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Peripheral Ulcerative Keratitis (PUK) is a group of destructive
inflammatory diseases Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molecu ...
involving the peripheral cornea in human eyes. The symptoms of PUK include pain, redness of the eyeball,
photophobia Photophobia is a medical symptom of abnormal intolerance to visual perception of light. As a medical symptom photophobia is not a morbid fear or phobia, but an experience of discomfort or pain to the eyes due to light exposure or by presence of ...
, and decreased vision accompanied by distinctive signs of crescent-shaped damage of the cornea. The causes of this disease are broad, ranging from
injuries An injury is any physiological damage to living tissue caused by immediate physical stress. An injury can occur intentionally or unintentionally and may be caused by blunt trauma, penetrating trauma, burning, toxic exposure, asphyxiation, or o ...
,
contamination Contamination is the presence of a constituent, impurity, or some other undesirable element that spoils, corrupts, infects, makes unfit, or makes inferior a material, physical body, natural environment, workplace, etc. Types of contamination ...
of contact lenses, to association with other systemic conditions. PUK is associated with different
ocular Eyes are organs of the visual system. They provide living organisms with vision, the ability to receive and process visual detail, as well as enabling several photo response functions that are independent of vision. Eyes detect light and con ...
and
systemic disease A systemic disease is one that affects a number of organs and tissues, or affects the body as a whole. Examples * Mastocytosis, including mast cell activation syndrome and eosinophilic esophagitis * Chronic fatigue syndrome * Systemic vas ...
s. Mooren's ulcer is a common form of PUK. The majority of PUK is mediated by local or systemic immunological processes, which can lead to
inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...
and eventually tissue damage. Standard PUK diagnostic test involves reviewing the medical history and a completing
physical examination In a physical examination, medical examination, or clinical examination, a medical practitioner examines a patient for any possible medical signs or symptoms of a medical condition. It generally consists of a series of questions about the pati ...
s. Two major treatments are the use of medications such as corticosteroids or other immunosuppressive agents and surgical resection of the
conjunctiva The conjunctiva is a thin mucous membrane that lines the inside of the eyelids and covers the sclera (the white of the eye). It is composed of non-keratinized, stratified squamous epithelium with goblet cells, stratified columnar epithelium ...
. The prognosis of PUK is unclear with one study providing potential complications. PUK is a rare condition with an estimated incidence of 3 per million annually.


Signs and symptoms

The most easily identifiable sign is a visible
lesion A lesion is any damage or abnormal change in the tissue of an organism, usually caused by disease or trauma. ''Lesion'' is derived from the Latin "injury". Lesions may occur in plants as well as animals. Types There is no designated classif ...
of the cornea presented usually in a crescent shape. Common reasons for destruction are stromal degradation and epithelial defects on the inflammatory cells. There would be a change in conformation of the peripheral cornea, depending on the severity of corneal thinning. This process is usually accompanied by the possibility of concealing perforation. The formation of an oval-shaped ulcer at the margin of the cornea is also a sign. Symptoms of PUK include pain, redness, tearing, increased sensitivity to bright light, impaired or blurred vision, and the feeling of foreign objects trapped in the eyes.


Association

There are several associations of PUK to ocular and
systemic disease A systemic disease is one that affects a number of organs and tissues, or affects the body as a whole. Examples * Mastocytosis, including mast cell activation syndrome and eosinophilic esophagitis * Chronic fatigue syndrome * Systemic vas ...
s.
Rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are invol ...
(RA),  Wegner's granulomatosis (WG), and
Polyarteritis Nodosa Polyarteritis nodosa (PAN) is a systemic necrotizing inflammation of blood vessels (vasculitis) affecting medium-sized muscular arteries, typically involving the arteries of the kidneys and other internal organs but generally sparing the lungs' ...
(PAN) are the most common systemic conditions. *
Rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are invol ...
: Approximately 50% of PUK are related to collagen vascular diseases, in which RA is the most common category. Around 34-42% of PUK patients have RA. * Wegner's granulomatosis: WG is a rare autoimmune disease associated with PUK. It causes
vasculitis Vasculitis is a group of disorders that destroy blood vessels by inflammation. Both arteries and veins are affected. Lymphangitis (inflammation of lymphatic vessels) is sometimes considered a type of vasculitis. Vasculitis is primarily caused ...
of the lower and upper respiratory tracts, and it also affects multiple organs, including eyes. Without timely initiation of
systemic therapy In psychotherapy, systemic therapy seeks to address people not only on the individual level, as had been the focus of earlier forms of therapy, but also as people in relationships, dealing with the interactions of groups and their interactional p ...
, WG patients will develop
conjunctiva The conjunctiva is a thin mucous membrane that lines the inside of the eyelids and covers the sclera (the white of the eye). It is composed of non-keratinized, stratified squamous epithelium with goblet cells, stratified columnar epithelium ...
l and scleral inflammations. The inflammation will eventually cause corneal thinning and worsen PUK. *
Polyarteritis Nodosa Polyarteritis nodosa (PAN) is a systemic necrotizing inflammation of blood vessels (vasculitis) affecting medium-sized muscular arteries, typically involving the arteries of the kidneys and other internal organs but generally sparing the lungs' ...
: PAN is another autoimmune disease in which the body's immune system attacks small and medium-sized arteries of its own by mistake. PUK is one of the predominant ocular inflammatory manifestations of PAN.


