<h2>What molecular pathways are implicated in cGVHD?</h2>
Several pathways have been shown to be key mediators of disease progression in chronic graft-versus-host disease.1

The rho-associated coiled-coil–containing protein kinase (ROCK) molecular pathway plays a key role in immune and fibrotic disease.2,3&nbsp;Additionally, ROCK is downstream of major profibrotic mediators and regulates multiple fibrotic processes, such as myofibroblast activation and profibrotic gene transcription.3 ROCK2, specifically, is involved in both the inflammatory and fibrotic components of cGVHD and has been shown to play an important role in modulating immune homeostasis.2 
 Selective ROCK2 inhibition has been shown to help resolve immune dysregulation by downregulating pro-inflammatory T helper (Th) 17 cells and increasing regulatory T (Treg) cells.2&nbsp;Furthermore, selective ROCK2 inhibition has been shown to downregulate key fibrotic processes, such as TGF-β and LPA, leading to a decrease in fibrosis and collagen deposition.3-5

ROCK

black

Following HCT, B-cell homeostasis and tolerance mechanisms are disrupted, resulting in reduced memory B-cell formation.6&nbsp;These host-reactive B cells are associated with the development of cGVHD.7 
 BTK is a signaling molecule of the B-cell antigen receptor and cytokine receptor pathways,8&nbsp;which is expressed mainly in B cells and other hematopoietic tissues.9&nbsp;Signaling via BTK results in the activation of pathways necessary for B-cell trafficking, chemotaxis and adhesion.8

JAK1 and JAK2 are signal mediators of several cytokines and growth factors that are necessary for hematopoiesis and immune function. STATs are recruited to cytokine receptors during JAK signaling, leading to modulation of gene expression.10 In cGVHD pathogenesis, JAK-STAT molecular pathways regulate the development, proliferation and activation of various immune cell types.10

IL-2, a cytokine signaling molecule, is essential for normal Treg cell development, expansion, activity and survival. CD4+&nbsp;Treg cells play a role in immune tolerance and controlling immune responses.&nbsp;Impaired Treg cell function is characteristic of cGVHD and is associated with loss of tolerance and autoimmunity.11

IL-2

Research continues to uncover the role of these pathways.

Learn more about inflammation and fibrosis

What manifestations are caused by the activation of these pathways?

Abbreviations

References

Molecular Pathway

CHRONIC-GRAFT-VERSUS-HOST-DISEASE-CGVHD

TRANSPLANT

<h2>What is the Pathogenesis of cGVHD?</h2>
Chronic graft-versus-host disease is a complex multisystem disorder caused by an immune imbalance following an allogeneic HCT, which leads to serious and potentially life-threatening complications from both inflammatory and fibrotic processes. cGVHD is mediated by multiple immune pathways and is characterized by1

Early inflammation due to tissue injury

Chronic inflammation and a dysregulated adaptive immune system

Chronic graft-versus-host disease presents multiple challenges for both clinicians and patients, specifically through manifestations of inflammation and fibrosis.
Although advances have been made in the understanding of cGVHD, many questions still remain.

Understanding the manifestations of cGVHD

What roles do the inflammatory and fibrotic processes play in cGVHD?

cGVHD is a significant burden on patients, affecting them physically, mentally, emotionally and financial

What is the full impact of cGVHD on patients' lives?

How targeting alternative molecular pathways may offer a different treatment approach

What is under clinical development?

cGVHD,chronicgraft-versus-hostdisease.
Although the understanding of the pathophysiology of cGVHD is improving, there is still much to be uncovered about the nature of the inflammatory cascade and the complex dynamics of the inflammatory and fibrotic processes.
Improving comprehension of these manifestations could help in the development of more targeted treatments.

Learn more about ROCK, BTK, JAK and IL-2

What molecular pathways are implicated in cGVHD?

