Reacciones sarcoideas relacionadas con inhibidores de puntos de control inmunitario / Sarcoid-like Reactions to Immune Checkpoint Inhibitors

Los inhibidores de puntos de control inmunitario (ICI) pueden producir toxicidades cutáneas inmunomediadas entre las que se encuentran las reacciones sarcoideas. Nuestro objetivo fue analizar retrospectivamente los datos clínicos e histológicos de los pacientes en tratamiento con ICI que desarrollaron reacciones sarcoideas cutáneas entre 2019 y 2022. Se incluyeron siete pacientes (seis mujeres y un varón, con una edad mediana de 65años). La mediana de tiempo de instauración de la clínica fue de 4meses y la forma de presentación más frecuente fue la sarcoidosis papulosa de las rodillas, seguida de la sarcoidosis subcutánea. En todos se confirmó el diagnóstico histológicamente y no se observaron diferencias respecto a la sarcoidosis idiopática. Solo en dos casos fue preciso retirar la inmunoterapia. Las reacciones sarcoideas por ICI suelen ser leves y no suelen requerir la interrupción del tratamiento. Es fundamental obtener una confirmación histológica para distinguirlas de la progresión tumoral (AU)

Immune checkpoint inhibitors (ICIs) can cause immune-mediated cutaneous adverse events, including sarcoid-like reactions. The aim of this study was to retrospectively analyze clinical and histologic data from patients who developed cutaneous sarcoid-like reactions between 2019 and 2022 while under treatment with ICIs. We studied 7 patients (6 women and 1 man) with a median age of 65years. Median time to onset of symptoms was 4months. The most common presentation was papular sarcoidosis of the knees followed by subcutaneous sarcoidosis. Diagnosis was confirmed histologically in all cases, and no differences were observed relative to idiopathic sarcoidosis. Discontinuation of ICI therapy was required in just two patients. ICI-induced sarcoid-like reactions tend to be mild and generally do not require treatment discontinuation. Histologic confirmation is essential for distinguishing these reactions from tumor progression (AU)

[Translated article] Sarcoid-like Reactions to Immune Checkpoint Inhibitors / Reacciones sarcoideas relacionadas con inhibidores de puntos de control inmunitario

Immune checkpoint inhibitors (ICIs) can cause immune-mediated cutaneous adverse events, including sarcoid-like reactions. The aim of this study was to retrospectively analyze clinical and histologic data from patients who developed cutaneous sarcoid-like reactions between 2019 and 2022 while under treatment with ICIs. We studied 7 patients (6 women and 1 man) with a median age of 65years. Median time to onset of symptoms was 4months. The most common presentation was papular sarcoidosis of the knees followed by subcutaneous sarcoidosis. Diagnosis was confirmed histologically in all cases, and no differences were observed relative to idiopathic sarcoidosis. Discontinuation of ICI therapy was required in just two patients. ICI-induced sarcoid-like reactions tend to be mild and generally do not require treatment discontinuation. Histologic confirmation is essential for distinguishing these reactions from tumor progression (AU)

Los inhibidores de puntos de control inmunitario (ICI) pueden producir toxicidades cutáneas inmunomediadas entre las que se encuentran las reacciones sarcoideas. Nuestro objetivo fue analizar retrospectivamente los datos clínicos e histológicos de los pacientes en tratamiento con ICI que desarrollaron reacciones sarcoideas cutáneas entre 2019 y 2022. Se incluyeron siete pacientes (seis mujeres y un varón, con una edad mediana de 65años). La mediana de tiempo de instauración de la clínica fue de 4meses y la forma de presentación más frecuente fue la sarcoidosis papulosa de las rodillas, seguida de la sarcoidosis subcutánea. En todos se confirmó el diagnóstico histológicamente y no se observaron diferencias respecto a la sarcoidosis idiopática. Solo en dos casos fue preciso retirar la inmunoterapia. Las reacciones sarcoideas por ICI suelen ser leves y no suelen requerir la interrupción del tratamiento. Es fundamental obtener una confirmación histológica para distinguirlas de la progresión tumoral (AU)

