Scleromalacia perforans

Key Points at a Glance

Highlights of This Disease

• Scleromalacia perforans (SP) is a necrotizing scleritis without inflammation, a rare disease accounting for approximately 4% of all scleritis cases.
• It commonly occurs in elderly women with long-standing rheumatoid arthritis.
• In a quiet eye without redness or pain, necrosis and thinning of the sclera progress slowly.
• As thinning progresses, the uvea becomes exposed, and there is a risk of eyeball rupture from minor trauma.
• Treatment is based on a combination of systemic steroids and immunosuppressive agents, and collaboration with a rheumatologist is essential.
• In cases where the uvea is exposed, a preserved scleral patch graft is required.
• The overall prognosis is guarded and closely related to the control of inflammation.

1. What is Scleromalacia Perforans?

Scleromalacia Perforans (SP) is a rare and severe ocular disease classified as anterior necrotizing scleritis without inflammation. It is caused by autoimmune damage (type III allergic reaction) to the perforating vessels of the episclera and sclera. The ICD-10 code is H15.053.

First reported by van der Hoeve at the Dutch Ophthalmological Society in 1930. It is bilateral and begins with yellow or gray nodules under the conjunctiva. It progresses to scleral necrosis, perforation, and exposure of the uvea. It accounts for about 4% of all scleritis.

In the Watson classification, it is classified as “non-inflammatory” among the necrotizing types of anterior scleritis. Necrotizing scleritis has a poor prognosis among scleritis types, with onset in the 60s, older than other types. Bilateral involvement occurs in about 60% of cases, and without early appropriate treatment, blindness and difficulty in preserving the eye can occur.

Q Is scleromalacia perforans different from necrotizing scleritis?

A

Necrotizing scleritis is classified into “inflammatory” and “non-inflammatory” types. Scleromalacia perforans corresponds to non-inflammatory necrotizing scleritis, and differs from inflammatory necrotizing scleritis in that it is almost without redness or pain.

2. Main symptoms and clinical findings

Subjective symptoms

Onset is insidious. Many patients complain of non-specific irritation.

• Pain: Usually absent. Scleral changes suddenly appear in an eye without redness or pain.
• Vision: Not affected in the early stages. Often first noticed in severe cases that have progressed to necrotizing scleritis.
• Appearance changes: Noticed by family as a change in scleral color, or discovered by the patient in a mirror. May also be found during routine ophthalmic examinations.

Do not be complacent even if there is no pain

Scleromalacia perforans is a disease that is easily overlooked because it is accompanied by almost no inflammatory symptoms. If you notice a change in the color of the sclera, see an ophthalmologist early, even if there is no pain.

Clinical Findings

Initial Findings

Necrotizing scleral plaque: A white to yellow avascular area without vascular congestion appears near the corneal limbus.

Nodule formation: Begins as a yellow or gray nodule under the conjunctiva.

Advanced Findings

Confluence and enlargement of necrotic areas: Necrotic areas merge and expand.

Scleral thinning: The sclera becomes thin, allowing the underlying dark uveal tissue to be seen.

Scleral staphyloma: In cases of elevated intraocular pressure, a bulge may form.

If thinning progresses further, it can lead to ocular perforation and loss of visual function. The thinned sclera remains even after inflammation subsides. Spontaneous perforation is rare, but there is a risk of globe rupture from minor trauma.

3. Causes and Risk Factors

The pathogenesis of scleromalacia perforans is a type III allergic reaction due to accumulation of immune complexes (antigen-antibody complexes). It is frequently associated with autoimmune diseases such as rheumatoid arthritis, and immune mechanisms are thought to be involved in the pathogenesis of endogenous scleritis.

It typically occurs in elderly women with long-standing rheumatoid arthritis (RA). Other associated diseases are as follows.

• Systemic lupus erythematosus (SLE)
• Granulomatosis with polyangiitis (GPA): formerly known as Wegener’s granulomatosis
• Polyarteritis nodosa
• Behçet’s disease
• Localized scleroderma
• Crohn’s disease
• Graft-versus-host disease (GVHD)

Porphyria and herpes zoster infection have also been reported to cause scleromalacia perforans. It may also occur as surgically induced necrotizing scleritis (SINS) triggered by a history of ophthalmic surgery, and is more likely to occur after strabismus surgery, trabeculectomy, scleral buckling surgery, or pterygium excision with mitomycin C.

After topical use of mitomycin C (MMC), scleral calcification or necrotizing scleritis (scleromalacia perforans) may develop months to years after surgery. Even a single dose of mitomycin C has been suggested to increase scleral gelatinase activity in addition to fibroblast suppression, potentially contributing to decreased collagen production and abnormal collagen arrangement.

