Introduction
Pembrolizumab is a humanized antibody that targets the programmed cell death-1 (PD-1)
receptor. It is currently approved by the US Food and Drug Administration for patients
with advanced melanoma and metastatic non–small cell lung cancer. As an immune checkpoint
inhibitor, pembrolizumab augments a patient's immune system against an underlying
malignancy.
Systemic toxicities associated with use of PD-1 inhibitors such as fatigue, pyrexia,
chills, and infusion reactions have been commonly reported.
1
We report a case of sarcoidosis flare associated with pembrolizumab, which is, to
our knowledge, the first reported case of sarcoidosis linked to PD-1 inhibition.
Case report
A 72-year-old woman with refractory, stage IV Hodgkin lymphoma diagnosed in 2014 was
placed on pembrolizumab, 200 mg intravenously every 3 weeks. Twelve years prior, the
patient had gallstone pancreatitis, and a chest x-ray at that time found bilateral
hilar adenopathy. Subsequent mediastinoscopy and lymph node biopsy were notable for
sarcoidosis, although the patient was never symptomatic and was never treated.
Approximately 6 months after starting pembrolizumab, the patient presented to the
dermatology clinic with slowly enlarging, asymptomatic subcutaneous nodules on her
arms. Physical examination found 2 nontender, subcutaneous nodules on the right extensor
forearm without overlying erythema, with the largest nodule measuring 10 cm in diameter
(Fig 1, A). There was a similar, smaller nodule on the left forearm. Punch biopsy
of the larger right forearm nodule found mild lymphohistiocytic perivascular dermatitis
with a focal, dermal epithelioid granuloma (Fig 2, A and B). Infectious stains and
tissue cultures were negative. Based on the clinical presentation and medical history,
a diagnosis of cutaneous sarcoidosis was made.
Pembrolizumab was held for the progressing skin lesions and a positron emission tomography/computed
tomography scan was performed to reassess the status of the lymphoma. The imaging
found new bilateral pulmonary parenchymal patchy ground glass opacities with septal
thickening. There were also new hypermetabolic areas within multiple bones, including
the left side of the scapula (Fig 3, A), sternum, and the right side of the iliac.
Interval increases in fludeoxyglucose (FDG)-avid mediastinal and bilateral hilar lymph
nodes (Fig 3, B), compared with 3 months prior were seen. It was unclear whether these
changes were secondary to lymphoma or sarcoidosis.
Soon thereafter, the patient had left eye pain, and evaluation by an ophthalmologist
found acute iritis attributable to sarcoidosis. In addition, she had dyspnea and was
referred to cardiothoracic surgery for consideration of video-assisted thoracoscopic
surgery to determine the etiology of the dyspnea and adenopathy. However, the patient
declined to pursue lung/lymph node biopsy. A decision was made to initiate an empiric
trial of prednisone at a dose of 60 mg orally daily, to see if there would be a favorable
clinical/radiographic response, based on the presumption that sarcoidosis induced
by pembrolizumab, and not lymphoma, was the etiologic culprit for the clinical and
imaging features.
Shortly after the initiation of prednisone, the left eye pain and dyspnea resolved,
and within 1 month, the skin nodules resolved (Fig 1, B). Reimaging performed approximately
3 months after the prior scans (1 month after starting prednisone) found complete
resolution of the FDG-avid skeletal regions previously noted (Fig 3, C) as well as
resolution of the hilar and mediastinal adenopathy (Fig 3, D). The patient's lymphoma
is currently in complete remission since she stopped taking pembrolizumab for the
last 4 months.
Discussion
Early reports of the PD-1 inhibitors pembrolizumab and nivolumab described exacerbation
of psoriasis for patients with a previous history of skin disease and de novo development
of psoriasis in patients who lacked both a personal and family history.2, 3, 4 More
severe cutaneous toxicities such as Stevens-Johnson syndrome have also been reported.
5
A retrospective review of 82 patients treated with PD-1 inhibitors for metastatic
melanoma found that 49% (40 of 82) of treated patients had some form of adverse cutaneous
event, with lichenoid dermatitis (17%), eczematous dermatitis (17%), and vitiligo
(15%) being the most common dermatoses.
6
In an additional retrospective case series of 83 patients, pembrolizumab use was associated
with skin toxicity in 42% (35 of 83), with papular eruptions (29%) most common, followed
by pruritus (12%), and hypopigmentation (8%).
7
Of particular concern, based on the method by which PD-1 inhibitors are effective
in unleashing an individual's immune system against an underlying cancer, would be
the exacerbation or de novo development of autoimmune disorders, cutaneous and systemic.
Although there is evidence that patients with diseases such as Churg-Strauss can be
treated successfully with PD-1 inhibition for melanoma without subsequent flare of
their vasculitis,
8
there are also cases in which PD-1 inhibitor use has led to rapid progression of previously
stable patients with autoimmune diseases such as myasthenia gravis.
9
Recent reports of the development of autoimmune blistering skin disorders such as
bullous pemphigoid from PD-1 blockade provide additional concerns about the risk of
autoimmune sequelae from immune checkpoint inhibitors.
10
Our case is notable beyond the fact that it is, to our knowledge, the first reported
case of sarcoidosis flare associated with PD-1 blockade. It highlights the diagnostic
difficulty of discerning the etiology of adverse events that may radiographically
mimic the disease for which the PD-1 inhibitor is being used; sarcoidosis, like lymphoma,
presents with increased FDG avidity on positron emission tomography/computed tomography
scans. Our patient's skin nodules were bothersome, but the acute iritis and dyspnea
necessitated prednisone use, which eventually led to the resolution of the clinical
and imaging features. Without tissue confirmation of sarcoid involving the skin and
the development of sarcoidal iritis, it is conceivable that the mediastinal, pulmonary,
and skeletal lesions could have been falsely attributed to progression of the lymphoma.
While our patient had a history of asymptomatic pulmonary sarcoidosis, the development
of dyspnea, iritis, and subcutaneous nodules after several months of pembrolizumab
use implicates PD-1 blockade in the progression of sarcoidosis in this circumstance.
This case highlights the importance of being mindful of the spectrum of toxicities
associated with PD-1 inhibitors and ensuring that these toxicities don't obfuscate
a favorable clinical response. More importantly, it should raise awareness that PD-1
inhibition, although helpful in redeploying an individual's immune response against
an underlying malignancy, may exacerbate underlying autoimmune conditions such as
sarcoidosis, as an unexpected consequence.