[Translated article] Sarcoid-like Reactions to Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICIs) can cause immune-mediated cutaneous adverse events, including sarcoid-like reactions. The aim of this study was to retrospectively analyze clinical and histologic data from patients who developed cutaneous sarcoid-like reactions between 2019 and 2022 while under treatment with ICIs. We studied 7 patients (6 women and 1 man) with a median age of 65years. Median time to onset of symptoms was 4months. The most common presentation was papular sarcoidosis of the knees followed by subcutaneous sarcoidosis. Diagnosis was confirmed histologically in all cases, and no differences were observed relative to idiopathic sarcoidosis. Discontinuation of ICI therapy was required in just two patients. ICI-induced sarcoid-like reactions tend to be mild and generally do not require treatment discontinuation. Histologic confirmation is essential for distinguishing these reactions from tumor progression.

Sarcoid-like Reactions to Immune Checkpoint Inhibitors. / Reacciones sarcoideas relacionadas con inhibidores de puntos de control inmunitario.

Immune checkpoint inhibitors (ICIs) can cause immune-mediated cutaneous adverse events, including sarcoid-like reactions. The aim of this study was to retrospectively analyze clinical and histologic data from patients who developed cutaneous sarcoid-like reactions between 2019 and 2022 while under treatment with ICIs. We studied 7 patients (6 women and 1 man) with a median age of 65years. Median time to onset of symptoms was 4months. The most common presentation was papular sarcoidosis of the knees followed by subcutaneous sarcoidosis. Diagnosis was confirmed histologically in all cases, and no differences were observed relative to idiopathic sarcoidosis. Discontinuation of ICI therapy was required in just two patients. ICI-induced sarcoid-like reactions tend to be mild and generally do not require treatment discontinuation. Histologic confirmation is essential for distinguishing these reactions from tumor progression.

Rare immune-related adverse events in a patient with metastatic melanoma: a case report highlighting sarcoidosis-like reactions triggered by immune-checkpoint inhibitors.

Pembrolizumab and ipilimumab/nivolumab (ipi/nivo) combination are FDA-approved immune checkpoint inhibitor (ICI) therapies for metastatic melanoma. ICIs could result in various inflammation responses known as immune-related adverse events (IRAEs). We report a patient with metastatic melanoma who developed multiple IRAEs including sarcoidosis-like reaction (SLR), diabetic ketoacidosis (DKA), and worsening hypothyroidism on ICIs. A 71-year-old man with stage IIIC melanoma and lymph node metastasis began adjuvant therapy with pembrolizumab in May 2021. A surveillance positron emission tomography-computed tomography (PET-CT) scan four months later showed diffuse nodal uptake indicating potential metastases although the patient remained asymptomatic. His treatment was temporarily switched to ipi/nivo before biopsy was obtained for definitive diagnosis, which revealed non-caseating granulomas consistent with SLR. After resuming pembrolizumab, he developed DKA and worsening hypothyroidism in November 2021, both of which were attributed to IRAEs. His surveillance PET scan in March 2022 again revealed new hypermetabolic activity in several bones, subcutaneous tissue, and the left inguinal lymph node. Left inguinal node biopsy showed disease recurrence, while biopsies of hypermetabolic subcutaneous nodules and bone demonstrated non-caseating granulomas. Our case described a patient on ICIs who developed several IRAEs. SLR is often asymptomatic but remains a diagnostic challenge due to its indistinguishable appearance on imaging studies compared to metastasis. Better understanding of IRAEs and improved surveillance strategies are needed for optimal patient outcomes.

Sarcoidosis-like reaction induced by immune checkpoint inhibitor in a patient with hepatocellular carcinoma: a case report.