Causes

There are three major causes for PUK. One possible cause is injury due to any kind of scratches by sharp or hard objects on the surface of the cornea. The scratched area forms an opening in the cornea, allowing
microorganism A microorganism, or microbe,, ''mikros'', "small") and ''organism'' from the el, ὀργανισμός, ''organismós'', "organism"). It is usually written as a single word but is sometimes hyphenated (''micro-organism''), especially in olde ...
s to access the cornea and lead to infection. Contamination of contact lenses is another cause as
fungi A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately from ...
,
bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic microorganisms. Typically a few micrometr ...
and
parasites Parasitism is a close relationship between species, where one organism, the parasite, lives on or inside another organism, the host, causing it some harm, and is adapted structurally to this way of life. The entomologist E. O. Wilson ha ...
, microscopic parasite
acanthamoeba ''Acanthamoeba'' is a genus of amoebae that are commonly recovered from soil, fresh water, and other habitats. ''Acanthamoeba'' has two evolutive forms, the metabolically active trophozoite and a dormant, stress-resistant cyst. Trophozoites are ...
, in particular, could inhabit the surface of the carrying case of the contact lens. When placing the contact lens to one's eyes, invisible microorganisms may contaminate the cornea resulting in PUK. An extended period of wearing contact lenses could also cause damage on the cornea surface, allowing the entry of microorganisms to the cornea. Other than contamination of contact lenses, contamination occurring in water could also cause PUK. Especially in places like the ocean, rivers, lakes and hot tubs, massive amounts of
bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic microorganisms. Typically a few micrometr ...
,
fungi A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately from ...
, and
parasites Parasitism is a close relationship between species, where one organism, the parasite, lives on or inside another organism, the host, causing it some harm, and is adapted structurally to this way of life. The entomologist E. O. Wilson ha ...
exist. When there is an injury on the cornea surface, contact with contaminated water could transfer unwanted microorganisms into the cornea resulting in PUK. Virus and bacteria are sources of infection to the cornea. Herpes virus and bacteria that cause
gonorrhea Gonorrhea, colloquially known as the clap, is a sexually transmitted infection (STI) caused by the bacterium ''Neisseria gonorrhoeae''. Infection may involve the genitals, mouth, or rectum. Infected men may experience pain or burning with u ...
are some examples.


