A Case Series of Raynaud’s Phenomenon in the Setting of Immune Checkpoint Inhibitors

Abstract

Although immune checkpoint inhibitors (ICIs) have improved oncological outcomes, they can cause a myriad of inflammatory conditions known as immune-related adverse events (irAEs). Raynaud’s phenomenon (RP) is a rare rheumatologic irAE that may arise de novo or present as an exacerbation of preexisting disease. This case series aims to describe ICI-induced RP in patients without a rheumatological diagnosis seen at a large, specialized cancer center. Our case series describes five patients with ICI-induced RP who were evaluated by rheumatology at a cancer center during the past 3 years where their cancers, type of ICIs, diagnostic tests, and treatments are discussed in detail. Among our five patients, one patient had preexisting psoriatic arthritis, and one had preexisting RP. The outcome of our patients’ ICI-induced RP varied widely. Although three patients had significant digital ischemia resulting in ulceration requiring epoprostenol infusions, the remaining two patients had mild digital ischemia that were controlled conservatively. However, none of our patients had clinical features to suggest systemic sclerosis (SSc), where RP is often the first symptom. Interestingly, interferon-γ and interleukin-6 were the most frequently elevated cytokines when checked in these patients. This is the first case series, to the authors’ knowledge, to describe ICI-induced RP, which may occur without other clinical features of an autoimmune rheumatological disease. The severity of the disease may vary, but it warrants increased awareness and prompt initiation of appropriate treatment.

INTRODUCTION

Immune checkpoint inhibitors (ICIs) have significantly improved long-term cancer survival but can trigger immune-related adverse events (irAEs), including de novo or preexisting autoimmune disorders flare-ups.[1] One rare rheumatological irAE, although possibly underrecognized because some cases may be mild, is Raynaud’s phenomenon (RP), which can have serious consequences.[2] RP may be primary or secondary. Although primary RP usually occurs alone and early in a person’s life, secondary RP, often related to endothelial dysfunction, can signal development of an autoimmune connective tissue disorder, particularly systemic sclerosis (SSc).[3]

Here, we report five patients with different malignancies treated with ICIs who developed either de novo RP or exacerbated preexisting RP (Table 1). The severity of their RP varied widely and warranted close monitoring because some had severe digital ischemia and ulcerations. Finally, an exploratory cytokine analysis, at the onset of their RP, may possibly provide us more clues on risk factors for developing ICI-induced RP and a window to understanding the pathogenesis of autoimmune connective tissue disorders.

Table 1.

Timeline of ICI-related Raynaud’s phenomenon (RP) development and treatment

Patient and Cancer Diagnosis	Dose and Frequency of ICI	RP Onset After the Last Dose of ICI	Treatment Initiated	Outcome	Other irAEs
Patient 1: Stage III squamous cell lung cancer	Durvalumab 1500 mg once	2 weeks	Conservative	Cancer stable and RP controlled well	None
Patient 2: Stage III sigmoid colon adenocarcinoma	Two cycles of a combined PD-1 and CTLA-4 inhibitors	2 days	Nitroglycerine paste, amlodipine sildenafil, and epoprostenol infusion	Cancer in remission and RP controlled with amlodipine	Dermatitis
Patient 3: Stage IV melanoma	Combined nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks and nivolumab 480 mg once	Preexisting RP worsened after ICI started	Amlodipine	Cancer stable and RP controlled with amlodipine	Reactive arthritis and colitis
Patient 4: Stage IV lung adenocarcinoma	Pembrolizumab 200 mg once and combined ipilimumab 1 mg/kg and nivolumab 360 mg every 6 weeks for two cycles	3 weeks	Prednisone, amlodipine, and epoprostenol infusion	Expired due to oncological complications and RP controlled well	Dermatitis
Patient 5: Stage IV renal cell carcinoma	Nivolumab 240 mg every 2 weeks for 16 cycles and 480 mg every 4 weeks for eight cycles and pembrolizumab 200 mg every 3 weeks for 20 cycles	40 months after last nivolumab and 4 weeks after last pembrolizumab	Nifedipine, sildenafil, prednisone, epoprostenol infusion, and percutaneous transluminal angioplasty	Expired due to oncological complications and RP controlled well	None

ICI: immune checkpoint inhibitor; irAEs: immune-related adverse events.