Nowadays, immune checkpoint inhibitors (ICI) have become the cornerstone of treatment for many tumors, either as monotherapy or in combination with other therapies. However, these drugs are associated with several new side effects that need early detection. We present the case of a 41-year-old male patient who has been diagnosed with advanced hepatocellular carcinoma (HCC) with metastatic retroperitoneal lymph nodes and a subdiaphragmatic metastatic lesion, undergoing second-line treatment with a combination of nivolumab and ipilimumab. After completing four cycles, the patient was admitted to the hospital due to intermittent fever and profuse sweating. A CT scan showed multiple pathologically enlarged lymph nodes in several locations, raising suspicion of disease progression. The patient's clinical progress was favorable after symptomatic treatment (antipyretics) and was discharged one week after admission. Several days later, the patient complained about painful bilateral ocular redness and was diagnosed with bilateral anterior uveitis. Further blood tests showed elevated angiotensin-converting enzyme (ACE) levels of 67 U/L (normal range: 8 - 52) and decreasing alpha-fetoprotein (AFP) levels of 698 ng/mL (previously 1210 ng/mL), indicative of non-progression of the oncological disease. Finally, an excisional biopsy confirmed the presence of non-necrotizing granulomatous lymphadenitis, leading to the diagnosis of sarcoidosis-like reaction (SLR) induced by immunotherapy as the etiology of the polyadenopathy syndrome. SLR, although uncommon, is an adverse effect of ICI treatment resulting from immune system dysregulation, which can mimic disease progression. It is crucial to be aware of this adverse event and to understand the optimal management approach.

Immunotherapy-induced exclusively cutaneous sarcoid-like reaction.

Sarcoid-like reactions (SLRs) are rare, granulomatous inflammatory reactions to immune checkpoint inhibitors (ICIs) that can involve any organ but frequently affect the lungs, mediastinal lymph nodes and skin. We present a rare case of an exclusively cutaneous SLR due to pembrolizumab that clinically resembled dermatomyositis. A literature review yielded only 12 previously reported cases of ICI-induced cutaneous SLR without any systemic involvement. Our case highlights the diversity of presentations of cutaneous SLR and emphasises the importance of histological evaluation of new cutaneous eruptions.

Hilar/mediastinal and cutaneous drug-induced sarcoidosis-like reaction associated with immune checkpoint inhibitors in metastatic colorectal cancer: a case report.

Background: Immune checkpoint inhibitors (ICIs) are the standard treatment for metastatic colorectal cancer (mCRC) with high microsatellite instability (MSI-H). Among immune-related adverse events (irAEs), drug-induced sarcoidosis-like reactions (DISR) are often difficult to differentiate from cancer progression. Main Body: This is a case of a woman in her mid-60s, with mCRC (RAS wild/BRAF mutant/MSI-H) and abdominal lymph node metastasis, treated with four courses of ipilimumab + nivolumab every 3 weeks, followed by nivolumab every 2 weeks as third-line treatment. After treatment, the original lymph node metastases shrank, but hilar/mediastinal lymph nodes appeared. Endoscopic ultrasound-guided fine-needle aspiration of these lymph nodes revealed multiple epithelioid granulomas without necrosis, indicating a sarcoidosis-like reaction. Fluorodeoxyglucose-positron emission tomography scan showed abnormal subcutaneous accumulation in bilateral forearms and bilateral knee joints. Biopsy of the cutaneous lesions was also performed, which revealed epithelioid granulomas. As the patient had no symptoms in other organs, no specific therapeutic intervention was administered. After the discontinuation of immunotherapy, the sarcoidosis-like reaction regressed without cancer relapse. Conclusions: Clinicians should be aware of the possibility of DISR as an irAE during the ICI treatment of mCRC. In suspected cases of DISR following ICI therapy, it is important to differentiate between cancer progression and DISR through histological diagnosis for the subsequent strategy, as radiological and serological findings are not definitive.

