Non-Small Cell Lung Cancer (NSCLC) Treatment & Management

Sarcoidosis Immune Biomarkers, Potential Targeted Treatment ID'd

An immune cell called a type 1 innate lymphoid cell is found at much higher levels in skin granulomas, that is, clumps of immune cells, of people with sarcoidosis relative to those with non-sarcoid skin granulomas, according to research that shows high levels of the cells were also found in blood and lung samples of sarcoidosis patients, meaning they may be a useful diagnostic biomarker of the disease.

In a mouse model of the disease, University of Pennsylvania researchers found that blocking an immune pathway called CXCR4 in the cells can prevent granulomas from forming. The study, "Recruitment of CXCR4+ type 1 lymphoid cells distinguishes sarcoidosis from other skin granulomatous disease," was published in The Journal of Clinical Investigation. The findings suggest measuring type 1 innate lymphoid cell levels may aid a sarcoidosis diagnosis and that current medications that inhibit the CXCR4 pathway may be able to treat the disease.

"By identifying a cause of the disease, we may have found a better way to diagnose the disease as well as a potential treatment that avoids major side effects," Thomas Leung, MD, PhD, an assistant professor of dermatology at Penn, said in a press release.

In sarcoidosis, granulomas form in different tissues and organs, and can cause scarring and interfere with an organ's function. About 25% of all sarcoidosis patients have cutaneous sarcoidosis where granulomas form on the skin, but patients also often have granuloma formation in other organs, commonly the lungs.

Diagnosing sarcoidosis is challenging because its symptoms vary greatly between people. Early symptoms are also shared with other disorders and there are no diagnostic tests to distinguish between sarcoidosis and other diseases.

"Knowing that type 1 innate lymphoid cells are a biomarker for sarcoidosis should lead to timelier diagnoses for patients," said Misha Rosenbach, MD, the director of Penn's Cutaneous Sarcoidosis and Granulomatous Disease Clinic.

Comparing immune cell types

Here, researchers compared unaffected and affected skin samples from 18 sarcoidosis patients against samples from 10 people with skin granulomas caused by diseases other than sarcoidosis. Most of the sarcoidosis patients exhibited the disease in multiple organs.

Samples showed affected skin from sarcoidosis patients contained on average five times more innate lymphoid cells than affected skin from granulomas of patients without sarcoidosis. Innate lymphoid cells are essential for managing immune reactions to disease-causing agents, controlling inflammation, healing tissues, and sustaining the balance of the immune system.

The researchers also compared immune cell types in the blood of 13 patients with sarcoidosis, five with non-sarcoidosis granulomas, and 17 healthy people.

While blood from those with granulomas not caused by sarcoidosis didn't exhibit higher levels of innate lymphoid cells, people with sarcoidosis had substantially higher levels of type 1 innate lymphoid cells. The researchers found 12 times greater levels of sarcoidosis type 1 innate lymphoid cells in those with active sarcoidosis who weren't treated relative to the healthy controls. When patients received treatment, these levels decreased by four times.

Elevated levels of innate lymphoid cells were also present in lung granulomas.

A genetic analysis of granulomas from sarcoidosis patients showed high levels of CXCR4, an immune-related gene, but its expression was minimal in people with psoriasis or healthy, unaffected skin. CXCR4, the protein produced by this gene, is critical for the movement of immune cells, including innate lymphoid cells, throughout the body.

Using a mouse model of sarcoidosis, the researchers found that type 1 innate lymphoid cells were required for granulomas to form. When mice were treated with plerixafor, an established clinically available CXCR4 inhibitor, they had fewer lung granulomas.

Similarly, after treatment with plerixafor, blood cells isolated from sarcoidosis patients, which naturally exhibited an increased capacity for cellular migration, no longer had increased migration in a laboratory setting. This confirmed that CXCR4-based signaling in immune cells is occurring in sarcoidosis patients and is necessary for tissue granulomas to form.

"CXCR4 inhibitors are already available in the clinic as an injection and used to safely mobilize stem cells before stem cell transplants," Leung said. "I'm eager to work with Misha Rosenbach and the sarcoidosis clinic at Penn to run a clinical test to study whether repurposing these medications may be the first targeted treatment for sarcoidosis. Repurposing medications is more efficient than developing a new drug because the safety and nuances of the drug are already well known."

Living With ILD: A Typical Patient Journey

Interstitial lung diseases (ILDs) are a group of disorders characterised by scarring and inflammation of the lung interstitium, common examples of which include idiopathic pulmonary fibrosis (IPF)and sarcoidosis. ILD is a challenging condition given the progressive nature of the disease which over time leads to worsening respiratory symptoms, poor quality of life and reduced life expectancy. 

This blog describes a typical ILD patient journey from the initial diagnosis through its long-term management to end-of-life care. A better understanding of the ILD patient journey can help guide research in the area helping to improve patient care and ILD outcomes.

