Giant Papillary Conjunctivitis

Key Points at a Glance

Giant papillary conjunctivitis (GPC) is a conjunctivitis characterized by papillary proliferation of 1 mm or more in diameter on the upper tarsal conjunctiva due to mechanical irritation from contact lenses, ocular prostheses, or surgical sutures.
The majority of cases are caused by soft contact lens (SCL) wear, also referred to as CL-GPC.
In the Japanese Guidelines for the Diagnosis and Treatment of Allergic Conjunctival Diseases (3rd edition), it is classified as an independent disease type alongside SAC, PAC, AKC, and VKC¹⁾.
Subjective symptoms begin with mild foreign body sensation and progress to viscous discharge, hyperemia, blurred vision, and poor CL fitting.
The papillae are round, well-defined, smooth-surfaced, and non-confluent, differing morphologically from the cobblestone giant papillae of vernal keratoconjunctivitis (VKC).
Serum antigen-specific IgE positivity and conjunctival eosinophil positivity rates are low, and cannot be explained by typical type I allergy alone.
The mainstay of treatment is discontinuation of CL wear or switching to daily disposable SCLs combined with anti-allergic eye drops.

1. What is Giant Papillary Conjunctivitis (GPC)?

Giant papillary conjunctivitis (GPC) is a chronic conjunctivitis characterized by giant papillae of 1 mm or more in diameter on the upper tarsal conjunctiva, caused by continuous contact and friction of contact lenses (CL), ocular prostheses, or exposed surgical sutures with the upper tarsal conjunctiva. In particular, cases caused by CL wear are called contact lens-associated giant papillary conjunctivitis (CL-GPC).

GPC itself has a good visual prognosis and does not lead to blindness, but it significantly affects patients’ quality of life because CL wear may become impossible, viscous discharge reduces quality of life, and recurrence is frequent. Furthermore, in recent years, the number of soft CL wearers for myopia correction has increased, along with those using cosmetic color CLs and orthokeratology lenses for myopia progression control, maintaining the clinical importance of GPC.

History and Terminology

The disease concept of GPC originated in 1977 when Allansmith et al. reported giant papillae formed on the upper tarsal conjunctiva of soft contact lens wearers as “giant papillary conjunctivitis” ²⁾. Subsequently, the term contact lens related papillary conjunctivitis (CLPC) has also been used to distinguish mild cases primarily caused by contact lens wear ¹⁾⁷⁾.

In the Japanese “Guidelines for the Diagnosis and Treatment of Allergic Conjunctival Diseases (3rd Edition)” (2021, Journal of the Japanese Ophthalmological Society, Vol. 125, No. 8), both GPC (giant papillary conjunctivitis) and CLPC (contact lens related papillary conjunctivitis) are listed in the abbreviation list, and GPC is given an independent position as one of the five types of allergic conjunctival diseases (ACD: SAC, PAC, AKC, VKC, GPC) ¹⁾.

Epidemiology

GPC most commonly occurs in contact lens wearers, with a particularly high frequency in soft contact lens wearers. Previous reports indicate that it occurs in approximately 1-5% of soft contact lens wearers and about 1% of hard contact lens wearers after more than one year of use, and the incidence increases with longer duration of contact lens wear ⁴⁾⁵⁾. In recent years, with the widespread use of silicone hydrogel contact lenses, new material-specific papilla formation patterns have also been reported ⁸⁾¹¹⁾.

In Japan, Shoji et al. reported that the tear fluid total IgE positivity rate in GPC patients was 75.0% (6/8) in their study of tear fluid total IgE testing ³⁾. In the same study, the tear fluid IgE positivity rate for all allergic conjunctival diseases was 72.2% (161/223) ³⁾. In the 2017 survey of allergic conjunctival diseases by the Japanese Society of Ocular Allergology, GPC was counted as a disease type that accounts for a certain frequency among conjunctival allergic diseases in contact lens wearers ⁹⁾.

With the decreasing age of contact lens initiation, CL-GPC in children has also been reported in recent years. In children, contact lens care methods and wearing time management tend to be insufficient, making care guidance important. Even without an allergic predisposition, giant papillary proliferation on the upper eyelid can occur due to contact lens wear, and attention should be paid to pediatric cases as contact lens use starts at younger ages.

GPC in artificial eye wearers was common in the past, but its frequency has been decreasing due to advances in artificial eye materials and surface treatment technology. On the other hand, suture-related GPC caused by exposed sutures after corneal transplantation is still relatively rare, and it often resolves quickly after removal of the 10-0 nylon suture.