Anatomy and pathogenesis

The
corneal epithelium The corneal epithelium (epithelium corneæ anterior layer) is made up of epithelial tissue and covers the front of the cornea. It acts as a barrier to protect the cornea, resisting the free flow of fluids from the tears, and prevents bacteria fro ...
consists of five to six layers of cells with a total thickness of around 0.52mm. The cornea thickens to 0.65mm towards the periphery of the cornea. Stroma, which accounts for 90% of the corneal thickness, refers to the middle layer between epithelium and
endothelium The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vesse ...
. It is present in the peripheral cornea to act as a transitional zone between the sclera and
cornea The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Along with the anterior chamber and lens, the cornea refracts light, accounting for approximately two-thirds of the eye's total optical ...
. Limbal
vasculature The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
, deriving from capillaries that surround the peripheral cornea, supplies the stroma. Various molecules normally diffuse from these
capillaries A capillary is a small blood vessel from 5 to 10 micrometres (μm) in diameter. Capillaries are composed of only the tunica intima, consisting of a thin wall of simple squamous endothelial cells. They are the smallest blood vessels in the body: ...
at the periphery to the central cornea. With limited
diffusion Diffusion is the net movement of anything (for example, atoms, ions, molecules, energy) generally from a region of higher concentration to a region of lower concentration. Diffusion is driven by a gradient in Gibbs free energy or chemica ...
, there is a higher concentration of
IgM Immunoglobulin M (IgM) is one of several isotypes of antibody (also known as immunoglobulin) that are produced by vertebrates. IgM is the largest antibody, and it is the first antibody to appear in the response to initial exposure to an antig ...
, factor C1 of the
complement cascade The complement system, also known as complement cascade, is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and ...
, and
Langerhans cell A Langerhans cell (LC) is a tissue-resident macrophage of the skin. These cells contain organelles called Birbeck granules. They are present in all layers of the epidermis and are most prominent in the stratum spinosum. They also occur in the ...
s.   Any kind of inflammatory stimulus present in the peripheral cornea results in recruitment of
neutrophil Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...
and activation of both classical and alternative pathways of
immune response An immune response is a reaction which occurs within an organism for the purpose of defending against foreign invaders. These invaders include a wide variety of different microorganisms including viruses, bacteria, parasites, and fungi which could ...
, namely the
humoral Humoral immunity is the aspect of immunity that is mediated by macromolecules - including secreted antibodies, complement proteins, and certain antimicrobial peptides - located in extracellular fluids. Humoral immunity is named so because it invo ...
and cell-mediated autoimmune responses.'''' These responses will lead to the formation of antigen-specific antibodies to combat foreign
antigen In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune respons ...
s. However, antigen-antibody complexes formed may deposit in the
vascular The blood vessels are the components of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide away f ...
endothelium and activate complements leading to severe local inflammation. Under this circumstance, inflammatory cells, such as macrophages and neutrophils, enter the peripheral cornea. These inflammatory cells release enzymes
protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
and
collagenase Collagenases are enzymes that break the peptide bonds in collagen. They assist in destroying extracellular structures in the pathogenesis of bacteria such as ''Clostridium''. They are considered a virulence factor, facilitating the spread of ...
s, causing potential disruption of the corneal stroma. The additional release of
cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
s, for example,
interleukin-1 The Interleukin-1 family (IL-1 family) is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults. Discovery Discovery of these cytokines began with studies on t ...
, from these cells further accelerates the process of stromal destruction.


Mooren's ulcer and relevant classification

Mooren's ulcer is a common form of PUK. One classification of Mooren's ulcer, based on the clinical presentation, includes bilateral indolent mooren's ulcer, bilateral aggressive mooren's ulcer and unilateral mooren's ulcer. Unilateral mooren's ulcer, meaning ulcer of one eye, mainly affects elderly above 60 years old. Rapid onset with redness and severe pain of the affected eye and either slow or extremely quick progression are some typical characteristics of unilateral mooren's ulcer. Bilateral aggressive mooren's ulcer is prevalent in Indian between age 14 to 40. The common presentation includes the appearance of lesions in one eye, followed by the development of lesions in another eye. Finally, bilateral indolent mooren's ulcer is common in patients of at least 50-year-old. It usually progresses slowly and causes little or no pain. Other classification methods also exist. The first one is classifying Mooren's ulcers based on clinical presentation and prognosis into two categories. The first type is usually presented unilaterally, accompanied by symptoms ranging from mild to moderate. Therefore, it has a more effective response to treatment. In contrast, type II appears in a bilateral manner, with severe symptoms and poor outcome of treatment. The second classification is based on severity. Grade I refers to corneal thinning, grade II describes impending
corneal perforation Corneal perforation is an anomaly in the cornea resulting from damage to the corneal surface. A corneal perforation means that the cornea has been penetrated, thus leaving the cornea damaged. The cornea is a clear part of the eye which controls an ...
, and grade III is corneal perforation with a diameter greater than 2mm.