Reference

Understanding cGVHD

<h2>cGVHD has a significant impact on the overall well-being of patients</h2>
cGVHD impacts patients' QOL
The&nbsp;inflammation and fibrosis&nbsp;associated with chronic graft-versus-host disease lead to multiple physical ailments, some of which include

Skin thickening or tightening, as well as painful rashes and lesions on the skin1-3

Joint stiffness and loss of mobility and dexterity2

Lung function impairment, which leads to significant 
 morbidity3-6

Results from multiple studies show that patients with cGVHD reported significantly worse QOL,&nbsp;as measured by various tools, such as the Lee Symptom Scale, the SF-36 and the FACT-BMT.7,8 
 A multicenter, prospective, observational cohort study evaluated 298 patients with cGVHD. When compared with age- and sex-matched US population normative data, patients with cGVHD had significantly lower scores, as measured by the SF-36 and the FACT-BMT, for8

When comparing mean SF-36 scores of patients with moderate to severe cGVHD with those of other chronic health conditions, patients with cGVHD had PCS comparable with8
✓ Systemic sclerosis ✓ Systemic lupus erythematosus ✓ Multiple sclerosis
Patients with moderate to severe cGVHD also showed greater impairment when compared with other conditions, including8
✓ Chronic lung disease ✓ Hypertension ✓ Diabetes ✓ Arthritis
Fibrosis, in particular, has a negative effect on QOL, especially when affecting the joints or extensive areas of the skin.2,9 This can lead to chronic disability and, in cases where fibrosis spreads to organs such as the lungs, significant mortality.4-6

Impact on Patients

<h2>WHAT ARE OTHER TREATMENT OPTIONS?</h2>
There are several adjunctive options for the treatment of patients with chronic graft-versus-host disease, including targeted therapies and ECP. However, there is currently limited guidance regarding when each should be considered and for which patients these treatments will be most effective.1-4

ECP is a nonpharmacologic immunomodulatory therapy that involves leukapheresis of patient peripheral blood mononuclear cells, exposure of the cellular product to UV-A light in the presence of 8-methoxypsoralen and reinfusion of the ex vivo–treated cells.1 
 The mechanisms of ECP are not completely understood, although it is believed that ECP suppresses alloimmune responses by altering the maturation and function of dendritic cells, as well as through the induction of Treg cells.1&nbsp;The procedure has shown benefit in patients with steroid-refractory cGVHD,1&nbsp;as well as in those with skin, oral, and liver cGVHD.5 
 ECP requires venous or central access and involves a variety of treatment schedules to identify the appropriate dose intensity and length of treatment.6

BTK inhibitors form a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. Nonclinical studies have shown that this class of drug inhibits the proliferation and survival of malignant B cells in vivo, as well as cell migration and substrate adhesion in vitro.3&nbsp;Some BTK inhibitors also inhibit IL-2–ITK, which is highly expressed in T cells and is closely related to BTK.1 
 Both B and T cells play important roles in the pathogenesis of cGVHD,7&nbsp;and the inhibition of BTK and ITK has shown clinical benefit.1,7 
 Warnings and precautions associated with BTK inhibitors include infections and cytopenias, which include thrombocytopenia, neutropenia and anemia.3

BTK inhibitors

JAK1 and JAK2 mediate receptor signaling for a variety of pro-inflammatory cytokines, which are elevated in cGVHD.1 
 Inhibitors of this pathway have been shown to decrease expression of inflammatory cytokines and reduce GVHD in murine models,1,2&nbsp;as well as suppress activation and differentiation of dendritic cells and T cells.1&nbsp;This approach has shown promising results in patients with steroid-refractory cGVHD.1,8 
 Safety considerations associated with JAK inhibitors include monitoring for pruritus, infections, thrombocytopenia and leukopenia.8

JAK inhibitors

A greater number of treatments that address both the inflammatory and fibrotic processes of cGVHD are needed.

Learn more about potential targeted options

Are there new approaches to the treatment of cGVHD under clinical development?