Q What is the difference between GPC and CLPC?

These two concepts overlap and have no clear boundary. GPC (giant papillary conjunctivitis) is a classic form with giant papillae ≥1 mm in diameter, caused not only by CLs but also by ocular prostheses and sutures. On the other hand, CLPC (contact lens related papillary conjunctivitis) refers to all papillary conjunctivitis caused by CL wear, including mild cases with papillae <1 mm. In the Japanese guidelines for allergic conjunctival diseases, both are comprehensively treated as GPC (CL-GPC when caused by CLs)¹⁾.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

The subjective symptoms of GPC gradually worsen in CL wearers. Initially, there is only mild foreign body sensation and slight itching, but within weeks to months, viscous discharge, hyperemia, and blurred vision appear, eventually forcing a reduction in wearing time.

Early Symptoms

Mild foreign body sensation: The earliest symptom, first noticed during CL wear.

Mild itching: A feeling of wanting to rub the upper eyelid.

Mild hyperemia: Slight redness spreading across the white of the eye.

Advanced Symptoms

Viscous (stringy) discharge: Increases upon waking in the morning, also adheres to the CL surface causing cloudiness.

Poor CL fitting: The CL shifts easily, slides down, or moves excessively during blinking.

Blurred vision: Vision becomes hazy during CL wear.

Reduced wearing time: The tolerable wearing time gradually shortens.

Objective Findings

The key to diagnosing GPC is direct visualization of giant papillae by everting the upper tarsal conjunctiva. Papillae occur preferentially on the upper tarsal conjunctiva and are rare on the lower tarsal conjunctiva. The characteristics of papillae are as follows.

Size: Papillae with a diameter of 1 mm or more are defined as giant papillae¹⁾.
Shape: Round, well-defined borders, smooth surface, not fused with adjacent papillae, and relatively low elevation.
Central vessels: Each papilla has a blood vessel at its center.
Distribution: Scattered throughout the upper tarsal conjunctiva.
Corneal complications: Usually not observed. Shield ulcers and corneal plaques do not occur.

Conjunctival findings include conjunctival hyperemia and chemosis in severe cases. After contact lens removal, fluorescein staining often reveals punctate staining at the tips of papillae and mild epithelial damage of the upper tarsal conjunctiva.

Severity Assessment (Allergic Conjunctival Disease Clinical Guidelines, 3rd Edition)

The 3rd edition of the Allergic Conjunctival Disease Clinical Guidelines classifies the severity of giant papillae into three grades based on the extent of elevation in the upper tarsal conjunctiva¹⁾.

Severity	Findings
Mild (+)	Papillae are flattened
Moderate (++)	Papillae elevated in less than half of the upper tarsal conjunctiva
Severe (+++)	Papillae elevated in half or more of the upper tarsal conjunctiva

For ordinary papillae less than 1 mm in diameter, a three-grade evaluation is used: 0.1–0.2 mm (mild), 0.3–0.5 mm (moderate), and 0.6 mm or more (severe)¹⁾.

Differentiation between GPC and vernal keratoconjunctivitis (VKC)

GPC often poses a diagnostic challenge in differentiation from vernal keratoconjunctivitis (VKC). Both conditions present with giant papillae, but their morphological features differ significantly.

Feature	GPC	VKC (vernal keratoconjunctivitis)
Papillary morphology	Round, well-defined borders, smooth surface	Polygonal, irregular, ill-defined borders
Papillary fusion	No fusion	Fused in a cobblestone pattern
Elevation height	Relatively low	High and prominent
Corneal complications	Almost none	Shield ulcer, corneal plaque present
Serum antigen-specific IgE	Low positivity rate	High positivity rate
Eosinophils (conjunctival scraping)	Low positivity rate	High positivity rate
Age of onset	Contact lens wearers, all ages	Boys around 10 years old
Cause	Mechanical irritation (CL, artificial eye, sutures)	Type I allergy + type IV hypersensitivity reaction

GPC rarely causes corneal epithelial damage, and serum/local eosinophil and IgE positivity rates are low, which are decisive differences from VKC and AKC. In terms of pathogenesis, VKC/AKC are based on endogenous allergic predisposition, whereas GPC requires exogenous mechanical stimulation (CL, artificial eye, suture) as an essential condition. Therefore, in GPC, most symptoms often improve simply by removing the causative device, whereas VKC/AKC require long-term immunosuppressive therapy.

