Immune checkpoint inhibitor therapy in patients with cancer and pre-existing systemic sclerosis

Abstract

Objective:

Immune checkpoint inhibitor (ICI) therapies have dramatically improved outcomes in multiple cancers. ICI’s mechanism of action involves immune system activation to augment anti-tumor immunity. Patients with pre-existing autoimmune diseases, such as systemic sclerosis (SSc), were initially excluded from initial ICI clinical trials due to concern that such immune system activation could precipitate an autoimmune disease flare or new, severe immune related adverse events (irAE). In the present study, we report our experience with ICIs in patients with pre-existing SSc.

Methods:

Patients with SSc who received ICI therapy for cancer were identified from the Johns Hopkins Scleroderma Center Research Registry. Through chart review and prespecified definitions, we identified whether patients experienced worsening SSc activity or new irAEs. SSc disease activity worsening was pre-defined as an increase in modified Rodnan skin score (mRSS), new scleroderma renal crisis, progression of interstitial lung disease (ILD) on CT scan, increased Raynaud’s phenomenon frequency or severity, new pulmonary hypertension, or myositis flare. IrAEs also included active inflammatory arthritis and dermatitis.

Results:

Eight patients with SSc who received ICI therapy for cancer were included. Overall, SSc symptoms remained stable during and after ICI therapy. None of the patients with long-standing sine or limited cutaneous SSc (lcSSc) had progressive skin thickening after ICI therapy. One patient, who was early in his diffuse cutaneous SSc (dcSSc) disease course, experienced worsening skin thickening and renal crisis. Three patients (38%) experienced a total of five irAEs (grade 2: diarrhea, mucositis and dermatitis; grade 3: pneumonitis, and grade 4: nephritis). The patient with grade 4 nephritis developed scleroderma renal crisis and immune checkpoint related nephritis simultaneously. There were no deaths due to irAEs.

Conclusion:

In this study, ICI therapy was well tolerated in patients with longstanding, sine or lcSSc. IrAE were common but generally manageable. Patients with early, active SSc may be at greater risk from ICI therapy, but more research is needed.

Introduction

Immune checkpoint inhibitor (ICI) therapies have transformed treatment of myriad cancers, including melanoma, non-small cell lung cancer, renal cell carcinoma and microsatellite-instability–high/mismatch-repair–deficient colorectal cancer.^1-5 Because these medications work by activating the immune system to increase anti-tumor immunity, patients often experience off-target immune-related adverse events (irAEs). These irAEs range from mild, asymptomatic rashes to fatal cardiomyopathies.⁶

Due to concern that patients with autoimmune disease could experience more severe irAEs and worsening of their underlying autoimmune disease, patients with autoimmune disease were initially excluded from ICI clinical trials. Emerging evidence indicates that ICI therapy is at least as effective in patients with established autoimmune diseases. Although patients with pre-existing autoimmune diseases are at risk for flare after exposure to ICI therapy, whether new or severe irAEs are more common in patients with pre-existing autoimmune diseases compared to the general population is unclear.^7-9 Despite the association between systemic sclerosis (scleroderma, SSc) and cancer, there is very limited data regarding the safety of immune checkpoint inhibitor therapy in patients with established SSc.^10-12

Herein, we report the safety of ICIs in patients with pre-existing or concurrent SSc seen in the Johns Hopkins University Scleroderma Center.

Methods

Patient selection.

This observational study included all patients enrolled in the Johns Hopkins Scleroderma Center Research Registry (1982-2022) with SSc who received ICI therapy (anti-CTLA-4 and/or anti-PD-1/PD-L1) for cancer treatment. Registry participants meet at least one of the following criteria for SSc: 1) 2013 ACR/EULAR classification criteria, 2) 1980 ACR criteria, 3) at least 3 of 5 features of the CREST (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias) syndrome, or 4) definite Raynaud’s phenomenon, abnormal nailfold capillaries and a scleroderma-specific autoantibody.^13,14

The Johns Hopkins Scleroderma Center Research Registry prospectively collects demographic and longitudinal disease information during routine clinical care. Patients are classified as having limited cutaneous SSc (lcSSc) if skin thickening is present distal to the elbows or knees with or without facial involvement; whereas, patients are classified as having diffuse cutaneous SSc (dcSSc) if skin, thickening is proximal to the elbows, knees, or involves the trunk.¹⁵

We defined interstitial lung disease as fibrotic changes on computerized tomography (CT) scan. Patients were considered to have myositis if they had proximal muscle weakness and elevated muscle enzymes. GI disease was defined by symptoms or signs of gastroesophageal reflux disease (GERD) or esophageal, gastric, small bowel or colonic dysmotility.