Other Treatment Options

<h2>WHAT ROLES DO THE INFLAMMATORY AND FIBROTIC PROCESSES PLAY IN cGVHD?</h2>
Chronic graft-versus-host disease is characterized by a combination of tissue inflammation and fibrosis, which manifest across multiple organ systems.1-4 
 The relationship between these 2 processes in cGVHD is complex and not fully understood.3&nbsp;Fibrosis may be viewed as a natural consequence of inflammation, as an independent process or as interrelated with inflammation in some ways but not completely dependent on it.5

Because of chronic inflammatory changes, cGVHD can present with collagen-producing fibroblasts,2 resulting in fibrotic lesions.2,4
Fibrotic lesions can develop across multiple organs4

SKIN

MOUTH

JOINTS

EYES

GI TRACT

ESOPHAGUS

LIVER

LUNGS

Fibrosis is a major contributor to life-threatening complications and significant morbidity.6

<h3>Patients develop multiorgan manifestations, including skin, mouth, joint/fascia, eye, upper and lower GI tract, esophagus, liver, genitourinary and/or lung manifestations.4,7,8</h3>

Skin manifestations are the most common, occurring in

Approximately half of patients have lung involvement,

which can manifest as bronchiolitis obliterans, a fibrotic manifestation that can be especially difficult to treat.

<div>
 Although the inflammation associated with cGVHD can be addressed, there is limited evidence regarding the impact of current treatments on fibrosis.10-15
</div>

Learn more about patient quality of life

How do inflammation and fibrosis affect patients’ lives?

Learn more about current treatment options

What treatments are currently available for cGVHD?

Inflammation and Fibrosis Role

<h2>WHAT TREATMENTS ARE UNDER CLINICAL DEVELOPMENT?</h2>
There are multiple novel therapies currently being investigated for the treatment of chronic graft-versus-host disease with the hopes of improving patient outcomes.

Selective rho-associated coiled-coil–containing protein kinase (ROCK) 2 inhibitors have been studied as a potential treatment option for cGVHD, given that this molecular pathway&nbsp;mediates both the inflammatory and fibrotic components&nbsp;of the disease.1,2 
 Selective ROCK2 inhibition has been shown to help resolve immune dysregulation by downregulating pro-inflammatory T helper (Th) 17 cells and increasing regulatory T (Treg) cells. Furthermore, selective ROCK2 inhibition has been shown to downregulate key fibrotic processes, such as TGF-β and LPA, leading to a decrease in fibrosis and collagen deposition.1-4 
 Clinical studies are currently ongoing to evaluate the potential benefifits of selective ROCK2 inhibition in cGVHD.

Selective ROCK2 inhibitors

The involvement of JAKs in the signaling of pro-inflammatory cytokines involved in cGVHD pathogenesis has been a large area of interest. The potential use of JAK1 selective inhibitors in the treatment of cGVHD is currently being explored.

Selective JAK1 inhibitors5

The important role that IL-2 plays in Treg cell development, expansion, activity and survival has led to interest in its use for the treatment of cGVHD. Clinical studies in patients with cGVHD have shown that low-dose subcutaneous IL-2 has increased Treg cells, with minimal effect on CD4+&nbsp;T cells. Clinical studies are currently ongoing to explore the potential benefits of IL-2 therapy.

IL-26

Combination therapy that is intended to disrupt each phase of the GVHD cascade is another area in which research is underway. This approach to therapy would ideally use synergistic agents with different mechanisms of action and nonoverlapping toxicities

Combination therapy7

As research continues, promising targets in cGVHD are being uncovered, with the possibility of offering patients more comprehensive and optimized treatments in the near future.

What are the manifestations of cGVHD that need to be addressed?

