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What's Causing Cancer Patient's Joint Pain While on Checkpoint Inhibitor?

— Here is how clinicians diagnosed this rare inflammatory side effect

MedpageToday
Photo of 72-year-old woman being evaluated for mild pain and joint stiffness in her hand.
Clinical image shows extensive discoloration and woody induration of the patient's right forearm.

A 72-year-old woman presented to a rheumatology clinic for evaluation of mild pain and joint stiffness in her hands. She explained that the symptoms developed about 3 weeks after starting treatment with cemiplimab (Libtayo) for metastatic cutaneous squamous cell carcinoma involving the parotid gland and thoracic vertebral bodies.

She noted that the severity of pain tended to worsen over the course of the day and was aggravated by exertion. She had no other symptoms such as joint swelling, fatigue, mouth dryness, difficulty swallowing, or skin changes, and she said she had not participated in any vigorous exercise.

She had no medical history of autoimmune or hematologic disease. Physical examination showed small Heberden nodes on the first two fingers on each hand, but no other unusual findings.

Lab test results included elevated titers of anti-nuclear antibody (1:1,280), rheumatoid factor (101 IU/mL), and Sjogren's Syndrome A antibody (64 AU/mL).

The medical team decided, based on the patient's clinical history and physical examination, that her joint pain was not likely related to an autoimmune problem, and arrived at a presumptive diagnosis of osteoarthritis.

She was advised to have treatment with non-steroidal anti-inflammatory drugs (NSAIDs) as needed, and to return for further tests if the symptoms worsened; several weeks of treatment, however, the symptoms did show improvement.

The patient's chemotherapy continued, and for the following year she received cemiplimab, and then was transitioned to carboplatin and radiation therapy. However, the cancer unfortunately relapsed shortly after the start of radiation and she resumed treatment with cemiplimab.

Within 2 weeks of restarting cemiplimab, the patient developed severe joint pain, morning stiffness, skin discoloration, and woody induration extending along both forearms to the wrist, with sparing of the distal forearms and hands.

Physical examination showed depression along the course of the basilic veins, suggestive of the Groove sign. The patient was also unable to extend her elbows without severe pain.

Clinicians noted that she had full range of motion of the cervical spine, with normal flexion, extension, and lateral movement; her lumbosacral spine was also normal. There was normal abduction, flexion, extension, external rotation, and internal rotation of both hips and shoulders. Her grip strength was decreased (3/5 on the left and 4/5 on the right).

Laboratory studies, including hemoglobin, white blood cells, platelets, electrolytes, and calcium, were within normal limits:

  • Absolute eosinophil count: 0.28 K/uL (reference range 0.1-0.5 K/uL)
  • Erythrocyte sedimentation rate: 3 mm/h (reference range 0-30 mm/h)
  • Serum creatine phosphokinase level: 35 U/L (reference range 26-192 U/L)
  • Aldolase: 4.7 U/L (reference range 1.0-7.5 U/L)

Clinicians performed a full-thickness skin biopsy of an affected region on the patient's right forearm, which showed fibrosis of the subcutaneous connective tissue, cellular infiltration by eosinophils and monocytes, and thickening of the fascia mononuclear infiltrate with plasma cells and eosinophils. After considering the clinical, laboratory, and histopathologic findings, the team diagnosed the patient with eosinophilic fasciitis (EF).

The medical team excluded differential diagnoses of systemic sclerosis, given the atypical, pattern of skin involvement, and of myositis in light of the patient's normal levels of serum creatine phosphokinase and aldolase.

Cemiplimab was discontinued and clinicians advised treatment with methotrexate, which the patient declined, based on concern that it might increase her risk of developing a second malignancy. She was instead treated with hydroxychloroquine 200 mg twice daily, prednisone 40 mg once daily, and sulfasalazine 500 mg twice daily.

Her symptoms improved within a week, and resolved within a month. Thereafter, she resumed treatment with cemiplimab at a reduced dose, and was monitored bi-weekly for adverse effects.

Discussion

The authors presenting this of EF in a patient on chemotherapy with a checkpoint inhibitor (CPI) noted that prompt recognition and treatment of this rare adverse effect are essential to reduce pain and optimize quality of life.

The authors explained that EF can often be diagnosed based on clinical presentation of key symptoms such as woody induration of the skin and joint stiffness, although in some cases, a skin biopsy may be necessary.

Immune checkpoints are inhibitory immune pathways that maintain self-tolerance by regulating the immune responses in tissues, with PD-1, its ligand PDL-1, and cytotoxic T-lymphocyte-associated protein 4 playing a well-documented role.