Diagnosis

There are many investigative modalities available for diagnosing PUK, including history review and physical examination. A thorough history of ocular infections, contact lens usage, other medication, or surgery is necessary to identify possible presence of associated diseases. An ophthalmic examination helps identify whether it is due to local pathogenesis. Physical examinations allow more understanding of the underlying systemic process. A standard testing procedure includes
hematological Hematology ( always spelled haematology in British English) is the branch of medicine concerned with the study of the cause, prognosis, treatment, and prevention of diseases related to blood. It involves treating diseases that affect the produc ...
investigations,
immunological Immunology is a branch of medicineImmunology for Medical Students, Roderick Nairn, Matthew Helbert, Mosby, 2007 and biology that covers the medical study of immune systems in humans, animals, plants and sapient species. In such we can see there ...
testing, followed by chest
X-ray An X-ray, or, much less commonly, X-radiation, is a penetrating form of high-energy electromagnetic radiation. Most X-rays have a wavelength ranging from 10  picometers to 10  nanometers, corresponding to frequencies in the range 30&nb ...
. Hematological investigations are blood tests estimating hemoglobin, platelet counts, total white blood cell counts,
erythrocyte sedimentation rate The erythrocyte sedimentation rate (ESR or sed rate) is the rate at which red blood cells in anticoagulated whole blood descend in a standardized tube over a period of one hour. It is a common hematology test, and is a non-specific measure of ...
and
viscosity The viscosity of a fluid is a measure of its resistance to deformation at a given rate. For liquids, it corresponds to the informal concept of "thickness": for example, syrup has a higher viscosity than water. Viscosity quantifies the inte ...
. Other common body checks include
urinalysis Urinalysis, a portmanteau of the words ''urine'' and ''analysis'', is a panel of medical tests that includes physical (macroscopic) examination of the urine, chemical evaluation using urine test strips, and microscopic examination. Macroscopic ...
and liver and renal function tests. The selection of immunological testing for various markers is based on numerous additional medical examinations and clinical history of the patient. Possible markers are antinuclear antibodies, anti-rheumatoid antibodies, and antibodies to cyclic citrullinated peptides. Finally, a chest X-ray helps distinguish whether there are complications, such as pulmonary diseases, due to systemic conditions associated with PUK. One of the common causes of PUK is ocular infections by microorganisms such as bacteria, viruses, and fungi. To detect the causative microorganism, doctors usually collect samples before the commencement of therapy and send them to laboratories. Laboratory personnel then perform smear examination, inoculate the samples on culture media, and perform serological testing. Serological testing is an antibody test providing information on PUK etiology. The diagnosis of PUK due to systemic conditions requires a combination of serological and hematological testing, together with imaging techniques such as
radiography Radiography is an imaging technique using X-rays, gamma rays, or similar ionizing radiation and non-ionizing radiation to view the internal form of an object. Applications of radiography include medical radiography ("diagnostic" and "therapeu ...
and CT scanning.


Treatments

Various PUK therapies are of different objectives, for example, inflammation control, halting of disease progression, stroma repairment, avoidance of secondary complications, and vision restoration. A thorough understanding of PUK and different therapies is important. Medical and surgical treatments are two major approaches to manage PUK.


Medical therapy

As for medical therapy, there are several types of drugs available for PUK.
Topical corticosteroids Topical steroids are the topical forms of corticosteroids. Topical steroids are the most commonly prescribed topical medications for the treatment of rash, eczema, and dermatitis. Topical steroids have anti-inflammatory properties and are classifie ...
usually serve as therapy for milder unilateral cases of RA-associated PUK. Systemic corticosteroids in the form of an oral dose are the acute management of more severe cases. However, there are side effects with prolonged usage of oral corticosteroids. Immunosuppressive agents, such as
azathioprine Azathioprine (AZA), sold under the brand name Imuran, among others, is an immunosuppressive medication. It is used in rheumatoid arthritis, granulomatosis with polyangiitis, Crohn's disease, ulcerative colitis, and systemic lupus erythematosus, ...
, cyclophosphamide, and methotrexate, have demonstrated efficacy in treating inflammatory eye diseases, including PUK. The combined therapy of systemic corticosteroids up to 100 mg/day and immunosuppressive agents are used for severe cases of PUK. Biological agents, such as anti-tissue necrosis factors (anti-
TNF Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
), is a well-established treatment of systemic inflammatory diseases,
Infliximab Infliximab, a chimeric monoclonal antibody, sold under the brand name Remicade among others, is a medication used to treat a number of autoimmune diseases. This includes Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spon ...
and
Adalimumab Adalimumab, sold under the brand name Humira, among others, is a monoclonal antibody used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurati ...
are TNF blockers for treating RA-associated PUK. However, the high cost and uncertainty of long-term side effects are the possible drawbacks.