Abbreviation

Treatment under Clinical Development

<h2>cGVHD impacts patients’ psychological health</h2>
Approximately one-third of patients with moderate to severe cGVHD have clinically significant psychological distress, including depression or anxiety.10 
 In a prospective observational study evaluating 53 patients with moderate to severe cGVHD, the rates of clinically significant depression and anxiety symptoms were

Greater cGVHD symptom burden was associated with an increased rate of depression.10 
 In a multicenter, prospective, observational cohort study of 298 patients, when comparing mean SF-36 scores with those of other chronic health conditions, patients with severe cGVHD had MCS comparable with depression.8

cGVHD poses multiple economic challenges for patients
Patients who undergo an allogeneic HCT face financial hardship, which may be further amplified by a diagnosis of cGVHD.
 A multicenter, prospective, observational cohort study evaluated 298 patients wiA study that supplemented data from the multicenter, prospective, observational Chronic GVHD Consortium Response Measures Validation Study found that11

reported having difficulty paying medical bills

24%

did not have enough money at the end of the month

28%

reduced spending on utilities and other expenses

49%

used retirement savings

31%

borrowed money or sold assets&nbsp;&nbsp; &nbsp;

16%

Factors that contributed to this financial burden included multiple treatments, inability to return to work, frequent physician visits and losing/changing insurance.11

<table align="center" border="0" cellpadding="1" cellspacing="1" style="width: 1500px;">
 <tbody>
 <tr>
 <td style="text-align: center; background-color: rgb(136, 146, 153); border-color: rgb(136, 146, 153);">Sixty-six percent of patients with cGVHD face a financial challenge&nbsp;after transplant, regardless of insured status.11&nbsp;Twenty-five percent of patients will lose 20 years of&nbsp;earnings because of permanent disability.12&nbsp;Overall, patients with cGVHD are significantly&nbsp;less likely to return to the workforce, even 2 to 3 years after transplant,&nbsp;compared with those without cGVHD.13</td>
 </tr>
 </tbody>
</table>

Even in patients receiving treatment, cGVHD has a considerable impact on QOL, as well as psychological and financial well-being.

Learn more about treatment options

Could optimizing treatment help improve patient outcomes?

Psychological & Economical impact

To read the full content, activate your Sanofi Campus account. Please confirm your email address in the email you received.

If you didn't receive our first email at {email} to confirm your account you can request a new one below. If you don't see it, you may need to check your spam folder.

This information will only be used to validate your account and will not be distributed.

title

Before starting exploring, we can suggest you specific and relevant content

Title

This website is for healthcare professionals only.

Welcome to BP Sanofi Campus

Create new password

To offer you a personalised experience, you must

Your profile is incomplete

The ADCT gives a measure of how controlled the eczema is. Answer these 6 simple questions with your patient to find the ADCT score. It will indicate proper course of action.

Atopic dermatitis, a type of eczema, may be affecting your Patient's life in more ways than you know.

Take the Atopic Dermatitis Control Test (ADCT)

Enjoy more exclusive content{newline}by <a>registering today</a>

Already have an account? <a>Sign in here</a>

Best practices on optimising patient care

Get a customised view of the topics that you're interested in, along with the ability to save content to watch or read at a later date.

Unlimited access to premier content, white papers, case studies, research papers, webinars, training, and up-to-date scientific medical resources.

Personalised content based on your areas of interest

Connect and stay up-to-date with peers in your area of speciality and topics of interest through free events and leadership forums.

Please sign in to continue and read the full article

Please sign up to continue reading the full article.

We respect your privacy and will not share your information with any 3rd parties.

Topical guides written specifically for patients

Unlimited access to the latest patient guide guides and resources. Share content with your patients with easy-to-use online tools.

Please complete your profile to read the content.

Your profile is not validated yet. Please verify your inbox.

Restricted Access

We can't find the page you're looking for

You are going to a website that is not operated by Sanofi. Sanofi has no control over the content or availability of linked sites or resources, and accepts no liability or responsibility for them or for any loss or damage that may arise from your use of them. Please ensure that you read the legal and privacy policy sections of any third-party site to which you link.

You are about to leave Sanofi Campus website.

You are now leaving this site to visit a partner website.

Thank you for visiting COPD Sanofi Campus.

Welcome to COPD Sanofi Campus.

Welcome to COPD Sanofi Campus

Welcome to CSU Sanofi Campus

Please refresh the page to access the content

Sorry, something went wrong

We're usually a treasure chest of knowledge, but we couldn't find what you're looking for.

We were unable to find what you're searching for

You are about to leave Campus.sanofi/uk.