The humanized monoclonal antibody blocks the PD1/PDL1 pathway and is used in treatment of squamous cell carcinoma.

CPIs are known to cause musculoskeletal manifestations such as arthralgia, myalgia, and arthritis. The case authors noted that scleroderma or scleroderma-like manifestations – classified under non-musculoskeletal – are less likely to be seen with the use of these drugs.

EF, previously called Shulman syndrome, is a rare inflammatory condition marked by "erythema and edema of the trunk and limbs, followed by diffuse collagenous thickening of the subcutaneous fascia," the case authors explained. The condition is often associated with persistent hypergammaglobulinemia, and with eosinophilia, which may decrease and resolve with disease progression.

EF often affects young adult men, although it has also been reported in children and the elderly. As in this patient, EF is typically marked by woody induration with skin thickening and orange-colored hyperpigmentation of the trunk and/or extremities. Localized morphea -- i.e., inflammation in the reticular dermis and superficial panniculus -- has also been reported.

EF generally spares the face and hands, although in this patient the upper and lower extremities were affected on the left and right sides. The case authors emphasized that in some patients, skin symptoms of EF may not occur at all, or may develop later in the disease course.

In patients who do not present with classic skin symptoms, investigations should include lab tests for eosinophilia and hypergammaglobulinemia and MRI assessment of the fascia to establish a diagnosis of EF.

The disease commonly causes muscle weakness and rigidity, with synovitis and contractures occurring less frequently. Because EF with those of many other diseases, diagnosis is often delayed.

According to the , acrocyanosis affects 80-99% of people with EF, while fasciitis, myositis, and paresthesia occur in 5-29% of individuals with EF.

Histopathology analysis of a full-thickness biopsy sample showed fibrosis of the subcutaneous connective tissue, cellular infiltration by eosinophils and monocytes, and thickening of the fascia, the authors noted.

They added that diagnosis does not require the presence of eosinophils and that clinical rather than pathological features can be used to differentiate EF from progressive systemic sclerosis.

Major diagnostic criteria for EF include the following:

  • Symmetric or asymmetric swelling
  • Induration and thickening of the skin or subcutaneous tissues
  • Full-thickness wedge biopsy showing fascial thickening with lymphocytes and macrophages, with or without eosinophils

Minor diagnostic criteria include:

  • Peripheral eosinophilia
  • Hypergammaglobulinemia
  • Muscle weakness
  • Groove sign
  • MRI showing T2 hyperintensity of the fascia

The authors referenced nine other case reports of EF related to immune checkpoint inhibitors atezolizumab, nivolumab, pembrolizumab, and ipilimumab; the team noted, however, that they believe this to be the first report of EF related to use of cemiplimab.

EF has also been associated with simvastatin, atorvastatin, phenytoin, and lansoprazole, as well as with medications including L-tryptophan, the authors noted: In addition, EF has been linked with use of nutritional supplements, and with Borrelia afzelii infection. Chronic autoimmune disease has also been suggested as a possible etiology.

The of CPI-induced EF has not been identified: persistent T and B cell activation may lead to "secretion of cytokines that promote eosinophil hyperactivation and the release of transforming factor beta," which in turn may increase "expression of type I collagen and other substances implicated in the classic manifestations of EF," the case authors stated.

Further study of the association of CPIs with EF is warranted, they said.

While there are no clinical guidelines for the management of immune CPI-associated EF, treatment generally involves cessation of the offending medication, and use of methotrexate and/or corticosteroids, depending on individual patient characteristics and preferences.

Because this patient refused methotrexate due to her concern about the possibility of a second malignancy, the medical team offered a regimen of corticosteroids, hydroxychloroquine, and sulfasalazine, and while each of these has been used to treat EF separately, the combination has not been studied, the authors noted.

Conclusion

They concluded that although EF is seldom fatal, prompt recognition and treatment is essential to reduce pain and optimize quality of life. There are no clinical guidelines for the management of immune CPI-related EF, but a regimen of immunosuppressant medications, which can include methotrexate and/or corticosteroids, and temporary cessation of the "offending agent" may control symptoms and prevent progression.

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    Kate Kneisel is a freelance medical journalist based in Belleville, Ontario.

Disclosures

The case report authors noted no conflicts of interest.

Primary Source

American Journal of Case Reports

Boppana SR, et al "Drug-associated eosinophilic fasciitis: A case of eosinophilic fasciitis secondary to cemiplimab therapy" Am J Case Rep, 2021; 22: e932888.