Renal Sarcoidosis-like Reaction Induced by PD-1 Inhibitor Treatment in Non-Small Cell Lung Cancer: A Case Report and Literature Review.

Monoclonal antibodies directed against immune checkpoint proteins have been widely used to treat various cancers and have resulted in favorable clinical outcomes. Despite these beneficial properties, immune checkpoint inhibitors (ICIs) can induce side effects called immune-related adverse events, including sarcoidosis-like reactions (SLR) across multiple organs. Here, we report a case of renal SLR after ICI treatment, and we review the related literature. A 66-year-old Korean patient with non-small cell lung cancer was referred to the nephrology clinic for renal failure after the 14th pembrolizumab treatment dose. A renal biopsy revealed multiple epithelioid cell granulomas, with several lymphoid aggregates in the renal interstitium and a moderate degree of inflammatory cell infiltration in the tubulointerstitium. A moderate dose of steroid therapy was initiated, and the serum creatinine level partially recovered after four weeks of treatment. Judicious monitoring of renal SLR is, therefore, required during ICI therapy, and a timely diagnosis by renal biopsy and appropriate treatment are important.

Granulomatous tattoo reaction treated with topical allopurinol.

Granulomatous reactions to tattoo ink have been frequently associated with exogenous pigment, although sometimes they are the manifestation of a cutaneous or an underlying systemic sarcoidosis. We report a case of a patient with a granulomatous reaction to a black tattoo pigment treated with 3% topical allopurinol for 3 months. We observed complete resolution without any side-effects. Examination and follow-up ruled out sarcoidosis. Oral allopurinol has been proven to be effective for the management of granulomatous reactions to tattoos. Based on the significant improvement we have described in our patient, we recommend new studies to reveal all the potential benefits of the topical use of allopurinol for the treatment of granulomatous reactions to tattoo ink.

Sarcoid-Like Reaction in the Kidney Following Rituximab for Mantle Lymphoma in a 60-Year-Old Man.

The sarcoid-like reaction is a rare autoinflammatory disease that can affect lymph nodes or organs but does not meet the diagnostic criteria for systemic sarcoidosis. Several drug classes have been associated with the development of a systemic sarcoid-like reaction, which defines drug-induced sarcoidosis-like reactions and can affect a single organ. Anti-CD20 antibodies (rituximab) have rarely been reported as responsible for this reaction and this adverse effect has mainly been described during the treatment of Hodgkin's lymphoma. We report a unique case of a sarcoid-like reaction complicating rituximab following the treatment of a mantle cell lymphoma and interesting only the kidney. The 60-year-old patient presented with severe acute renal failure 6 months after the end of his r-CHOP protocol and the urgent renal biopsy revealed acute interstitial nephritis rich in granulomas without caseous necrosis. After ruling out other causes of granulomatous nephritis, a sarcoid-like reaction was retained since infiltration was limited to the kidney. The temporal relationship between rituximab administration and the sarcoid-like reaction onset in our patient supported the diagnosis of a rituximab-induced sarcoidosis-like reaction. Oral corticosteroid treatment led to rapid and lasting improvement in renal function. Clinicians should be warned of this adverse effect and regular and prolonged monitoring of renal function should be recommended during the follow-up of patients after the end of treatment with rituximab.

New Onset Isolated Granulomatous Dacryoadenitis During Etanercept Therapy.

Anti-tumor necrosis factor alpha (TNF- α) biological agents can rarely cause sarcoid-like granulomatosis. A 20-year-old woman presented with a 1-month history of painful left upper eyelid swelling. She was on subcutaneous etanercept and methotrexate for 1 year for juvenile idiopathic arthritis. Imaging showed diffuse enlargement of the left and minimal enlargement of the right lacrimal gland. There was no finding in favor of sarcoidosis on systemic evaluation. Incisional biopsy of the left lacrimal gland revealed non-caseating granulomatous dacryoadenitis. The findings showed significant regression 1 month after cessation of Etanercept therapy. To the best of our knowledge, this report illustrates the first case of an isolated granulomatous dacryoadenitis during TNF-α antagonist therapy.