CASE SUMMARIES

Case 1

A 77-year-old woman (former smoker) with psoriatic arthritis on leflunomide 20 mg daily and stage III squamous cell lung cancer, treated with surgery, weekly carboplatin 93 mg, weekly paclitaxel 50 mg/m², and radiation was evaluated after one-time durvalumab 1500 mg. Two months before starting durvalumab, the patient underwent five cycles of carboplatin and paclitaxel without issues. However, 2 weeks after receiving durvalumab, the patient developed a psoriasis flare, as well as cold and purple feet that resolved with rewarming. She had no uncontrolled diabetes, no peripheral neuropathy symptoms, and no peripheral vascular disease based on ankle-brachial indices. She denied having other SSc symptoms such as puffy hands, skin tightening, calcinosis, telangiectasia, dysphagia, acid reflux, bloating, constipation, and diarrhea. She had dry cough due to radiation pneumonitis and was on prednisone 40 mg daily. Her physical examination showed an ulcer on the right second toe due to trauma and crackles in the right lung field. Other than psoriasis on her elbows, the rest of her physical examination did not suggest SSc development (e.g., no skin thickening, puffy hands, sclerodactyly, synovitis, calcinosis, or telangiectasia). The patient’s autoimmune labs are shown in Table 2. Cytokine panel was checked while her cancer was stable with no other irAEs, but she had been on prednisone 40 mg daily for 35 days for radiation pneumonitis.

Table 2.

Autoimmune serum workup

Laboratory Test	Patient 1	Patient 2	Patient 3a	Patient 4	Patient 5
ANA	Negative	Negative	Negative	1:640 nucleolar	Negative
Anti-Scl70 Ab (< 1 U)	Negative	NA	Negative	Negative	Negative
Anti-RNA polymerase 3 Ab (< 20 U)	Negative	NA	55.4	Negative	Negative
Anti-Smith Ab (< 1 U)	Negative	NA	Negative	Negative	Negative
Anti-RNP Ab (< 1 U)	Negative	NA	Negative	1.1	Negative
Anti-dsDNA Ab (< 30 IU/mL)	Negative	Negative	Negative	Negative	Negative
Anti-SS-A Ab (< 1 U)	Negative	Negative	Negative	Negative	Negative
Anti-SS-B Ab (< 1 U)	Negative	Negative	Negative	Negative	Negative
RF (< 14 IU/mL)	Negative	Negative	Negative	Negative	Negative
Anticyclic citrullinated peptide Ab (< 20 U)	Negative	NA	Negative	Negative	Negative
Cryoglobulin	Negative	Negative	Negative	Negative	Negative
Antimyeloperoxidase Ab (< 0.4 U)	NA	Negative	NA	Negative	Negative
Antiproteinase 3 Ab (< 0.4 U)	NA	Negative	NA	Negative	Negative
Lupus anticoagulant	NA	NA	NA	Negative	Negative
Anticardiolipin IgG (< 15 GPL)	NA	Negative	NA	Negative	Negative
Anticardiolipin IgM (< 15 GPL)	NA	Negative	NA	Negative	Negative
Anti-β2 glycoprotein IgG (< 15 SGU)	NA	Negative	NA	Negative	Negative
Anti-β2 glycoprotein IgM (< 15 SGU)	NA	Negative	NA	Negative	Negative
C3 (75–175 mg/dL)	133	115	141	169	63
C4 (14–40 mg/dL)	31	26	31	37	17
Erythrocyte sedimentation rate (< 20 mm/h)	26	39	75	50	25
C-reactive protein (< 1 mg/dL)	9.3	8.44	76	186	81.87
Interferon-γ (< 5 pg/mL)	2.9	8	18	NA	49
Tumor necrosis factor-α (< 22 pg/mL)	28	21	21.9	NA	59
Interleukin-6 (< 5 pg/mL)	28	< 5	26	NA	25

Note - Abnormal values are shown in bold.

^aFor patient 3, the discrepancy between the negative ANA and anti-RNA polymerase 3 was rechecked and confirmed with our divisional research lab. ANA was negative on multiple occasions, so it is likely that the anti-RNA polymerase 3 auto-antibody is negative.

Ab: antibody; ANA: antinuclear antibodies; C3: complement 3; C4: complement 4; dsDNA: double stranded DNA; IgG: immunoglobulin G; IgM: immunoglobulin M; NA: not available; RF: rheumatoid factor; RNP: ribonucleoprotein; Scl70: Scleroderma-70.SS-A: Sjogren’s syndrome-related antigen A; SS-B: Sjogren’s syndrome-related antigen B.