Severity classification and clinical course

In mild GPC, subjective symptoms are mild, limited to foreign body sensation or slight itching during wear, and the papillae on the upper tarsal conjunctiva are flat to slightly elevated. As it progresses to moderate, viscous discharge and poor CL fitting become apparent, and giant papillae elevate over less than half of the upper tarsal conjunctiva. In severe GPC, giant papillae elevate over more than half of the upper tarsal conjunctiva, making CL wear almost impossible ¹⁾.

Q How are giant papillae confirmed?

Observe by everting the upper eyelid. While gently pressing near the eyelash line with a cotton swab or finger, evert the upper eyelid and observe the entire upper tarsal conjunctiva with a slit lamp using diffuse and slit light. Multiple scattered round elevations ≥1 mm in diameter are giant papillae, and the tips may stain punctately with fluorescein. If the patient wears CL, remove the CL first before observation.

3. Causes and risk factors

Main causative devices

GPC requires persistent mechanical stimulation to the upper tarsal conjunctiva as an essential condition for onset. The main causative devices are the following four ¹⁾⁴⁾⁵⁾.

Contact lenses: Most common cause. Frequency of onset is higher for soft CL > hard CL > gas-permeable CL. Onset has also been reported with silicone hydrogel CL ⁸⁾¹¹⁾¹²⁾.
Artificial eye: In artificial eye wearers, deposits on the surface or poor polishing can be triggers.
Surgical sutures: Exposed 10-0 nylon or silk sutures after corneal transplantation or scleral buckling surgery irritate the upper tarsal conjunctiva.
Other foreign bodies: Exposed scleral buckles, exposed haptics of intraocular lenses, and ocular surface foreign bodies in patients with proptosis can also be causes.

The risk of GPC onset in CL wearers is associated with the following factors ⁴⁾⁵⁾⁶⁾.

Wear duration: Longer wear increases risk. Incidence rises in wearers of more than one year.
Wearing time: Extended wear is higher risk than daily wear⁶⁾¹⁴⁾.
CL material: Silicone hydrogel CLs can also cause GPC compared to conventional low-water-content CLs⁸⁾¹¹⁾¹²⁾.
CL surface deposits: Deposits on the CL surface are associated with the development of GPC¹⁰⁾.
Poor lens care: Poor hygiene such as not rubbing the lens or infrequent replacement of disinfecting solution.
Lens edge design: A steep edge shape causes stronger mechanical irritation to the conjunctiva.
Decreased blink rate: Reduced blinking during VDT work increases deposits on the lens surface.
Atopic predisposition: Patients with atopic dermatitis or other allergic conjunctival diseases are more prone to develop GPC.

Prosthesis-related GPC: The longer the duration of prosthesis wear, the higher the risk. Microscopic scratches or protein deposits on the prosthesis surface act as antigens.
Suture-related GPC: Exposed sutures after corneal transplantation can become problematic months to years after surgery. Typically occurs when the head of a 10-0 nylon suture is exposed on the conjunctival side.

Q Which contact lens wearers are more likely to develop GPC?

People who have worn soft contact lenses for a long time (especially over 1 year), those who wear them overnight (extended wear), those who use lenses with heavy protein deposits due to poor care, those with allergic conditions such as atopic dermatitis or allergic rhinitis, and those using silicone hydrogel lenses with a stiff edge design are at risk. Switching to daily disposable soft contact lenses is the most effective preventive measure.

4. Diagnosis and Examination Methods

Diagnostic Approach

The basic principle of diagnosing GPC is through history taking and clinical observation by upper eyelid eversion. In the Japanese “Allergic Conjunctival Disease Clinical Practice Guidelines (3rd Edition)” clinical diagnostic flowchart, among cases with subjective symptoms such as itching and hyperemia and conjunctival proliferative findings, GPC is differentiated based on the presence or absence of contact lens wear¹⁾.

The diagnostic procedure is as follows:

History taking: Confirm CL wear history, duration of wear, care status, wearing time, changes in symptoms after discontinuation, and history of artificial eye or ophthalmic surgery.
Removal of CL: If wearing CLs, remove them temporarily.
Upper eyelid eversion: Evert the upper eyelid under a slit-lamp microscope and observe the entire upper tarsal conjunctiva.
Evaluation of papillae: Assess the presence, distribution, and severity (mild to severe) of giant papillae with a diameter of 1 mm or more.
Fluorescein staining: Evaluate corneal epithelial damage, bulbar conjunctival epithelial damage, and staining of the papillary tips.
Severity classification: Classify as mild, moderate, or severe according to the guideline severity criteria¹⁾.

