Melanocortin Receptors and Their Role in Noninfectious Uveitis

NEW AGENTS FOR UVEITIS

Uveitis is not a singular disorder. In certain cases, it is the “manifestation of potential systemic diseases that may have very specific individual therapeutic targets,”⁵² or it may be one of many forms of inflammation isolated to the eye. Often, the inflammation is undifferentiated or idiopathic.

MELANOCORTIN RECEPTORS

Melanocortins are endogenous peptides that have been shown to inhibit leukocyte activation and promote inflammation resolution; they may affect behavior, the cardiovascular system, central and peripheral electrophysiological parameters, and food intake; and they may be protective against tissue damage.^53-55

The literature shows MCRs may induce regulatory immunity against autoantigens that are in the eye; the literature discusses melanocortin protection of retinal cells and expression of MCRs in the retina.^53,56-60

Melanocortins — adrenocorticotropic hormone (ACTH), α-melanocyte–stimulating hormone (α-MSH, β-MSH and γ-MSH) — are polypeptides derived from a common precursor pro-opiomelanocortin (POMC).54 To date, five subtypes of MCR have been identified (MC1 to MC5), and ACTH can activate all five.⁵⁴

Outside the eye, the effects of α-MSH on expression of cytokines and metalloproteinase suggest a role in the inflammatory and degenerative processes.⁵⁸,61 α-MSH activates all known MCRs (except MC2) and exerts protective effects on retinal vascular endothelial cells.⁵³

MC3, MC4, and MC5 are expressed in the innerneural retinal layers, with MC3 and MC4 expression has been found in retinal ganglion cells.⁵⁶ MC1 has been detected in retinal pigment epithelial cells.^61,62

UNDERSTANDING MCRS

At the cellular level, inflammation is a dynamic tissue response that defends the host against insults from infection, trauma, or damage.⁶³ To prevent the development of persistent or chronic inflammation, the inflammatory reaction must be entirely resolved to prevent further tissue damage. In the past few decades, researchers have determined the resolution of inflammation is a “carefully managed active process,” and deficiency in any one of the components can result in uncontrolled chronic inflammation,⁶⁴ not unlike that what occurs in NIU.

Studies have shown that by binding to the MCRs, repository corticotrophin may have both anti-inflammatory and immunomodulatory properties.^65,66 Further, MCR activation has been shown to decrease the activity of T-helper cells and increase the number and activity of T-regulatory cells.⁶⁶ The dual mechanism of action of H.P. Acthar Gel provides the potential to treat the acute inflammation, as well as to induce long-term remission in NIU.

MCRS AND OCULAR INFLAMMATORY DISEASE

Repository corticotropin was approved by the US Food and Drug Administration in 1952 for the treatment of severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as: keratitis, iritis, iridocyclitis, diffuse posterior uveitis and choroiditis, optic neuritis, chorioretinitis, and anterior segment inflammation. This approval was granted with safety data alone. Consequently, there is currently not enough evidence to endorse first-line use of this class of drugs in ocular inflammatory disease, including NIU.

However, inflammatory cells (including lymphocytes, monocytes/macrophages, and neutrophils), as well as tissue-based cells express MCR.54 The literature confirms ACTH as a steroid-sparing treatment for numerous systemic inflammatory disorders, and it has been found to be more effective than corticosteroids in some studies.^67-69 A recent review of ACTH has suggested new ACTH-like melanocortin drugs devoid of steroidogenic actions (and therefore, side effects) should be developed.⁷⁰

Faculty members of this panel are evaluating H.P. Acthar Gel in uveitis, including as twice- or thrice-weekly treatment for NIU. One published case study has suggested it may be a “safe and viable therapeutic option” for NIU and retinal vasculitis.⁷¹ The faculty is in agreement that the clinical efficacy and safety of ACTH gel needs additional study, especially in NIU. There may be potential cost savings with using this class of medications over immunomodulatory agents, especially if long-term control and remission of NIU can be established.

PROPOSED NEXT STEPS

It is this panel’s consensus that the evidence published to date warrants increased evaluation of MCRs in ocular-specific cells. The faculty members hypothesize that the mechanism by which MCRs have been proven useful in diseases, such as rheumatoid arthritis and multiple sclerosis, may be duplicated in ocular inflammatory diseases that include NIU. Repository corticotropin is approved for ocular inflammation and ocular inflammatory diseases, and therefore deserves serious careful evaluation for possible clinical utility in NIU.

However, there are currently no Level 1 randomized clinical trial data for clinicians to evaluate the role of ACTH as a steroid-sparing treatment for NIU. This panel recognizes the difficult undertaking a randomized clinical trial would be in NIU; however, the faculty believes that these types of trials will help clinicians and scientists understand the level of efficacy and better identify “appropriate” patients for various treatments.

Among its numerous indications, H.P. Acthar Gel may be used to treat rheumatic, collagen, dermatologic, allergic, respiratory, and edematous disease states.⁷² It is also used to treat autoimmune diseases that have potential ophthalmic manifestations,^7-14 including sarcoidosis9 and rheumatoid arthritis.^10,11,14,15

The faculty members also advocate additional post-marketing studies to further confirm the safety and long-term efficacy of this ACTH treatment in NIU. Ongoing studies in both scleritis (the ATLAS Study) and intermediate, posterior, and pan-uveitis (the ACTHAR Study) may yield data to address these queries. Equally important, the long-term data will also help to determine the ability of the MCR agonist class of medications to induce permanent remission of uveitis.

CONCLUSIONS

Additional data are necessary before recommending this class of drugs for the treatment algorithm of uveitis. The expert panel recommends phase 4 post-marketing studies and is cautiously optimistic about the mechanism of action and potential benefits of this class of drugs in the treatment of NIU. At this time, there is not enough evidence to support first-line use of H.P. Acthar Gel over corticosteroids and immunomodulators (as recommended by the American Uveitis Society and other societies and authorities in the field) in specific uveitic conditions. However, there is anecdotal evidence on the mechanism of action of MCRs to warrant consideration as a potential therapy in patients with recalcitrant and chronic ocular inflammatory diseases.

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