Surgical treatment

In terms of surgical treatment, conjunctival resection is a common procedure, which can temporarily remove local inflammatory mediators and
collagenase Collagenases are enzymes that break the peptide bonds in collagen. They assist in destroying extracellular structures in the pathogenesis of bacteria such as ''Clostridium''. They are considered a virulence factor, facilitating the spread of ...
s and therefore slow down the disease progression. Other surgical management includes corneal gluing, or keratoplasty procedures. Corneal transplantation is a management option when there is severe corneal melting or perforation although one possible disadvantage is the risk of rejection. Surgical treatment helps maintain the integrity of the globe, but it is usually complementary because it alone cannot influence the underlying immunological process. Therefore, medical and surgical treatments are commonly used in conjunction.''''


Choice of treatment

The choice of treatment may be different depending on the nature of PUK, infectious or noninfectious. Selection of the right targeted antimicrobial therapy for infectious PUK is based on clinical judgement and culture results. For example, the appropriate treatment for bacterial infections is antibiotics, such as
fluoroquinolones A quinolone antibiotic is a member of a large group of broad-spectrum bacteriocidals that share a bicyclic core structure related to the substance 4-quinolone. They are used in human and veterinary medicine to treat bacterial infections, as we ...
. As for Mooren's ulcers, 56% of unilateral PUK and 50% of bilateral PUK in one eye showed recovery with intensive topical steroids. Only 18% of patients with bilateral ulcers occurring simultaneously in both eyes show improvements with topical steroids alone; therefore a combination of immunosuppressive agents and systemic steroids should be given in early courses of management. Corticosteroids are the first line of therapy, but side effects may arise from long-term usage. In addition, conjunctival resection can be performed to temporarily remove local inflammatory mediators, followed by the use of
immunosuppressants Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent activity of the immune system. Classification Immunosuppressive drugs can be classified int ...
.


Prognosis

Currently, there are limited studies regarding the prognosis of PUK. However, one study has pointed out possible complications surrounding PUK include moderate to severe
vision loss Visual impairment, also known as vision impairment, is a medical definition primarily measured based on an individual's better eye visual acuity; in the absence of treatment such as correctable eyewear, assistive devices, and medical treatment ...
,
corneal perforation Corneal perforation is an anomaly in the cornea resulting from damage to the corneal surface. A corneal perforation means that the cornea has been penetrated, thus leaving the cornea damaged. The cornea is a clear part of the eye which controls an ...
and increased risk of recurrence.


Epidemiology

PUK is a rare condition with an estimated incidence of 3 per million annually.{{Cite journal, last1=Gomes, first1=Beatriz Fiuza, last2=Santhiago, first2=Marcony R., date=March 2021, title=Biology of peripheral ulcerative keratitis, url=https://linkinghub.elsevier.com/retrieve/pii/S0014483521000233, journal=Experimental Eye Research, language=en, volume=204, pages=108458, doi=10.1016/j.exer.2021.108458, pmid=33493475, s2cid=231710506 Studies have reported that most patients with PUK are older than 60 years of age (32%). Among them, men have a higher occurrence rate in men (60%). Most patients live in rural areas (66%) and are in the lower socioeconomic groups. The age of those with PUK ranges from 5 to 89 years, with a mean age of 45.5 years. The
mortality rate Mortality rate, or death rate, is a measure of the number of deaths (in general, or due to a specific cause) in a particular population, scaled to the size of that population, per unit of time. Mortality rate is typically expressed in units of d ...
after PUK diagnosis in an investigation of 34 patients with and without immunosuppressive medication is 53% and 5%, respectively. Another single-centre study involving 46 patients with RA reported a mortality rate of 15%. Reports have also shown a possibility of PUK occurrence after any ocular surgery. In a retrospective study of 771 eyes, 1.4% of participants reported developing late-onset PUK at an average of 3–6 months after surgery.


References

Immunology Inflammations Disorders of sclera and cornea