For this study, a worsening in SSc disease activity was pre-defined as an increase in modified Rodnan skin score (mRSS), new scleroderma renal crisis, progression of radiographic interstitial lung disease (ILD) either radiographically noted on CT scan or to confirm worsening pulmonary function was related to ILD rather than metastatic cancer or pneumonitis, active inflammatory arthritis, increased Raynaud’s phenomenon frequency or severity, new pulmonary hypertension, or myositis flare.

If sera were available, research antibodies were assayed using the Euroimmun platform (Euroline Systemic Sclerosis Profile, Euroimmun Diagnostics, Lubeck Germany), using cutoffs recommended by the manufacturer to determine a positive antibody status.

Cancer history.

For patients in the Johns Hopkins Scleroderma Center Research Registry, cancer diagnoses are captured at baseline and longitudinally. Pathology reports and medical records are reviewed to confirm cancer diagnoses, cancer diagnosis date, and treatments.¹⁶ Immune-related adverse events and change in SSc disease activity after ICI therapy were captured through retrospective chart review.

This study was approved by the Johns Hopkins Institutional Review Board.

Results

Eight patients with SSc who received ICI therapy for cancer were included (Table 1). Five (63%) were female. Five (63%) were White, two (25%) were Black, and one (13%) was Hispanic. Cases are reviewed in detail below following summary data.

Table 1:

Demographic and phenotypic characteristics of patients with systemic sclerosis and cancer treated with immune checkpoint inhibitors (N=8)

Characteristic*
Sex (female)	5 (63%)
Race
White	5 (63%)
Black	2 (25%)
Other	1 (13%)
Hispanic/Latino	1 (13%)
Age of SSc onset (years), median (IQR)	49.5 (40.5, 58)
Age of cancer onset (years), median (IQR)	62 (56, 66.5)
SSc-Cancer interval (years), median (range)	13.5 (0-23)
SSc subtype
Diffuse	1 (13%)
Limited	6 (75%)
Sine	1 (13%)
Cancer types
Head and neck	3 (38%)
GI	2 (25%)
Lung	1 (13%)
Angiosarcoma	1 (13%)
GU	1 (13%)
Prior cancer treatment
Surgery	3 (13%)
Chemotherapy^	7 (13%)
Radiation	2 (25%)
ICI therapy
Durvalumab	2 (25%)
Nivolumab	1 (13%)
Pembrolizumab**	6 (75%)
Cycles of ICI, median (range)	8.5 (3-32)
SSc manifestations
Digital ulcers	5 (63%)
Gastrointestinal disease	7 (88%)
Inflammatory arthritis	4 (50%)
Interstitial lung disease	3 (38%)
Inflammatory Myositis	1 (13%)
Raynaud’s Phenomenon	7 (88%)
SSc autoantibodies
Anti-nuclear antibody	7 (88%)
Anti-centromere antibody	1 (13%)
Anti-RNA polymerase III antibody	2 (25%)
Anti-scl-70 antibody	0 (0%)
Anti-fibrillarin antibody	1 (13%)
Anti-PM-SCL	1 (13%)
Anti-RNP antibody	2 (25%)
Anti-Ro52	2 (25%)
Anti-ThTo	2 (25%)
Prior immunomodulatory treatment for SSc
None	3 (38%)
Corticosteroids	2 (25%)
Hydroxychloroquine	3 (38%)
Methotrexate	2 (25%)
Mycophenolate mofetil	2 (25%)

^*number (%) unless otherwise specified,

^**one patient received pembrolizumab after durvalumab,

^{^}two patients received ICI therapy with chemotherapy as first line treatment.

Abbreviations: ICI, immune checkpoint inhibitor; IQR, interquartile range; SSc, systemic sclerosis

Cancer characteristics.

The median (IQR) age at cancer onset was 62 (56, 66.5) years. The most common cancer type was head and neck (see Table 1 for more details).

ICI therapy.

Two patients received ICI therapy as part of first-line treatment. Most (75%) received pembrolizumab (See Table 1 for more details). Two (25%) received durvalumab (one of whom later received pembrolizumab), and one (13%) received nivolumab.