Prevention and daily care

• If you are being treated for collagen diseases such as rheumatoid arthritis, have regular eye examinations.
• If you notice a change in the color of the sclera, see an ophthalmologist even if you have no pain.
• If diagnosed with scleromalacia perforans, it is very important to avoid eye trauma. Consider using protective eyewear.

Q Does rheumatoid arthritis always cause this condition?

A

Most patients with rheumatoid arthritis do not develop scleromalacia perforans. Scleromalacia perforans is a rare condition accounting for about 4% of all scleritis cases, and it is more common in elderly women with a long history of RA. Other autoimmune diseases may also be the cause.

4. Diagnosis and Testing Methods

Scleromalacia perforans is a clinical diagnosis. Characteristic findings include the presence of scleral necrotic plaques without hyperemia and progressive scleral thinning.

Clinical Examination

• Observation under natural light: Scleritis appears dark red, but necrotizing scleritis without inflammation is characterized by white to yellow necrotic foci without congestion. In long-standing cases, localized scleral thinning appears bluish-black. Observation under natural light is better for grasping the overall picture than slit-lamp microscopy.
• Slit-lamp examination: Evaluate dilation and tortuosity of scleral vessels, extent of necrosis, and degree of thinning. Also examine the cornea and anterior chamber to check for peripheral corneal infiltration or anterior uveitis.
• Epinephrine eye drop test: Superficial congestion subsides with 1:1000 epinephrine eye drops, but deep scleritis congestion does not. This is useful for differentiating from conjunctivitis and episcleritis.

Blood tests

To evaluate underlying autoimmune diseases, the following tests are necessary.

Test item	Purpose
CBC, ESR, CRP	Assessment of inflammation
RF, antinuclear antibody, anti-DNA antibody	Screening for collagen disease
ANCA (c-ANCA, p-ANCA)	Assessment of vasculitis

Additionally, urinalysis, syphilis serology, serum uric acid, and sarcoidosis screening are performed.

Differential Diagnosis

• Scleral hyaline plaque: Age-related hyaline degeneration of the sclera. The plaque is located just anterior to the insertion of the medial rectus muscle within the palpebral fissure.
• Senile scleral malacia: A progression of senile scleral plaque, where calcified plaques detach and form.
• MALT lymphoma: A pale pink mass commonly found in the conjunctival fornix. The inability to see scleral vessels is a key point of differentiation from necrotizing scleromalacia.

Q Should I see a doctor even if I have painless scleral changes?

A

Scleromalacia perforans progresses without redness or pain. The later it is discovered, the more the treatment window is missed and the prognosis worsens. If you notice a change in the color of the sclera, prompt ophthalmologic consultation is recommended even if there are no symptoms.

5. Standard Treatment

Management of scleromalacia perforans is fundamentally systemic treatment and requires an aggressive, multidisciplinary approach. If treated early, therapeutic effects can be achieved, but by the time typical findings appear, the treatment window is often already missed. Necrotizing scleritis is said to have a blindness rate of 40%.

Pharmacotherapy

Corticosteroids

Systemic corticosteroids are the mainstay of treatment.

• Oral prednisolone: Start at 0.5–1 mg/kg/day and gradually taper.
• Steroid pulse therapy: Intravenous methylprednisolone. Used in severe cases or when response to oral steroids is poor.

Local periocular injection of steroids should be avoided because it may increase collagenase activity and lead to further scleral melting or perforation.

Side effects of steroids

• Long-term use of systemic steroids requires attention to increased intraocular pressure, decreased resistance to infection, gastric irritation, osteoporosis, weight gain, hyperglycemia, and mood changes.
• When corticosteroids or immunosuppressants are administered for a long period, pay close attention to the occurrence of side effects.

Immunosuppressive drugs

Immunosuppressive therapy complementary to steroids is essential, and collaboration with a rheumatologist is recommended. Methotrexate is often chosen for rheumatoid arthritis, and cyclophosphamide for systemic vasculitis.

• Cyclophosphamide: Oral 2–3 mg/kg/day. Considered most effective for non-infectious necrotizing scleritis.
• Methotrexate: 7.5–20 mg weekly
• Azathioprine: Starting dose 2.5 mg/kg/day. Some reports indicate slightly lower efficacy for scleritis.
• Cyclosporine: 2.5–5.0 mg/kg/day. Adjust to keep trough level below 150 mg/mL. Caution required for renal impairment.
• Mycophenolate mofetil: 2–3 g/day

Biologic agents

Consider introduction for scleritis refractory to the above immunosuppressive therapy.