Images from <a>iStockphoto.com</a>, Fotolia.de, <c>gettyimages.de</c>, <d>pexels.com</d> and <e>photocase.de</e> were used for our websites.

Thank you for registering. Before we get started, we need to confirm your email address to ensure that we have the correct information.

Please follow these steps to complete your registration:

Would you like to receive future text messages about Beyfortus updates?

Sanofi is here to help support your patients, their families, and caregivers. For more information regarding Beyfortus®, call <a.callPhoneNumberBeyfortus>1-855-BEYFORTUS (1-855-239-3678)</a.callPhoneNumberBeyfortus> or sign up below to receive the latest updates via email or text. All fields are required.

Would you like to learn more about Beyfortus® (nirsevimab-alip) 50 mg and 100 mg injection? Leave us your contact details, and a Sanofi representative will be in touch. All fields are required.

Would you also like to receive future messages and updates about Beyfortus?

Do you want to participate in the Beyfortus Reservation Program?

What information are you interested in learning more about? (Optional)

Are you enrolled in CENRIFKI REMS?

Request a visit from your local ALPROLIX representative to learn more. Call <a.callPhoneNumberAltuviiio>1-800-745-4447</a.callPhoneNumberAltuviiio>, Option 5, or complete the form below. The information you provide will be maintained in accordance with our <a.usPrivacyPolicy>Privacy Policy</a.usPrivacyPolicy>. All fields are required.

Request a visit from your local ALTUVIIIO representative to learn more. Call <a.callPhoneNumberAltuviiio>1-800-745-4447</a.callPhoneNumberAltuviiio>, Option 5, or complete the form below. The information you provide will be maintained in accordance with our <a.usPrivacyPolicy>Privacy Policy</a.usPrivacyPolicy>. All fields are required.

Request a visit from your local QFITLIA representative to learn more. Call <a.callPhoneNumberAltuviiio>1-800-745-4447</a.callPhoneNumberAltuviiio>, Option 5, or complete the form below. The information you provide will be maintained in accordance with our <a.usPrivacyPolicy>Privacy Policy</a.usPrivacyPolicy>. All fields are required.

Sign up to schedule an office visit with your ALPROLIX® Representative or receive updates about ALPROLIX. Please complete the form below. The information you provide will be maintained in accordance with our <a.usPrivacyPolicy>Privacy Policy</a.usPrivacyPolicy>. All fields are required.

Sign up to schedule an office visit with your local Sanofi representative and/or to receive updates about Qfitlia. Please complete the form below. The information you provide will be maintained in accordance with our <a.usPrivacyPolicy>Privacy Policy</a.usPrivacyPolicy>. All fields are required (unless otherwise specified).

All fields are required. (unless otherwise specified)

This site is intended for healthcare professionals only and contains information on Sanofi medicines, educational resources and more. Please click the appropriate button below. By entering this site, you are confirming that you are a healthcare professional. This site contains promotional information. Please note that some of the content on the website is only relevant for HCPs.

Welcome to Sanofi Campus

Welcome to ITP Sanofi Campus

This content is only available to registered users. Please sign in or register to view this content.

Please Sign In

Email verification

You're seeing a preview of the portal. Clear your cookies (by closing your browser window for example) to go back to public mode.

We've updated our privacy notice to better protect your data and enhance your experience. Please take a moment to review the changes by <privacyNewTab>clicking here</privacyNewTab>. Your privacy matters for us. Please click on continue to confirm you have read the new privacy notice.

Privacy Notice Update

Communication consent

My consents

Password

Confirm password

{resultsCount, plural, one {result} other {results}}

Please log in to access to the results

You need to sign-in to your account in order to access medical content.

Please Log In

To access the results, please register in under 1 minute

You are now leaving the Sanofi content section of our site and entering the external medical bibliographic search content section.

You are entering to the External Scientific Content Site

You are now leaving the external medical bibliographic search section of our site and entering the Sanofi content section.

chronic GRAFT-VERSUS-HOST DISEASE (cGVHD)

Latest Articles