Cancer outcomes.

One patient entered a sustained remission and is cancer free seven years from her cancer diagnosis. One patient experienced a prolonged, 4.5-year period of cancer stability, and is alive five years after cancer diagnosis. The remaining six patients had cancer progression despite ICI therapy and died from cancer complications during follow up. Among those who died, the median (IQR) time between cancer diagnosis and death was 2.18 (0.74, 4.04) years and the median (IQR) time between immunotherapy initiation and death was 0.86 (0.55, 1.40) years.

SSc characteristics.

The median (IQR) age at SSc onset was 49.5 (40.5, 58) years. Seven out of eight patients (88%) had sine or lcSSc with longstanding, inactive disease at the time of ICI therapy. Among patients with limited or sine cutaneous disease, the SSc-cancer interval ranged from 7-23 years. The remaining patient co-developed cancer and anti-RNA polymerase III positive diffuse cutaneous SSc (dcSSc). This patient received ICI therapy while in an early-active stage of dcSSc.

SSc features included Raynaud’s phenomenon in seven patients (88%), five (71%) of whom had a history of digital ulcers. Three patients (38%) had interstitial lung disease (ILD), four (50%) had inflammatory arthritis, one (13%) had myositis, and seven (88%) had GI disease. Five patients (63%) received SSc-related treatment, which included corticosteroids (2 patients, 25%), hydroxychloroquine (3, 38%), methotrexate (2, 25%) and mycophenolate mofetil (MMF, 2, 25%). Methotrexate and MMF were discontinued in all cases before ICI initiation. One patient remained on HCQ, and two patients were on low-dose prednisone (≤10 mg) at ICI therapy initiation.

irAEs.

Three patients (38%) experienced a total of five irAEs (Table 2). IrAEs included grade 2 diarrhea, mucositis, and dermatitis, grade 3 pneumonitis, and grade 4 nephritis. Two patients received oral corticosteroids with resolution of IrAE. The third patient received oral corticosteroids, a TNF-inhibitor, and MMF. None of the patients died due to irAEs.

Table 2:

ICI therapy outcomes

Outcome	SSc patients (number, %)
irAEs (N=8)	3 (38%)
Aphthous ulcers	1 (13%)
Colitis	1 (13%)
Dermatitis	1 (13%)
Nephritis	1 (13%)
Pneumonitis	1 (13%)*
irAE CTCAE grade (N=5)
Grade 1	0 (0%)
Grade 2	3 (60%)
Grade 3	1 (20%)
Grade 4	1 (20%)
Grade 5	0 (0%)
irAE treatment (N=3)
Corticosteroids	3 (100%)
MMF	1 (33%)
TNF-inhibitor	1 (33%)
SSc post-ICI (N=8)
ILD progression	0 (0%)
New pulmonary hypertension	0 (0%)
Worsening of mRSS	1 (13%)
Worsening Raynaud’s phenomenon	0 (0%)
Renal crisis	1 (13%)
Inflammatory arthritis flare	0 (0%)
Myositis flare	0 (0%)

^*A second patient had possible pneumonitis, but ultimately thought most consistent with infection. Resolved without immunosuppression.

Abbreviations: CTCAE, common terminology criteria for adverse events; irAE, immune related adverse event; MMF, mycophenolate mofetil; SSc, systemic sclerosis; mRSS, modified Rodnan skin score

None of the patients experienced ILD progression, inflammatory arthritis, or myositis flare after ICI therapy. None of the patients with long-standing sine or lcSSc had progressive skin thickening after ICI therapy. The patient with early, dcSSc was noted to have progression of skin involvement before, during and post-ICI therapy. This patient also had scleroderma renal crisis in the setting of recent corticosteroid use, anti-RNA polymerase III antibodies, and ICI-associated acute interstitial nephritis.