An important point is that to understand fluctuations in clinical findings, it is recommended to perform periodic observations by upper eyelid eversion at key timings such as the initial visit, 2 weeks and 4 weeks after starting treatment, and 1 month after remission. Evaluation of treatment response is objectified by recording changes in the severity of giant papillae along with improvement in subjective symptoms.

Tests for Definitive Diagnosis

Clinical diagnosis alone is often sufficient for GPC, but the following tests may be added to differentiate from other allergic conjunctival diseases or to evaluate systemic allergic predisposition.

Test	Method	Positive rate/significance in GPC
Total tear IgE test (Allerwatch®)	Insert test strip into lower palpebral conjunctival sac to detect tear IgE	75.0% (6/8) in GPC ³⁾. Evaluates local ocular allergic predisposition
Serum antigen-specific IgE antibody	Measure specific IgE against mites, house dust, etc. via blood sampling	Low positivity rate in GPC ¹⁾. Evaluates systemic allergic predisposition
Conjunctival scraping eosinophil test	Scrape upper palpebral conjunctiva and stain with Hansel stain	Low positivity rate in GPC. Confirms type I allergic reaction
Skin test	Prick/scratch test	Aids in antigen identification
CL wearing status and care evaluation	Interview and observation of CL case	Essential for planning cause removal

The total tear IgE test is a clinical diagnostic test recommended in the 3rd edition of the Guidelines for the Diagnosis and Treatment of Allergic Conjunctival Diseases ¹⁾. However, for GPC, the positivity rate of eosinophils and specific IgE in the conjunctiva is low, and it should be noted that in many cases, the diagnosis remains a “clinical diagnosis” rather than a “definitive diagnosis.”

Differential Diagnosis

Differential Disease	Key Points for Differentiation
Vernal Keratoconjunctivitis (VKC)	Boys around 10 years old, cobblestone-like giant papillae, corneal complications, high serum IgE
Atopic Keratoconjunctivitis (AKC)	Associated with atopic dermatitis, predominantly lower eyelid, chronic course, corneal complications
Seasonal Allergic Conjunctivitis (SAC)	No proliferative changes, seasonal, clear allergens such as pollen
Perennial Allergic Conjunctivitis (PAC)	Perennial, mild papillary hypertrophy, caused by mites and house dust
Superior Limbic Keratoconjunctivitis (SLK)	Hyperemia and proliferation of the superior bulbar conjunctiva and limbus, can also occur with contact lens wear
Infectious Conjunctivitis	Acute onset, predominantly follicular (viral) or purulent discharge (bacterial)
Conjunctival folliculosis	Miliary follicles in the lower fornix, asymptomatic

Q Is a definitive diagnosis of GPC necessary?

In most cases, a clinical diagnosis of GPC is sufficient. A history of contact lens wear and the presence of giant papillae on the upper tarsal conjunctiva allow a clinical diagnosis, and symptom improvement after discontinuing CL use confirms the diagnosis. Tear IgE tests, eosinophil tests, and serum-specific IgE tests are added to differentiate from more severe allergic conjunctival diseases such as vernal keratoconjunctivitis and atopic keratoconjunctivitis, and to evaluate systemic allergic predisposition.

5. Standard Treatment

Basic Treatment Principles

Treatment of GPC is based on two main pillars: removal of the mechanical irritation and anti-allergic eye drops. The Japanese ‘Allergic Conjunctival Disease Clinical Practice Guidelines (3rd Edition)’ recommends for GPC treatment: ‘If contact lenses are the cause, discontinue contact lens use in principle to avoid mechanical irritation and antigens. First-line treatment is anti-allergic eye drops, and for severe cases, add steroid eye drops.‘¹⁾

Step 1: Remove the Cause

Discontinue contact lens use: If possible, stop wearing lenses first.

Switch to daily disposable SCLs: For patients who cannot stop, switch to daily disposable soft contact lenses.

Change CL material and design: Switch to a product with lower water content, higher rigidity, or different edge design.

Refabrication or polishing of ocular prosthesis: For prosthesis-related GPC, remake or polish the surface of the prosthesis.

Remove sutures: For suture-related GPC, remove exposed sutures.

Step 2: Pharmacotherapy

Anti-allergic eye drops: Use mediator release inhibitors or H1 receptor antagonists 4 times daily.

Steroid eye drops: Short-term use in severe cases. Intraocular pressure management is essential.

Adjunctive therapy during CL wear cessation: Artificial tears and punctal plugs to improve the ocular surface environment.