Efficacy and safety of methylprednisolone pulse followed by oral prednisone vs. oral prednisone alone in sarcoidosis tubulointerstitial nephritis: a randomized, open-label, controlled clinical trial.

BACKGROUND: We determine the benefit of pulsed methylprednisolone for improving kidney function in patients with sarcoidosis tubulointerstitial nephritis. METHODS: We conducted a multicenter, prospective, randomized, open-label, controlled trial in patients with biopsy-proven acute tubulointerstitial nephritis caused by sarcoidosis at 21 sites in France. Patients were randomly assigned to receive a methylprednisolone pulse 15 mg/kg/day for 3 days, then oral prednisone (MP group) or oral prednisone 1 mg/kg/day alone (PRD group). The primary end point was a positive response at 3 months, defined as a doubling of estimated glomerular filtration rate (eGFR) compared with the eGFR before randomization. RESULTS: We randomized 40 participants. Baseline eGFR before PRD was 22 mL/min/1.73m2 {interquartile range [IQR], 16-44} and before MP was 25 mL/min/1.73m2 (IQR, 22-36) (P = .3). The two groups did not differ in underlying pathological lesions, including mean percentage of interstitial fibrosis and intensity of interstitial infiltrate. In the intent-to-treat population, the median eGFR at 3 months did not significantly differ between the PRD and MP groups: 45 (IQR, 34-74) and 46 (IQR, 39-65) mL/min/1.73m2. The primary end point at 3 months was achieved in 16 of 20 (80%) PRD patients and 10 of 20 (50%) MP patients (P = .0467). The eGFR was similar between the two groups after 1, 3, 6, and 12 months of treatment. For both groups, eGFR at 1 month was strongly correlated with eGFR at 12 months (P < .0001). The two groups did not differ in severe adverse events. CONCLUSION: Compared with a standard oral steroid regimen, intravenous MP may have no supplemental benefit for renal function in patients with tubulointerstitial nephritis caused by sarcoidosis.Trial Registration: ClinicalTrials.gov: NCT01652417; EudraCT: 2012-000149-11.

Sarcoidosis incidence after mTOR inhibitor treatment.

OBJECTIVE: Mechanistic target of rapamycin (mTOR) inhibitors are effective in animal models of granulomatous disease, but their benefit in sarcoidosis patients is unknown. We evaluated the incidence of sarcoidosis in patients treated with mTOR inhibitors versus calcineurin inhibitors. METHODS: This was a cohort study using the Optum Clinformatics® Data Mart (CDM) Database (2003-2019), IBM® MarketScan® Research Database (2006-2016), and Danish health and administrative registries (1996-2018). Patients aged ≥18 years with ≥1 year continuous enrollment before and after kidney, liver, heart, or lung transplant treated with an mTOR inhibitor or calcineurin inhibitor were included. Patients diagnosed with sarcoidosis before, or up to 90 days after, transplant were excluded. The incidence of sarcoidosis by treatment group was calculated. RESULTS: In the Optum CDM/IBM MarketScan cohort, 1,898 patients were treated with an mTOR inhibitor (mean age 49 years; 34% female) and 9,894 patients were treated with a calcineurin inhibitor (mean age 50 years; 37% female). The mean follow-up in the mTOR inhibitor group was 1.1 years, with no incident sarcoidosis diagnosed. In the calcineurin inhibitor group, the mean follow-up was 2.2 years, with 12 incident sarcoidosis cases diagnosed. In the Danish cohort, 230 patients were treated with an mTOR inhibitor (mean age 49; 45% female), with no incident sarcoidosis diagnosed. There were 3,411 patients treated with a calcineurin inhibitor (mean age 45; 40% female), with 10 incident cases of sarcoidosis diagnosed. CONCLUSIONS: This study indicates a potential protective effect of mTOR inhibitor treatment compared with calcineurin inhibitor treatment against the development of sarcoidosis.