The patient’s RP was managed conservatively because amlodipine caused hypotension. Her ulcer healed with wound care. Durvalumab was stopped because of concerns that it may worsen radiation pneumonitis. Despite not having received additional durvalumab, her RP continues to occur daily and is managed conservatively. Her cancer remains stable.

Case 2

A 46-year-old woman (never smoker) with Lynch syndrome and stage III sigmoid colon adenocarcinoma on programmed cell death 1 (PD-1) and cytotoxic T-cell lymphocyte-associated protein 4 inhibitor (CTLA-4) inhibitor (clinical trial), without prior systemic chemotherapy, was evaluated for new-onset RP. The patient previously had ICI-induced dermatitis.

Two days after the second cycle of ICIs, her right fifth digit turned dusky after a finger stick. Five days later, her right second digit turned dusky without trauma. The color change initially worsened with cold or stress and improved with rewarming but became less responsive later. She denied having other SSc symptoms. Physical examination showed dusky and cool right second and fifth digits, a weaker right radial pulse compared with the left side, and a diffuse erythematous rash over her back and chest. Similar to patient 1, she had absent SSc findings.

The patient’s autoimmune laboratory workup is shown in Table 2. Her cytokine panel was checked when her cancer had been improving; she was on prednisone 10 mg daily for ICI dermatitis. Her computed tomography angiogram (CTA) of the right upper extremity showed no flow in the distal aspects of the index and small digits without evidence of occlusive embolus, which was confirmed by an angiogram that was obtained 2 days later that showed distal occlusion in the right second and fifth digits.

Initial treatments with nitroglycerine paste, amlodipine, and sildenafil did not alleviate the patient’s RP. Therefore, she received 5 days of epoprostenol infusion, which dramatically improved her symptoms. Anticoagulation with heparin infusion for 5 days followed by enoxaparin. Anticoagulation was used for the possibility that distal occlusions were due to thromboses. Together, the two treatments reversed the patient’s dusky fingers. She was discharged on amlodipine 10 mg daily, limiting her RP to about once daily. Treatment with ICIs was never resumed because of the severity of her RP.

Although microthrombi events may also have contributed to her initial ischemic event, RP likely played a major role because 2 years later, in the absence of anticoagulation, she continued to experience RP in not only the right hand but also the left hand, which is reduced in frequency to about once a week by amlodipine 10 mg daily. Her cancer remains in remission.

Case 3

A 77-year-old man (never smoker) with stage IV melanoma treated with four prior cycles of combined nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks and nivolumab 480 mg once was seen for reactive arthritis that developed after five cycles of ICIs. He had no systemic chemotherapy. The patient previously had ICI-induced colitis after the second cycle, which was treated with glucocorticoids and vedolizumab. A short course of glucocorticoids resolved his reactive arthritis.

During his initial visit, he was noticed to have RP, which started 2–3 years before his cancer diagnosis. He reported pale and blue hands in cold weather or stressful events, which were reversible with rewarming. However, now, his RP duration and frequency had substantially increased. He denied having other SSc symptoms, and physical examination was unremarkable for SSc. The patient’s serum autoimmune workup is shown in Table 2. A cytokine panel was checked when his cancer had been improving before corticosteroid injection for his reactive arthritis.

Although the patient received no additional ICI treatment because he had multiple irAEs (colitis and reactive arthritis), his RP continued to worsen in duration and frequency. Six months after his last ICI dose, he was started on amlodipine 5 mg daily, which decreased his RP’s duration and frequency. He also had not developed any other SSc symptoms or signs. The patient’s cancer is stable.

Case 4

A 71-year-old man (former smoker) with stage IV lung adenocarcinoma initially treated with pemetrexed 500 mg/m² once, carboplatin 450 mg once, and pembrolizumab 200 mg once and then two cycles of ipilimumab 1 mg/kg and nivolumab 360 mg every 6 weeks was evaluated for toe discoloration. Three weeks after his second ipilimumab and nivolumab cycle, the patient’s bilateral toes turned white with cooling but reversed with rewarming. However, 1 week after the initial color change, his right first, third, and fourth toes and left first and third toes intermittently became purple but remained reversible with rewarming. ICI treatment was stopped for this reason. He had dyspnea because of pleural effusions. He denied having other SSc symptoms. His only past irAE was dermatitis.

On physical examination, the patient’s hands were normal, but his right first, third, and fourth toes and left fifth toe were purple colored, which improved with rewarming. His left first and third toes were normal colored. He had mild crackles on the lung examination. Additional physical examination revealed no signs of SSc development. Serum autoimmune labs are presented in Table 2. Unfortunately, cytokine panel was not checked.