Stage-specific treatment

Stage 1: Removal of cause

The most important treatment for GPC is removal of the mechanical stimulus. For CL wearers, CL wear should generally be discontinued first, and symptom improvement should be confirmed. If discontinuation is difficult due to occupational or lifestyle reasons, stepwise management is performed in the following order¹⁾.

Switch to daily disposable soft contact lenses: The most effective alternative. Protein deposits are reset, providing high recurrence prevention.
Change of CL material: Try switching from silicone hydrogel to conventional hydrogel or vice versa. Also consider products with different edge designs.
Reduction of wearing time: Shorten daily wearing time and establish days without CL wear (CL holidays).
Improvement of care methods: Instruct daily rubbing, complete replacement of disinfecting solution, replacement of CL case, and thorough hand washing¹⁾.

For prosthetic eye-related GPC, consider polishing the prosthetic eye or, in some cases, replacing it¹⁾. For suture-related GPC, remove the causative suture (often exposed 10-0 nylon). For scleral buckle-related GPC, removal of the buckle itself may be necessary.

Stage 2: Anti-allergic eye drops (first-line)

Anti-allergic eye drops are the foundation of GPC treatment. The 3rd edition of the Guidelines for the Diagnosis and Treatment of Allergic Conjunctival Diseases lists mediator release inhibitors and histamine H1 receptor antagonists as the two major categories of anti-allergic eye drops¹⁾.

Classification	Generic name	Product name	Concentration	Dosage
Mediator release inhibitor	Pemirolast potassium	Alegysal®	0.1%	2 times daily
Mediator release inhibitor	Tranilast	Rizaben®	0.5%	4 times daily
Mediator release inhibitor	Acitazanolast	Zepelin®	0.1%	4 times daily
H1 receptor antagonist	Ketotifen fumarate	Zaditen®	0.05%	4 times daily
H1 receptor antagonist	Levocabastine hydrochloride	Livostin®	0.025%	4 times daily
H1 receptor antagonist	Olopatadine hydrochloride	Patanol®	0.1%	4 times daily
H1 receptor antagonist	Epinastine hydrochloride	Alesion®	0.05% / 0.1% (LX)	4 times daily (LX: 2 times daily)

Prescription example 1 (mild to moderate): Alesion® ophthalmic solution (0.05%) 4 times daily ¹⁾. Prescription example 2 (mild to moderate): Patanol® ophthalmic solution (0.1%) 4 times daily.

Anti-allergic eye drops reduce immediate-phase symptoms such as itching, conjunctival hyperemia, and discharge, and also suppress late-phase inflammatory cell infiltration. In many cases, symptoms resolve with discontinuation or change of contact lens wear and anti-allergic eye drops alone.

Stage 3: Steroid eye drops (severe cases)

In severe cases where symptoms are difficult to control with anti-allergic eye drops alone, short-term use of steroid eye drops is added. Because of ocular side effects such as increased intraocular pressure, infection induction, and cataracts, regular intraocular pressure measurement is essential ¹⁾.

Prescription example 3 (severe case): Discontinue contact lens wear + Flumetholon® ophthalmic solution (0.1%) 4 times daily. Measure intraocular pressure.

Fluorometholone is a low-absorption steroid with a relatively low risk of increased intraocular pressure and is suitable for short-term treatment of GPC. When symptoms improve, taper the steroid and then maintain with anti-allergic eye drops alone.

Stage 4: Management of refractory cases

In a small number of refractory cases, the following treatments may be considered. However, note that they are not covered by insurance for GPC, so recommendations for VKC and AKC are applied by analogy.

Tacrolimus ophthalmic solution (0.1%): According to the Allergic Conjunctival Disease Clinical Practice Guidelines, 3rd edition, CQ7, tacrolimus ophthalmic solution improves corneal epithelial disorders and giant papillae in vernal keratoconjunctivitis and atopic keratoconjunctivitis, and is strongly recommended (evidence A) ¹⁾¹³⁾. Although not covered by insurance for GPC, it may be used empirically in severe refractory cases similar to VKC.
Cyclosporine ophthalmic solution (0.1%, Papilock Mini®): An alternative immunosuppressive eye drop. Again, only indicated for VKC.
Subconjunctival steroid injection: Triamcinolone acetonide or betamethasone sodium phosphate suspension is injected under the palpebral conjunctiva of the upper eyelid. Care should be taken regarding increased intraocular pressure, and use in children is preferably avoided¹⁾.
Conjunctival papillae resection: This is considered in extremely rare cases where papillary proliferation progresses despite drug therapy and corneal epithelial disorders develop. Due to the widespread use of immunosuppressive eye drops, the number of cases requiring this procedure has markedly decreased¹⁾.
Punctal plugs: An adjunctive treatment to maintain drug concentration by retaining tears.