For more information about individual patient courses, we provide clinical summaries of the eight patients below:

Case 1:

The patient developed Raynaud’s phenomenon at 53 years old. Five years later, she was diagnosed with anti-centromere positive lcSSc based on GERD, esophageal dysmotility, telangiectasias, sclerodactyly, calcinosis, and Raynaud’s phenomenon complicated by digital ulceration. Subsequent research labs notable for positive anti-Th/To and anti-Ro52 antibodies. She did not require immunosuppression for her lcSSc. At age 69, she was diagnosed with colorectal cancer with microsatellite instability. She underwent exploratory laparotomy and right hemicolectomy with mass resection. Her cancer recurred six weeks after surgery. She was treated with nine cycles of pembrolizumab resulting in sustained remission. Her treatment course was complicated by grade 2 diarrhea causing weight loss, treated with diphenoxylate/atropine (Lomotil) and prednisone (max 60 mg daily). Colonoscopy with biopsies demonstrated mild colitis. Additional irAEs included grade 2 aphthous ulcers and mucositis treated with a steroid rinse. Her SSc did not flare. Her mRSS pre-ICI was 8 and improved to 4 after ICI therapy. She experienced no other SSc changes. She is currently seven years out from her cancer diagnosis without signs of cancer recurrence or worsening of her SSc.

Case 2:

At age 37, the patient developed Raynaud’s phenomenon with digital ulceration and arthritis. Workup revealed a positive ANA (1:1280) in a nucleolar pattern. Further research labs demonstrated positive anti-Ro52 and PM-Scl antibodies. Shortly thereafter she developed telangiectasias, GERD, limited skin thickening, calcinosis, myositis, a chronic pericardial effusion, and ILD. She was treated with methotrexate, but this was discontinued after a few months due to transaminitis. She was then treated with D-penicillamine for one year without improvement. Due to active myositis and arthritis, she was prescribed a prednisone taper (max dose 40 mg) and resumed methotrexate with improvement.

At age 54, methotrexate was discontinued after she developed a buccal ulceration. Biopsy of the lesion was consistent with locally advanced, squamous cell carcinoma. She underwent excision, which was complicated by trismus. Three years later, she was found to have recurrence in the mandible and a cervical lymph node. Radiation was avoided due to her SSc history. She initially received six cycles of carboplatin and docetaxel, followed by four cycles of pembrolizumab. She experienced no changes in her SSc disease activity (pre/post-ICI mRSS skin score of 2) or irAEs with ICI therapy, however CT scans demonstrated cancer progression. Of note, she was on 1 mg of prednisone daily while on ICI therapy. She transitioned to carboplatin and paclitaxel but was unable to tolerate this regimen due to side effects. She then underwent cryoablation and switched to cisplatin, but shortly thereafter transitioned to hospice care due to declining performance status. She died at age 58.

Case 3:

The patient developed Raynaud’s phenomenon at 51 years old in the setting of long-standing GERD. A few months later, he noted sclerodactyly and was started on hydroxychloroquine. Upon presentation to Johns Hopkins two years later, his exam was notable for telangiectasias and abnormal nailfold capillaries. He was diagnosed with lcSSc and hydroxychloroquine was discontinued. At age 54, he noted increased dyspnea and was found to have ILD on CT scan. He was started on MMF 3 grams per day. On this regimen, his pulmonary disease stabilized. Of note, research labs ultimately demonstrated positive anti-fibrillarin antibodies.

At age 58, he presented with hemoptysis. Workup revealed metastatic squamous cell carcinoma of the right base of the tongue with basaloid features. MMF was discontinued in the setting of the cancer diagnosis, and he was treated with radiation and cisplatin therapy. After completing this regimen, he was found to have biopsy-proven pulmonary metastasis. He was then treated with 6 cycles of carboplatin, 5-fluorouracil (5-FU), and cetuximab followed by cetuximab maintenance. He had mild progression, so he was planned to initiate nivolumab. Pre-ICI assessment was notable for a mRSS of 0, but he had a forced vital capacity (FVC) decline of 800 cc in the 6 months preceding ICI therapy. CT chest was notable for new pulmonary metastases and new ground glass changes in the left lower lobe. After starting the nivolumab he noticed an increase in wheezing and coughing, which improved with guaifenesin. Pulmonary function tests (PFTs) four months after nivolumab initiation showed a further decrease in FVC of 340 cc. CT demonstrated stable-to-slightly worsening pulmonary metastases, but stable basilar ground glass and cystic changes.

Six months after starting nivolumab, he presented with fevers and cough. He was initially diagnosed with left upper lobe pneumonia and treated with antibiotics, but his breathing worsened, and he required oxygen. He was diagnosed with grade 3 ICI-associated pneumonitis, which was treated with prednisone 1 mg/kg. After starting corticosteroids, his breathing improved, and the oxygen was discontinued. TTE was without evidence of pulmonary hypertension. He enrolled in a clinical trial of tisotumab vedotin. Unfortunately, despite initial cancer response, he progressed. He transitioned to hospice care and died at age 62 without worsening of his SSc.