The patient was started on amlodipine 10 mg daily and prednisone 20 mg daily for severe RP. However, 6 days after the initial evaluation, the patient was admitted for worsening RP. His CTA showed large nonocclusive emboli in the bilateral proximal common iliac arteries, occluded proximal left posterior tibial artery without distal reconstitution, near-occlusive stenosis of left anterior tibial artery with distal flow reconstituted in lower leg, and short-segment near-occlusive stenosis of the left proximal peroneal artery with distal reconstitution. Although the patient’s occlusions were all seen on the left side, the patient’s right side was the more ischemic side on physical examination, suggesting that RP played a significant role in his condition. Because of concerns for ischemia secondary to an overlap between microembolization and definitive RP, intravenous heparin and epoprostenol infusions were started, which improved his condition. Unfortunately, the patient developed worsening respiratory status due to pleural effusions secondary to cancer and elected home hospice.

Case 5

A 70-year-old man (active smoker) with metastatic renal cell carcinoma previously treated with partial nephrectomy, sunitinib 37.5 mg daily for 15 months, cabozantinib 60 mg daily for 4 months and 40 mg daily for 28 months, lenvatinib 18 mg daily for 5 months and 14 mg daily for 10 months, everolimus 5 mg daily for 15 months, nivolumab (240 mg every 2 weeks for 16 cycles and 480 mg every 4 weeks for eight cycles, last dose 40 months before evaluation), and pembrolizumab (200 mg every 3 weeks for 20 cycles, last dose 4 weeks before evaluation) was seen for new-onset RP.

Three weeks after the last ICI dose, the patient developed progressive whitening of the left second and third fingers and the right fifth digit. Although initially reversible with rewarming, the digits eventually turned dusky, painful, and unresponsive to rewarming. Therefore, ICIs were stopped. He denied having other SSc symptoms. Physical examination showed macules on lower extremities but no signs of SSc. Serum autoimmune labs are shown in Table 2. Cytokine panel was obtained when the patient’s cancer had slightly progressed; he had no coexisting irAEs so was not on any corticosteroids.

Initial treatments with nifedipine 90 mg daily and sildenafil 20 mg every 8 hours failed to result in any improvement. Because a skin biopsy (no immunofluorescence performed) of the macules showed sparse superficial perivascular lymphohistiocytic infiltrates, raising concerns for vasculitis causing his condition, he received methylprednisolone 1 mg/kg twice a day, five plasmapheresis sessions, and rituximab 1 g; none of which was effective. Subsequently, an angiogram showed diffuse small-vessel disease of the radial artery, ulnar artery, and deep palmar arch. Therefore, he underwent percutaneous transluminal angioplasty (PTA) of the left second interdigital artery and 5 days of epoprostenol infusion, which improved his RP.

Two months after PTA and epoprostenol infusion, the patient had developed necrosis of the left second and third digits and the right fifth digits and new RP of his bilateral feet. His local surgeon partially amputated the affected digits. At the 3-month follow-up with rheumatology, plans were made for additional IV epoprostenol treatment for worsening RP, but the patient expired from new-onset heart failure.

DISCUSSION

Endothelial dysfunction, a hallmark of secondary RP, is a cardinal feature of SSc. In SSc, an imbalance between vasodilators and vasoconstrictors may lead to endothelial cell ischemia, causing cell barrier breakage.[4] This breakage may lead to immune cells recruitment and immune system imbalance, resulting in endothelial cell apoptosis and fibroblast recruitment with cytokine involvement, such as interleukin 6 (IL-6), type I interferon (IFN), and IFN-γ.[4–10]

Although not completely understood, autoimmune disease is thought to develop in genetically susceptible individuals after an environmental trigger.[11] ICIs may act as a potential trigger; ICI-induced RP is interesting because it may possibly provide insight into the pathogenesis of SSc and other autoimmune rheumatological diseases. In our five patients, none had other symptoms or signs of SSc, but an interesting pattern emerged in the four patients where cytokine testing was performed at RP onset or worsening—three of the four patients had elevated IL-6 and/or elevated IFN-γ, possibly hinting their role in endothelial dysfunction. Although cytokines are naturally involved in cancer regulation, they are significantly affected by ICIs and have been proposed as biomarkers for irAEs.[12–14] However, the limited scope of our case series makes these findings more exploratory and hypothesis-generating in nature.