Timing of Resuming Contact Lens Wear

Resuming contact lens wear after symptom remission is possible when the following conditions are met:

Giant papillae on the upper tarsal conjunctiva have flattened (severity mild or negative).
Subjective symptoms have resolved.
Use daily disposable soft contact lenses (lowest risk of protein deposition).
Gradually increase wearing time (starting from about 4 hours per day).
Use anti-allergic eye drops before and after lens wear.
Discontinue immediately if signs of recurrence (foreign body sensation, viscous discharge) appear.

In recurrent cases, do not switch to lenses other than daily disposable soft contact lenses; consider complete transition to glasses if necessary. If continued contact lens wear is essential for occupational or competitive sports reasons, strictly limit wearing time (e.g., within 8 hours per day) and use anti-allergic eye drops prophylactically. Punctal plugs to retain tears may also be considered as an adjunctive measure to sustain the effect of eye drops.

Role of Punctal Plugs

Punctal plugs are not a direct treatment for GPC, but are used selectively to address coexisting dry eye or to prolong the effect of anti-allergic eye drops. By suppressing tear drainage, they extend the ocular surface retention time of eye drops, contributing to the reduction of allergic reactions. A common approach is to insert diagnostic absorbable collagen plugs, and if symptom improvement is observed, switch to long-term silicone plugs. However, the use of punctal plugs during contact lens wear may affect lens fitting due to changes in tear volume, requiring careful follow-up.

Selection of Eye Drops During Contact Lens Wear

When using contact lenses, there are issues of drug penetration into the lens and accumulation of preservatives. Some anti-allergy eye drops (e.g., Alesion® LX ophthalmic solution 0.1%, twice daily) are designed for use during lens wear, contributing to improved patient adherence. However, it is important to follow the manufacturer’s package insert to confirm whether the drops can be used while wearing lenses or whether they should be applied before or after lens insertion. For steroid eye drops (e.g., Flumetholon® 0.1%), instillation during lens wear should be avoided; in principle, lenses should be removed before application.

Importance of Patient Education

GPC is a highly recurrent disease, and patient education is key to successful treatment. Specifically, guidance should include: (1) regular replacement and rubbing cleaning of CL care products, (2) strict adherence to wearing time and avoidance of continuous wear, (3) early consultation when symptoms appear, (4) continued regular eye examinations, and (5) selection of CL storage and disinfecting solutions (proper use of multipurpose solutions). In addition, purchasing cheap CLs through overseas online shopping can lead to poor management and increase the risk of GPC; therefore, purchasing CLs via an ophthalmologist’s prescription is strongly recommended.

Q Can contact lens wear be resumed during treatment?

If symptoms remit and the giant papillae on the upper tarsal conjunctiva flatten, it is possible to gradually resume lens wear using daily disposable soft contact lenses. However, conditions include shorter wearing times, concomitant use of anti-allergy eye drops before and after lens wear, and regular ophthalmologic follow-up. If recurrence occurs, lens wear should be discontinued immediately. For causes other than CLs (e.g., ocular prostheses, sutures), improvement of the causative device is essential.

6. Pathophysiology and Detailed Mechanisms

The pathophysiology of GPC is considered to involve a combination of mechanical irritation and allergic reaction. Regarding the etiology of CL-GPC, there are two theories: the mechanical theory, which attributes the cause to friction and other mechanical stimuli, and the allergic theory, which attributes it to a hypersensitivity reaction to proteins adhering to the CL. Currently, it is thought to be a combined reaction of both.

Role of Mechanical Stimuli

CL, artificial eyes, and exposed sutures repeatedly rub the upper palpebral conjunctiva with each blink. This microtrauma damages the conjunctival epithelium and reduces its barrier function. Damaged epithelium releases inflammatory cytokines (IL-6, IL-8, TNF-α, etc.), inducing infiltration of inflammatory cells into the subconjunctival tissue. Furthermore, chronic mechanical stimulation causes hyperplasia and invagination of the conjunctival epithelium, leading to papillary elevations accompanied by angiogenesis and proliferation of fibrous tissue⁴⁾⁵⁾.

Role of allergic reaction

Deposits on the CL surface are involved in the pathology of GPC¹⁰⁾. It is thought that deposits and mechanical stimulation together induce a local inflammatory response in the conjunctiva.