Outcomes of prednisone-tapering regimens for cardiac sarcoidosis: A retrospective analysis demonstrating a benefit of infliximab.

BACKGROUND: The optimal treatment strategy for cardiac sarcoidosis has not been standardized. We examined the effectiveness of three prednisone-tapering treatment regimens for cardiac sarcoidosis. METHODS: We retrospectively reviewed prednisone-tapering treatment regimens for cardiac sarcoidosis that contained prednisone alone (P), prednisone plus methotrexate (P-M), and prednisone plus infliximab containing regimens (P-I). We defined the success of each regimen as the ability to lower the daily prednisone dose to 7.5 mg or less for 6 or more months without developing an adverse cardiac event. We also examined the lowest effective daily prednisone dose achieved without developing an adverse cardiac event. RESULTS: We identified 61 treatment regimens in 33 cardiac sarcoidosis patients that were analyzed. The success rate of prednisone-tapering regimens was significantly different P: 8/30, 27%; P-M: 3/23, 13%; P-I: 6/8, 75%., p = 0.04. The lowest effective daily prednisone dose for the regimens was also significantly different: P: 14.1 ± 10.1 mg; P-M: 16.9 ± 9.4 mg; infliximab: 7.8 ± 4.9 mg, (p = 0.03); by both measures the success was greatest with the P-I regimen. CONCLUSIONS: For the treatment of cardiac sarcoidosis, prednisone-tapering regimens containing infliximab are superior to those containing prednisone alone or prednisone plus methotrexate in terms of reaching 7.5 mg/day of prednisone for more than 6 months and achieving the lowest effective prednisone.

A Novel Development of Sarcoidosis Following COVID-19 Vaccination and a Literature Review.

BNT162b2 (Pfizer/BioNTech) is a coronavirus disease 2019 (COVID-19) vaccine containing nucleoside-modified messenger RNA encoding the severe acute respiratory syndrome coronavirus 2 spike glycoprotein. Recently, ocular complications of mRNA vaccines have been reported increasingly frequently. However, immunological adverse events due to mRNA vaccines in real-world settings are not fully known. We herein report the novel development of sarcoidosis manifested as uveitis, bilateral hilar lymphadenopathy, angiotensin-converting enzyme elevation, and epithelioid and giant cell granuloma formation in the lung soon after the first BNT162b2 injection and review the current literature, including three reported cases of sarcoid-like reaction following COVID-19 vaccination.

Drug-induced comorbidities in patients with sarcoidosis.

PURPOSE OF REVIEW: Sarcoidosis is a chronic multisystemic inflammatory disease of unknown aetiology with a wide range of highly variable clinical manifestations and unpredictable disease course. Sarcoidosis patients may present with specific organ-related symptoms involving functional impairments, and less specific symptoms. The decision whether and when to treat a sarcoidosis patient with pharmacotherapy depends on two major factors: risk of organ failure and/or death and impairment of quality of life. This decision is complex and not standardized. RECENT FINDINGS: Glucocorticoids (GCs) are recommended as initial treatment, when needed. Subsequent GC-sparing alternatives frequently follow. Comorbidities or adverse drug reactions (ADRs) from drugs used in sarcoidosis treatment are sometimes very hard to differentiate from symptoms associated with the disease itself, which may cause diagnostic dilemmas. An ideal approach to minimalize ADRs would involve genetic screening prior to prescribing certain 'high-risk drugs' and therapeutic drug monitoring during treatment. Pharmacogenomic testing aims to guide appropriate selection of medicines, with the potential of reducing unnecessary polypharmacy while improving clinical outcomes. SUMMARY: A multidisciplinary approach to the management of sarcoidosis may avoid unnecessary ADRs. It is important to consider the possibility of drug-induced damage in sarcoidosis, especially if the clinical situation deteriorates after the introduction of a particular drug.