We would also like to draw attention to RP development after ICI treatment as an irAE, as it is not typically on physicians’ screening for irAE symptoms. Our five cases show that the severity of ICI-induced RP has a wide range of severity, so milder cases may go underrecognized. They also illustrate the importance of early recognition and treatment of ICI-induced RP while ruling out comorbid conditions that may exacerbate ischemia. Imaging and biopsy to rule out overlap thrombotic vasculopathy and structural vascular disease such as vasculitis are critical if an overlap with these conditions is suspected. Early aggressive treatment with prostaglandins in combination with anticoagulation when needed is paramount in preventing digital ischemia and amputation. The use of corticosteroid or immunosuppression is not clear in treating ICI-induced RP, as RP is typically treated with only vasodilators. There have also been previous reports that described the patients developing digital ischemia due to vasculitis but initially presented with RP-like phenomenon.[15,16] Furthermore, based on our prior experience, nonthrombotic occlusions can occur simultaneously with RP, which can be successfully treated with prostaglandin and percutaneous revascularization.[17] Finally, although previous ICI-induced RP case reports (Table 3) exist, this is the first case series to describe ICI-induced RP and to have cytokines checked at RP’s onset. Although our sample size is limited, IFN-γ was elevated in three of the four patients tested, which has been shown to be elevated in patients with SSc.[6] Notably, the only patient without elevated IFN-γ had been on a moderate dose of prednisone at 40 mg daily for 35 days for radiation pneumonitis.

Table 3.

Previous case reports of ICI-induced Raynaud’s phenomenon^a

	Case 1	Case 2	Case 3	Case 4
Author, year	Kim et al,[18] 2019	Khan et al,[2] 2020	O’Connor et al,[20] 2020	Sumi et al,[19] 2022
Age/sex	70 y/Female	53 y/Female	45 y/Female	78 y/Male
Cancer	Gallbladder adenocarcinoma	Non–small lung cancer	Invasive ductal carcinoma of the breast	Squamous cell carcinoma
ICI	Pembrolizumab	Ipilimumab and nivolumab	Pembrolizumab	Pembrolizumab
Immunological findings	ANA positive (1:320)	ANA negative	ANA positive (1:160); RNA polymerase 3 weakly positive	ANA negative
Raynaud’s onset	New onset	New onset	New onset	Raynaud’s worsened after ICI administration
Other irAEs	Arthritis	Hypophysitis	None	None

^aPrevious case reports did not have any specific rheumatological laboratory findings or types of cancer or ICI to predict the development of Raynaud’s phenomenon.

ANA: Antinuclear Antibodies; ICI: immune checkpoint inhibitor; irAEs: immune-related adverse events.

As in previous case reports (Table 3), our patients did not demonstrate other autoimmune rheumatological findings.[2,18–20] There was no clear pattern in RP onset with respect to cancer type, ICI type, and treatment duration, but in all cases, RP either started or substantially worsened after ICI. Autoimmune labs such as antinuclear antibodies (ANAs) did not necessarily predict RP development. Patient 3 had a positive RNA polymerase (pol) 3 auto-antibody, but it is likely a false positive, as multiple ANA tests by immunofluorescence were negative. Patient 4 had a 1:640 nucleolar ANA pattern and a slightly elevated ribonucleoprotein (RNP) auto-antibody. Although the patient had no clinical symptoms to suggest SSc, nucleolar auto-antibodies such as Th/To, PM/SCL, and U3RNP were not obtained, as the patient had expired before having the opportunity to do so. Finally, none of our patients received further ICI treatment, but ICIs have been safely continued in previous cases.[2,18,19]

One limitation of our case series is the lack of capillaroscopy data. Clinically, however, all patients had definitive RP with cold or stress-induced digital color changes that improved with rewarming. Another weakness is that two of our patients had overlap with thromboses. However, one of them did not definitively have thromboses, as severe RP can also induce occlusions without thromboses seen; she also continued to suffer from RP in both hands ameliorated by amlodipine almost 2 years after the initial insult.[17] The other patient had thromboses on the less affected limb and had responded well to vasodilation therapy.

Our cases not only show the importance of identifying ICI-induced RP and the need for prompt treatment but also highlight that RP’s pathogenesis is not yet elucidated. ICI-induced RP, as shown by our case series, may possibly reveal cytokine pathway clues to understanding the link between immune dysregulation and vasculopathy in SSc and other autoimmune diseases. Understanding genetic risk factors for ICI-induced RP may also help oncologists predict the likelihood of ICI-induced RP. Further research with ICI-induced RP may help both oncological patients and non-oncological autoimmune rheumatological patients.