Histologically, in addition to invagination of the conjunctival epithelium, infiltration of eosinophils, mast cells, and basophils is observed in the subconjunctival tissue. However, the rates of serum antigen-specific IgE positivity and conjunctival eosinophil positivity are lower than in vernal keratoconjunctivitis and atopic keratoconjunctivitis, and a characteristic feature of GPC is that it cannot be explained by typical type I allergy alone¹⁾.

Complex mechanisms and individual differences

Currently, GPC is understood as a complex pathology in which the innate immune system (mast cells, eosinophils, basophils) is activated in the conjunctival epithelium damaged by persistent mechanical stimulation, and a local immune response (partly type IV hypersensitivity or non-IgE-mediated mast cell activation) is added, with CL surface deposits acting as antigens. In patients with atopic predisposition, IgE-mediated reactions are relatively strong, while in non-atopic patients, mechanical stimulation and innate immune system contributions are presumed to be stronger⁵⁾¹⁵⁾.

Cytokine and cellular-level changes

Th2-type inflammation (predominance of IL-4, IL-5, IL-13) elucidated in VKC and AKC may also be partially involved in GPC, but it has been shown that the elevation of these cytokines in GPC is milder compared to VKC¹⁵⁾. Epithelial cytokines such as IL-33 and TSLP derived from conjunctival epithelium activate mast cells and type 2 innate lymphoid cells (ILC2), and are attracting attention as molecular mechanisms linking mechanical stimulation and immune response. These epithelial cytokines are released by epithelial damage due to mechanical stimulation and may promote downstream mast cell activation and eosinophil recruitment, and are postulated as a plausible mechanism explaining the cascade of “mechanical stimulation → innate immune activation” in GPC.

Formation process of papillary tissue

Papilla formation in GPC is a combination of reactive hyperplasia of the conjunctival epithelium and fibrous tissue proliferation of the subconjunctival stroma. In the early stage, infiltration of lymphocytes and plasma cells is observed beneath the conjunctival epithelium, and gradually fibroblasts in the subconjunctival tissue proliferate to form small elevations. At the center of the elevation, a nutrient blood vessel runs, surrounded by inflammatory cells. When CL wear is discontinued, inflammatory cell infiltration decreases relatively quickly and stromal edema improves, but papillae in which fibrous tissue has already formed do not flatten completely and may remain as thin traces.

Effects on the Conjunctival Mucous Layer and Tear Film

In GPC, qualitative and quantitative changes in mucus secreted by conjunctival goblet cells are also observed. Deposits adhering to the CL surface destabilize the tear film, resulting in shortened tear film breakup time (BUT) and a tendency to develop dry eye symptoms during CL wear. Therefore, some GPC patients require treatment for dry eye as a comorbid condition, and adjunctive therapies such as artificial tears, hyaluronic acid eye drops, and punctal plugs are used in combination.

7. Recent Research and Future Perspectives

Reduction of GPC with the Popularization of Daily Disposable CLs

Santodomingo-Rubido et al. recorded adverse events including CLPC during an 18-month observation of silicone hydrogel CL wear and reported that daily wear had fewer adverse events than continuous wear ⁸⁾.

Silicone Hydrogel CLs and GPC

The high oxygen permeability of silicone hydrogel CL materials has contributed to the prevention of corneal hypoxia, but it has been shown that they are not necessarily preventive against GPC. Sorbara et al. reported the development of papillary conjunctivitis with silicone hydrogel lenses, suggesting that lens stiffness, edge design, and surface charge may be involved in the onset ¹²⁾. In an 18-month observational study by Santodomingo-Rubido et al., a certain proportion of silicone hydrogel wearers showed CLPC-like papilla formation ⁸⁾.

Management Protocol for Relapse Prevention

For relapse prevention, in Japanese clinical practice, it is recommended that all CL wearers undergo regular check-ups (every 3 to 6 months), longitudinal observation of papillary findings by upper eyelid eversion, and detailed recording of wearing time and days. In addition, prophylactic initiation of anti-allergic eye drops may be considered during seasons with overlapping environmental factors (pollen, yellow dust). In case of recurrence, early cessation of CL wear and continuation of anti-allergic eye drops for about 4 weeks before considering resumption of wear can reduce the long-term recurrence rate.

New Anti-Allergic Eye Drops

The introduction of sustained-release anti-allergic eye drops (e.g., Alegion® LX 0.1% twice-daily formulation) is expected to improve adherence by reducing the frequency of instillation. Development of new H1 receptor antagonists is also progressing, expanding treatment options for allergic conjunctival diseases including GPC.