Case 4:

At age 59, the patient presented with new-onset Raynaud’s phenomenon and swelling of his hands and feet. He was treated with prednisone at a maximum dose of 40 mg per day. Shortly thereafter, he was diagnosed with lcSSc based on Raynaud’s phenomenon with ulceration, dilated nailfold capillaries, skin thickening on his hands and feet, inflammatory arthritis, tendon friction rubs, GERD, constipation, nail fold changes, and a positive anti-RNA polymerase III antibody. Subsequent research labs were notable for positive anti-Th/To. He was started on methotrexate. MMF was added for skin disease (mRSS 15) and tendon friction rubs. He improved on this regimen and tapered off MMF after 10 months of treatment. He remained on methotrexate monotherapy for an additional four years before tapering off.

At age 68, he was diagnosed with stage IV adenocarcinoma of the right lower lobe of the lung with mucinous features. He underwent right lower lobectomy with four cycles of adjuvant carboplatin/pemetrexed followed by durvalumab. After the fifth dose of durvalumab he developed dyspnea. He tested positive for influenza A infection. He was also treated for possible superimposed bacterial pneumonia. He improved with antibiotic therapy. Infectious etiology was favored over pneumonitis, however further durvalumab was held due to low tumor proportion score for PD-1 expression (TPS<1%).

His cancer rapidly recurred and he was treated with four cycles of carboplatin, pemetrexed, and pembrolizumab followed by three cycles of maintenance, dose-reduced pemetrexed (400 mg/m²) and pembrolizumab. His SSc remained stable without worsening skin disease, inflammatory arthritis, or myositis. He reported active Raynaud’s without ulceration, which was managed with continuation of his baseline amlodipine and lifestyle modification. Unfortunately, he developed metastatic disease to his brain and liver. He was switched to docetaxel, but soon after died at age 69 following another viral infection.

Case 5:

The patient developed Raynaud’s phenomenon with digital ulceration in her 20s. At age 38, she developed discoid lupus and inflammatory arthritis, treated with hydroxychloroquine. At age 57, she was diagnosed with SSc and lupus overlap syndrome based on positive anti-RNP antibodies, Raynaud’s phenomenon complicated by digital ulcers and pits, abnormal nailfold capillaries, GERD, digital tapering, inflammatory arthritis, and discoid rash. She did not require immunosuppression and her mRSS was 0.

At age 64, she presented to her PCP with epigastric pain with associated emesis, jaundice, and weight loss. Workup revealed distal cholangiocarcinoma with metastases to distant lymph nodes and lung. She initiated durvalumab, gemcitabine and cisplatin. She completed two cycles of therapy without irAEs or change in her SSc activity. Unfortunately, a few days after the second treatment cycle, she had a right MCA stroke in the setting of hypoperfusion due to an upper GI bleed. She was transitioned to comfort measures and died at age 64.

Case 6:

The patient was in his usual state of health until age 65 when he noticed swelling in the middle toe on his left foot. Shortly after, the swelling included his bilateral feet, left calf, and hands. When he presented to care, his provider observed left cervical lymphadenopathy. CT scan confirmed an enlarged cervical lymph node. Repeat CT neck three months later noted progression of extensive necrotic left cervical chain lymphadenopathy most compatible with primary head and neck carcinoma of uncertain origin. He underwent US guided core needle lymph node biopsy, which demonstrated poorly differentiated carcinoma with partial neuroendocrine differentiation and extensive necrosis. The sample was notably HPV negative, with high Ki-67 expression. Positron emission tomography (PET)-CT scan revealed osseous, hepatic, muscular, and subcutaneous metastases compatible with stage IV disease.

He started carboplatin, etoposide, and denosumab. With the second cycle, pembrolizumab was added. After four cycles of immunotherapy, he noticed progression of his baseline skin thickening and edema, decreased joint mobility, and increasing dyspnea. Further doses of pembrolizumab were held. He was prescribed a two-week course of 10 mg of prednisone and referred to rheumatology, who diagnosed RNA-polymerase III-positive dcSSc. SSc manifestations included diffuse cutaneous disease, GERD, and abnormal nailfold capillaries. He did not receive treatment for SSc due to recent chemotherapy and active cancer.

