite marked improvement in her muscle enzyme levels and strength, the patient’s cutaneous eruption improved only minimally during this same period.

Given the prominent toxicity to ipilimumab, this therapy was discontinued. Notably, there are no data supporting the continued administration of ipilimumab in the setting of high-dose systemic corticosteroid use. The clinical trials leading to approval of ipilimumab excluded patients who required systemic corticosteroids, and existing ongoing clinical trials require that patients taper to no more than 10 mg of prednisone daily before restarting ipilimumab to avoid suppressing the immunomodulatory effects of ipilimumab. Although the patient’s metastatic disease stabilized for 4 months following reinduction with ipilimumab, she soon developed progressive disease. Subsequently, she was treated with a combination of B-RAF and mitogen-activated protein/extracellular signal–regulated kinase inhibitors (dabrafenib and trametinib) and experienced rapid and significant tumor shrinkage, but she continues to have only a partial response to this regimen.

To our knowledge, this is the first report of dermatomyositis developing as an irAE to ipilimumab in a patient with metastatic melanoma. Considering the role CTLA-4 plays in regulating tolerance to self-antigens, ipilimumab has been associated with various irAEs, reflecting its immunopotentiating mechanism of action.²

In our patient, a diagnosis of dermatomyositis was supported by classic cutaneous findings, proximal muscle weakness, and elevated muscle enzymes. There was a lack of classic inflammatory myositis noted on muscle biopsy, but this was potentially explained by the high-dose systemic corticosteroids received by the patient for 6 days prior to the biopsy. Notably, a diagnosis of dermatomyositis can be made based on the presence of proximal muscle weakness, elevated muscle enzymes, and classic cutaneous findings. In this patient, the timing of the presentation of clinical findings following initial administration of ipilimumab, followed by slow improvement and resolution after discontinuation of this therapy and recurrence of rash and muscle weakness after reinitiation of CTLA-4 blockade, suggest an ipilimumab-related adverse event.

Although most cases of dermatomyositis are idiopathic, 15% to 30% of adult-onset cases occur as a paraneoplastic syndrome.¹¹ In light of this patient’s known malignant melanoma, a paraneoplastic presentation of dermatomyositis could be considered, although dermatomyositis is only rarely associated with melanoma and the timing suggests a drug-related cause in this particular case. The recurrence of symptoms following rechallenge with ipilimumab points to a drug-induced presentation. Importantly, although the patient initially presented and then re-presented with metastatic disease, she developed findings of dermatomyositis only following administration of ipilimumab on both occasions, making a paraneoplastic presentation of dermatomyositis less likely. Some data on paraneoplastic rheumatic diseases suggest that the immune response to cancer is highly associated with the autoimmune disease.¹² It is possible that ipilimumab administration could alter the immune response to an underlying malignancy, hence requiring both the presence of the drug and the malignancy to develop this irAE. Given ipilimumab’s current indications, it will be challenging to learn whether ipilimumab alone could result in drug-induced dermatomyositis in the absence of an underlying malignancy.

A number of medications have been reported to induce or exacerbate dermatomyositis. In the largest series published on this subject to date, the most frequent drug associated with cutaneous dermatomyositis was hydroxyurea.¹³ Furthermore, multiple other therapies have been associated with inducing skin, muscle, and even pulmonary manifestations of dermatomyositis.¹³ Importantly, in the majority of these cases, discontinuation of the culprit agent led to subsequent improvement in dermatomyositis, further supporting the diagnosis of drug-induced disease.¹³ More recently, anti–tumor necrosis factor therapies have been associated with drug-induced or drug-exacerbated dermatomyositis, lending additional support to the concept of drug-associated dermatomyositis.^14,15

The co-occurrence of drug administration and clinical findings of dermatomyositis on administration and rechallenge with ipilimumab suggest that this patient’s presentation with dermatomyositis is an irAE caused by this agent. In the context of the expanding reports of irAEs associated with CTLA-4 blockade, this report adds another entity to the growing list of potential ipilimumab-related immune phenomena. Physicians should be aware of these potential irAEs related to ipilimumab and consider drug-associated dermatomyositis when evaluating patients receiving CTLA-4 blockade therapy.

Accepted for Publication: July 9, 2014.

Corresponding Author: Ruth Ann Vleugels, MD, MPH, Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Ave, Boston, MA 02115 (rvleugels@partners.org).

Published Online: October 15, 2014. doi:10.1001/jamadermatol.2014.2233.

Author Contributions: Drs Werchniak and Vleugels had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Werchniak and Vleugels represent co-last authors.

Study concept and design: Sheik Ali, Luke, Todd, Werchniak, Vleugels.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Sheik Ali, Goddard, Luke, Vleugels.

Critical revision of the manuscript for important intellectual content: All authors.

Administrative, technical, or material support: Sheik Ali, Luke, Vleugels.

Study supervision: Goddard, Luke, Werchniak, Vleugels.

Conflict of Interest Disclosures: None reported.

Additional Information: Dr Vleugels’ career has been supported by a Medical Dermatology Career Development Award from the Dermatology Foundation.