These new formulations contribute to improved patient adherence and quality of life for contact lens wearers.

GPC in Pediatric Contact Lens Wearers

In pediatric ophthalmology, the use of orthokeratology lenses and daily disposable soft contact lenses for myopia control is increasing. Consequently, cases of CL-GPC in children have been reported, emphasizing the importance of pediatric-specific care guidance and wear management. Balancing long-term lens wear for myopia control with the risk of GPC is an important clinical challenge for the future.

Research on Improving Contact Lens Materials and Designs

Research on lens improvements to reduce mechanical irritation to the conjunctiva is ongoing, including plasma treatment of lens surfaces, hydrophilic polymer coatings, and development of low-friction materials. Optimization of edge design and adoption of low-modulus (softer) materials are thought to contribute to reducing GPC risk. However, balancing oxygen permeability with reduced mechanical stimulation remains a technical challenge, and the optimal lens selection for each patient is left to the clinical judgment of the ophthalmologist.

Biologics and GPC

For severe allergic conjunctival diseases in general, there are reports of using anti-IL-4 receptor alpha antibody (dupilumab) and anti-IgE monoclonal antibody (omalizumab). However, dupilumab is known to paradoxically increase the risk of conjunctivitis (risk ratio 2.64 in meta-analysis), and its relationship with allergic conjunctival diseases including GPC requires careful evaluation¹⁾.

8. References

日本眼科アレルギー学会診療ガイドライン作成委員会. アレルギー性結膜疾患診療ガイドライン（第3版）. 日眼会誌. 2021;125(8):741-785.
Allansmith MR, Korb DR, Greiner JV, Henriquez AS, Simon MA, Finnemore VM. Giant papillary conjunctivitis in contact lens wearers. Am J Ophthalmol. 1977;83(5):697-708. PMID: 868963.
庄司純, ほか. アレルギー性結膜疾患診断における自覚症状, 他覚所見および涙液総IgE検査キットの有用性の検討. 日眼会誌. 2012;116(5):485-493.
Elhers WH, Donshik PC. Giant papillary conjunctivitis. Curr Opin Allergy Clin Immunol. 2008;8(5):445-449. PMID: 18769198.
Donshik PC, Ehlers WH, Ballow M. Giant papillary conjunctivitis. Immunol Allergy Clin North Am. 2008;28(1):83-103. PMID: 18282548.
Sankaridurg PR, Sweeney DF, Sharma S, Gora R, Naduvilath T, Ramachandran L, et al. Adverse events with extended wear of disposable hydrogels: results for the first 13 months of lens wear. Ophthalmology. 1999;106(9):1671-1680.
Skotnitsky C, Sankaridurg PR, Sweeney DF, Holden BA. General and local contact lens induced papillary conjunctivitis (CLPC). Clin Exp Optom. 2002;85(3):193-197.
Santodomingo-Rubido J, Wolffsohn J, Gilmartin B. Adverse events and discontinuations during 18 months of silicone hydrogel contact lens wear. Eye Contact Lens. 2008;34(6):327-334.
岡本茂樹, 藤島浩, 福島敦樹, 宮崎大, 庄司純, 深川和己, ほか. 2017年度日本眼科アレルギー学会アレルギー性結膜疾患実態調査. 日眼会誌. 2022;126(7):625-635.
Meisler DM, Keller WB. Contact lens type, material, and deposits and giant papillary conjunctivitis. CLAO J. 1995;21(1):77-80.
Skotnitsky CC, Naduvilath TJ, Sweeney DF, Sankaridurg PR. Two presentations of contact lens-induced papillary conjunctivitis (CLPC) in hydrogel lens wear: local and general. Optom Vis Sci. 2006;83(1):27-36.
Sorbara L, Jones L, Williams-Lyn D. Contact lens induced papillary conjunctivitis with silicone hydrogel lenses. Cont Lens Anterior Eye. 2009;32(2):93-96.
Shoji J, Ohashi Y, Fukushima A, Miyazaki D, Uchio E, Takamura E, et al. Topical tacrolimus for chronic allergic conjunctival disease with and without atopic dermatitis. Curr Eye Res. 2019;44(7):796-805. doi:10.1080/02713683.2019.1600197.
Dumbleton K. Adverse events with silicone hydrogel continuous wear. Cont Lens Anterior Eye. 2002;25(3):137-146.
Katelaris CH. Giant papillary conjunctivitis—a review. Acta Ophthalmol Scand Suppl. 1999;(228):17-20.

Related keywords