Shortly thereafter, he noted a diffuse, pruritic, papular rash covering >30% of his body surface area (grade 2 irAE). One month later, he developed hypertension, hemolytic anemia, thrombocytopenia, and renal failure. Given concern for scleroderma renal crisis, he was initiated on captopril with improvement of his hypertension, anemia, and thrombocytopenia, but with persistent severe renal injury. In this setting, renal biopsy was performed which demonstrated acute interstitial nephritis, thought to be secondary to checkpoint inhibitor use (grade 4 irAE, Figure 1A). Also noted was glomerular hypoperfusion, endothelial swelling, and rare afferent arteriole thrombi, which could be consistent with superimposed, resolving scleroderma renal crisis (Figure 1A-B). He was continued on captopril, initiated on prednisone (max dose 2 mg/kg) and MMF, and given one dose of infliximab. His renal function did not improve, and he ultimately required hemodialysis. He was tapered from prednisone and his MMF was discontinued. His skin disease continued to progress. He developed contractures of the knees, elbows, and PIPs and his mRSS increased from 22 to 27 over a period of three months. His cancer also progressed, and he was found to have brain metastases. He initiated whole brain radiation but succumbed to his cancer at age 66, a little over one year after symptom onset.

Figure 1: Patient 6 representative renal histology.

(A) Hypo-perfused glomeruli with increased mesangial matrix in a background of lymphocytic infiltrate, occasional lymphocytic aggregates, mild tubular injury, and moderate interstitial fibrosis (H&E, 100X)

(B) Small vessel with endothelial swelling in a background of lymphocytic infiltrate, mild tubular injury, and moderate interstitial fibrosis (H&E, 200X)

Case 7:

At age 28, the patient developed Raynaud’s phenomenon and arthritis, treated with nonsteroidal anti-inflammatory drugs (NSAIDs). A year later, she developed pleuritic chest pain and was diagnosed with lupus. She was treated with prednisone, NSAIDs, and hydroxychloroquine. Over the following years, she developed GERD and had recurrent digital ulcers complicated by distal digital amputation. About nine years after disease onset, she had mild dyspnea and was found to have GGOs on CT scan. She started prednisone 40 mg, which was titrated to 5 mg over 6 months. PFTs showed an FVC of 70% predicted and DLCO of 82% predicted. Around this time, she noted severe constipation and early satiety. A gastric emptying study was borderline for delayed emptying, and a barium enema showed a dilated colon with a possible transition point. She had a total colectomy with an ileoproctostomy with biopsy specimen showing patchy villous atrophy with associated fibrosis of the muscularis propria and submucosal fibrosis. Following colectomy, she experienced intermittent small bowel obstructions requiring temporary TPN. In this setting, she was noted to have sclerodactyly and diagnosed with anti-RNP+, lcSSc. She was also found to have autoimmune neutropenia. HCQ was discontinued. She remained on low-dose prednisone for neutropenia. She continued to experience significant GI symptoms and required intermittent antibiotics for small intestinal bacterial overgrowth.

At age 49, she presented to dermatology for scalp nodules. Biopsy demonstrated CD31 and ERG positive, high-grade, poorly differentiated angiosarcoma. She initiated paclitaxel, which she discontinued due to neuropathy. She subsequently progressed despite pazopanib followed by gemcitabine, then pembrolizumab. Of note, at the time of pembrolizumab she was on prednisone 10 mg for autoimmune neutropenia. She did not experience irAEs, however, she only received three pembrolizumab doses due to inefficacy. Her SSc did not flare with ICI therapy. She had very slight sclerodactyly prior to pembrolizumab, which was unchanged after ICI exposure. Her cancer progressed through additional cycles of gemcitabine, followed by doxorubicin, then paclitaxel. Unfortunately, a year and a half after cancer diagnosis, she died at age 51 in the setting of progressive cancer and C. difficile infection complicated by small bowel obstruction and refractory GI bleed.