The beginning of the journey

The ILD patient journey begins with the patient visiting their primary care physician (PCP).  Often ILD patients may visit their PCP multiple times and will receive numerous incorrect diagnoses and medications before ILD is suspected. One study found that 55% of all ILD patients receive at least one wrong diagnosis and 38% had two wrong diagnoses before being correctly diagnosed [1]. The high levels of misdiagnosis in ILD can be ascribed to the non-specific symptoms of ILD which cause it to be mistaken for other common respiratory conditions e.G. Asthma, bronchitis [1]. Other contributing factors include a lack of PCP knowledge of ILD symptoms, the poor sensitivity of diagnostic tests in particular x-rays and the presence of comorbidities (e.G. Gastroesophageal reflux disease) that can mask ILD symptoms. 

Those patients who show no improvement in their symptoms are often then referred to a pulmonary specialist. Around 30% of ILD patients visit their PCP at least four separate times before referral [2]. Following their referral, many patients will need to undergo invasive procedures e.G. Lung biopsy to confirm their diagnosis. One study found 61% of ILD patients underwent bronchoscopy or surgical lung biopsy, 45% a surgical lung biopsy and 21% may undergo both procedures to confirm a diagnosis of ILD [3]. These procedures can be stressful for patients and also carry significant risks. Consequently, ILD patients may wait as long as 4 to 5 years to receive a confirmatory diagnosis of ILD [2], This wait can impose a significant emotional toll on sufferers and impact their overall quality of life 

Diagnosis to disease management 

A confirmatory ILD diagnosis is important for the initiation of the appropriate treatment. Those available pharmacological treatments, while not curative, can provide patients with some relief from ILD symptoms and help improve their overall quality of life [4–6]. Other non-pharmacological options for ILD include pulmonary rehabilitation and oxygen therapy. One study found that over 40% of patients who attended a specialist ILD clinic were referred for pulmonary rehabilitation [7]. Pulmonary rehabilitation can improve exercise capacity, quality of life and lung disease knowledge in ILD patients [7]. 

As ILD progresses many patients begin to experience declines in lung function, worsening disease symptoms and a lower quality of life [8]. Consequently, ILD patients are required to attend regular clinic follow-up appointments. These follow-up appointments typically involve the patient undergoing repeat imaging and pulmonary function testing [9]. However, many patients with advanced ILD report challenges in being able to both travel to and attend clinic appointments and perform pulmonary function tests e.G. Spirometry due to their worsening respiratory symptoms  [10].

Some ILD patients may also experience acute exacerbations characterised by the rapid onset of breathlessness, coughing, fatigue and sometimes fever. ILD exacerbations may occur because of disease progression or may be triggered by infections, gastroesophageal reflux disease, air pollution or certain medications. It is estimated that 4% of IPF patients experience an acute exacerbation each year [11]. ILD patients who experience exacerbations may be admitted to hospital where they receive antibiotics and supportive care. Approximately half of all ILD patients who suffer an exacerbation do not survive to discharge [11].

The end of the journey

At the end of their journey, ILD patients experience significant escalations in disease symptoms and declines in functional capacity. Some ILD patients may undergo a lung transplant of either one or both lungs. Lung transplants can be life-saving for ILD patients with a median survival of around 7 years [12]. The procedure itself is however not without risk with an estimated 20% of patients not surviving 1-year post-transplant [13]. The long-term prognosis for ILD patients who do not undergo lung transplantation is significantly poorer with a median survival of 3 to 4 years post-diagnosis [14]. Consequently, many ILD patients spend the last few months of their life in a hospital or hospice facility [15].

In conclusion, the journey for many ILD patients is a difficult one fraught with many challenges. These challenges include inaccurate and delayed diagnoses, limited treatment options with the ability to halt ILD progression and poor patient monitoring. Addressing these challenges will be key to optimising patient outcomes and improving the quality of life of ILD sufferers. 

References

[1] Cosgrove GP, Bianchi P, Danese S, et al. Barriers to timely diagnosis of interstitial lung disease in the real world: the INTENSITY survey. BMC Pulm Med. 2018;18:9.

[2] Lamas DJ, Kawut SM, Bagiella E, et al. Delayed Access and Survival in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med. 2011;184:842–847.

[3] Lederer DJ, Bianchi P, Loboda J, et al. AB017. Interstitial lung disease patient diagnostic journey (intensity). J Thorac Dis. 2016;8:AB017–AB017.

[4] Pitre T, Kawano-Dourado L, Kachkovski G V, et al. Systemic corticosteroids in fibrotic lung disease: a systematic review and meta-analysis. BMJ Open Respir Res. 2023;10:e002008.

[5] Richeldi L, du Bois RM, Raghu G, et al. Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis. New England Journal of Medicine. 2014;370:2071–2082.

[6] King TE, Bradford WZ, Castro-Bernardini S, et al. A Phase 3 Trial of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis. New England Journal of Medicine. 2014;370:2083–2092.