• TNF inhibitors: adalimumab, infliximab. Efficacy has been shown for sclerouveitis.
• Anti-CD20 antibody: rituximab

Local therapy

Frequent artificial tear instillation is recommended to improve comfort and protect the ocular surface. There are also reports of topical cyclosporine A use.

Surgical Treatment

Surgical Indications

Cases with uveal exposure: Surgery is necessary to maintain the integrity of the eyeball.

Necrotic area size: The smaller the area, the better the surgical prognosis. Prompt surgery without delay is important.

Surgical Key Points

Complete resection of necrotic tissue: Resect including surrounding healthy tissue.

Preserved scleral graft: Cryopreserved sclera is suitable in terms of strength and shape maintenance.

Complete coverage with conjunctiva: Cover the grafted scleral patch with conjunctiva.

Various materials are used for patch grafts. Reported materials include preserved sclera (fresh, frozen, glycerin-preserved), dermis, fascia lata, periosteum, cornea, amniotic membrane, synthetic materials (Gore-Tex), and conjunctival pedicle flaps. In cases with extensive conjunctival necrosis or corneal ulcer, autologous conjunctival graft or corneal epithelial transplantation is combined. Postoperative treatment includes oral and topical cyclosporine.

Q Will surgery cure the condition?

A

Surgery is a procedure to prevent structural breakdown of the eye and is not a cure for the disease itself. Systemic control of the underlying autoimmune disease is essential, and long-term follow-up with continued immunosuppressive therapy is required to prevent recurrence.

6. Pathophysiology and Detailed Pathogenesis

The pathology of perforating scleromalacia is based on a type III allergic reaction (Arthus reaction) caused by immune complex deposition. Immune complexes accumulate in the perforating vessels of the episclera and sclera, triggering vasculitis.

Young and Watson proposed three determinants of scleral destruction:

• Activation of scleral fibroblasts: Causes resorption of the pericellular matrix.
• Parenchymal infiltration by inflammatory cells: Cellular infiltration into the scleral stroma progresses tissue destruction.
• Prolonged local vascular occlusion: Persistent ischemia promotes scleral necrosis.

Histopathologically, chronic granulomatous changes are observed, with epithelioid cells surrounding a central necrotic mass (collagen, non-collagen fibers, and cellular debris). In scleromalacia perforans, dense plaques of necrotic tissue slough off, accompanied by full-thickness conjunctival defects and insufficient conjunctival epithelium to cover the exposed area.

As a general pathogenesis of scleritis, non-infectious scleritis is often seen as an ocular manifestation associated with systemic inflammatory diseases. If the underlying systemic disease is untreated, recurrence at the same site of the sclera is not uncommon.

Q Why does it progress without pain?

A

Scleromalacia perforans is classified as a “non-inflammatory” necrotizing scleritis. Typical scleritis involves hyperemia and severe pain due to vasculitis, but in scleromalacia perforans, vascular occlusion and tissue necrosis progress with little inflammatory response. Therefore, it is painless and often detected late.

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7. References

1. Figueiredo LQ, Lopes FOA, Franco AS, et al. Scleromalacia perforans as an early manifestation of late-onset rheumatoid arthritis: a case-based review. Rheumatol Int. 2024;44(1):177-184. PMID: 37925382
2. Promelle V, Goeb V, Gueudry J. Rheumatoid Arthritis Associated Episcleritis and Scleritis: An Update on Treatment Perspectives. J Clin Med. 2021;10(10):2118. PMID: 34068884 / PMCID: PMC8156434
3. Galor A, Thorne JE. Scleritis and Peripheral Ulcerative Keratitis. Rheum Dis Clin North Am. 2007;33(4):835-854. PMID: 18037120 / PMCID: PMC2212596
4. Sainz de la Maza M, Tauber J, Foster CS. Scleral grafting for necrotizing scleritis. Ophthalmology. 1989;96(3):306-310. PMID: 2710520
5. Nguyen QD, Foster CS. Scleral patch graft in the management of necrotizing scleritis. Int Ophthalmol Clin. 1999;39(1):109-131. PMID: 10083910
6. Yamazoe K, Shimazaki-Den S, Otaka I, Hotta K, Shimazaki J. Surgically induced necrotizing scleritis after primary pterygium surgery with conjunctival autograft. Clin Ophthalmol. 2011;5:1609-1611. PMID: 22140306 / PMCID: PMC3225457