Case 8:

At age 26 she developed Raynaud’s phenomenon. She was diagnosed with lcSSc at age 42. Her SSc features included calcinosis, severe GERD, constipation, early satiety with weight loss, and sclerodactyly. At age 60, she was diagnosed with muscle-invasive, high grade papillary urothelial carcinoma with micropapillary and signet ring cell features. She underwent transurethral resection of her bladder tumor, though the entire tumor was not able to be removed. Subsequent CT scan demonstrated numerous bone metastases and she was started on palliative carboplatin and gemcitabine. She was on this for five cycles but progressed. She was treated with radiation to several sites of bone metastases and initiated pembrolizumab with disease stabilization. She remained on pembrolizumab for 28 months and received a total of 32 cycles without irAEs or change in her SSc activity. Her skin score was 0 before and after receiving pembrolizumab. She did not develop any new SSc symptoms. Cystoscopy two years after last pembrolizumab, demonstrated local cancer progression. She underwent repeat transurethral bladder tumor resection with plan for cystectomy.

Discussion:

To our knowledge, this is the largest, single center study of patients with well-phenotyped, pre-existing SSc who were treated with ICI therapy for cancer.

Of the eight patients included in the study, seven patients (88%) had inactive, long-standing, sine or lcSSc and one patient (13%) had early, active diffuse SSc at the time of ICI therapy. Among the patients with inactive, long-standing SSc, none had worsening of their underlying SSc after ICI exposure. Skin disease remained stable-to-improved in all seven patients. Notably, although four patients had a history of inflammatory arthritis, none of the patients reported an arthritis flare with ICI treatment. No patient developed new ILD, and the three patients with pre-existing ILD remained stable following ICI use. One patient did have ICI-related pneumonitis which resolved with corticosteroids, but this patient’s CT scan confirmed stable ILD. No patients developed new pulmonary hypertension or required escalation of Raynaud’s therapy. The low SSc flare rate in our study contrasts with the 24% SSc flare rate previously reported in a registry sample of 17 patients with inactive SSc receiving ICI therapy.¹² The discrepancy in SSc flare rate may be due to the greater percent of patients with diffuse disease and shorter SSc-cancer interval in the prior study, both of which may increase the risk of SSc activity following ICI exposure. In fact, three of the four previously reported patients who had increased SSc activity after ICI exposure had diffuse cutaneous disease.

One patient in our study received ICI treatment when he was in the early, active phase of RNA-polymerase III-positive, diffuse cutaneous SSc that had not yet been diagnosed. His SSc was likely paraneoplastic given the co-development of SSc and cancer, as well as the presence of anti-RNA polymerase III antibodies, which have been associated with increased cancer risk.¹⁰ This patient’s course was complicated by progressive skin thickening and scleroderma renal crisis. Worsening skin involvement is expected at this early stage of disease, so whether ICI therapy contributed to his progressive skin involvement is unknown. Additionally, the patient was at risk for scleroderma renal crisis due to early disease, anti-RNA polymerase III antibody positivity and recent corticosteroid exposure. The co-occurrence of biopsy-proven ICI-related acute interstitial nephritis and scleroderma renal crisis, however, raises the possibility that one process may have contributed to the other.

Three patients (38%) experienced an irAE. This irAE incidence is similar to the 59% irAE incidence reported previously in patients with pre-existing SSc treated with ICI therapy.¹² In our study, two patients (25%) suffered grade 3-4 irAEs, which is higher than 6% previously reported.¹² The higher rate of grade 3-4 irAEs in our study may be due to the patient with early, active, diffuse SSc included in our study, as this patient had the most severe irAE (interstitial nephritis). Similar to prior studies, we found no association between antibody specificity and irAEs.¹²

Our study is limited by a small sample size. None of the patients in our study were anti-scl-70 antibody positive, and only one patient had dcSSc or early disease, limiting generalizability to such patients. Immune related adverse event risk in patients with diffuse disease and shorter disease duration warrants further study.

Conclusion:

We found ICI therapy was well tolerated in patients with longstanding, sine or lcSSc. ICI therapy may be associated with higher risk in patients with active diffuse disease. When immune checkpoint inhibitors are the preferred cancer therapy, we recommend patients, rheumatologists, and oncologists engage in multidisciplinary medical decision making to devise the most appropriate management and monitoring strategy.

Statement of clinical significance.

What was known:

• Immune checkpoint inhibitor therapies have dramatically improved outcomes for some cancers.

• There is concern that patients with pre-existing autoimmune diseases are at risk for autoimmune disease flare or more severe immune related adverse events after exposure to ICI therapy.

What was learned:

• ICI therapy was well tolerated in patients with longstanding, sine or limited cutaneous systemic sclerosis.

• The majority (80%) of immune related adverse events resolved with corticosteroids.