[7] Hoffman M, Mellerick C, Symons K, et al. Pulmonary rehabilitation for interstitial lung disease: Referral and patient experiences. Chron Respir Dis. 2021;18:147997312110460.

[8] Maqhuzu PN, Szentes BL, Kreuter M, et al. Determinants of health-related quality of life decline in interstitial lung disease. Health Qual Life Outcomes. 2020;18:334.

[9] National Institute for Health and Care Excellence (NICE). Idiopathic pulmonary fibrosis in adults: diagnosis and management Clinical guideline [Internet]. 2013. Available from: www.Nice.Org.Uk/guidance/cg163.

[10] Kumar D. Assessment and follow-up of interstitial lung disease. Indian J Rheumatol. 2021;16:69.

[11] Collard HR, Ryerson CJ, Corte TJ, et al. Acute Exacerbation of Idiopathic Pulmonary Fibrosis. An International Working Group Report. Am J Respir Crit Care Med. 2016;194:265–275.

[12] Chambers DC, Cherikh WS, Harhay MO, et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-sixth adult lung and heart–lung transplantation Report—2019; Focus theme: Donor and recipient size match. The Journal of Heart and Lung Transplantation. 2019;38:1042–1055.

[13] NHS Blood and Transplant. Benefits and Risks of Lung Transplants [Internet]. [cited 2024 May 12]. Available from: https://www.Nhsbt.Nhs.Uk/organ-transplantation/lung/benefits-and-risks-of-a-lung-transplant/.

[14] Kolb M, Vašáková M. The natural history of progressive fibrosing interstitial lung diseases. Respir Res. 2019;20:57.

[15] Cross SH, Ely EW, Kavalieratos D, et al. Place of Death for Individuals With Chronic Lung Disease. Chest. 2020;158:670–680.

UAB Sarcoidosis Joins As A Founding Member Of The Global Sarcoidosis Alliance

Left to right Kevin G. Dsouza, M.D.; Ishan Lalani, M.D., MPH; Joseph B. Barney, M.D.; Maria del Pilar Acosta Lara, M.D.; Kelli Montz, BSN, RN; Lanier O'Hare, Ph.D.

The University of Alabama at Birmingham's Multidisciplinary Sarcoidosis Clinic has joined the Foundation for Sarcoidosis Research (FSR) as a founding member in their Global Sarcoidosis Alliance (GSA). This new network of specialty clinics in the United States and globally creates a robust network for patient and clinician education, innovates sharing of information to advance new therapies for treatment of sarcoidosis, and creates collaborative referral networks to connect patients with complex sarcoidosis with specialists familiar with their disease. Sarcoidosis is an inflammatory disease characterized by the formation of granulomas in one or more organs of the body.

When left unchecked, chronic inflammation caused by granulomas can lead to fibrosis. This disorder affects the lungs in approximately 90% of cases, but it can affect almost any organ in the body. Despite increasing advances in research, sarcoidosis remains difficult to diagnose with limited treatment options and no known cure.

Disease presentation and severity varies widely among patients. In some cases, the disease goes away on its own. In others, the disease may not progress clinically but individuals will still suffer from some symptoms that challenge their quality of life. The rest of patients—up to a third of people diagnosed with the disease—will require long-term treatment. It's estimated that the prevalence of sarcoidosis in the US ranges between 150,000 and 200,000 (Baughman, RP et al), with an estimated 1.2 million individuals with sarcoidosis worldwide (Denning, DW et al.). The FSR Global Sarcoidosis Clinic Alliance brings together sarcoidosis clinics and hospitals committed to finding a cure and offering evidence-based, patient-centric care for those living with sarcoidosis. Alliance members will benefit from innovative resources, sustainable programming, and tools to accelerate treatment, research and the continuum of patient care.

"FSR believes in the power of many to join forces for true game-changing results in sarcoidosis care and research. The FSR Global Sarcoidosis Clinic Alliance will ensure every patient in every community across the world has access to education, care, and support, leading to improved patient outcomes," says Mary McGowan, FSR CEO. "The quality of life of approximately 1.2 million sarcoidosis patients impacted by sarcoidosis world-wide depends on a true global collaborative and that's exactly what this Alliance is all about." "We are excited to contribute to this new alliance and push the margin forward in understanding and eventually curing sarcoidosis for thousands of patients in Alabama and worldwide," said Joseph Barney, M.D., professor in the UAB Division of Pulmonary, Allergy and Critical Care Medicine and director of UAB's Multidisciplinary Sarcoidosis Clinic.

"We were initially motivated to join the alliance to foster collaboration between other providers from other clinics in the United States," said Pilar Acosta Lara, M.D., a member of the UAB Multidisciplinary Sarcoidosis Clinic.

"Since joining the alliance, we have been fostering working collaborations with other clinics in the US," Dr. Acosta Lara said. "Our patients share the same barriers as those in other alliance clinics - access to care, support care network geared towards patients, and access to clinical trials. This alliance will expand all of our efforts to improve the care of sarcoid patients"

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