Introduction

Pars planitis is a rare form of intermediate uveitis that primarily affects the peripheral retina and the vitreous base.¹ Patients typically present with blurred vision, floaters, or visual haze caused by inflammatory cells within the vitreous body.¹¹ On clinical examination, ophthalmologists may observe characteristic findings such as “snowballs”, aggregates of inflammatory cells suspended in the vitreous and “snowbanking”, a whitish exudate along the inferior pars plana.¹¹

The condition is considered idiopathic in most cases, although an autoimmune mechanism is strongly suspected.¹ While many patients respond well to corticosteroids, others experience chronic or recurrent inflammation that can threaten their vision.⁹ Persistent disease may result in cystoid macular oedema, cataract formation, epiretinal membrane, or even retinal detachment.⁵ For these severe or steroid-refractory cases, immunosuppressive therapy plays a central role in preserving visual function.¹⁰
This article reviews the underlying disease mechanisms and summarises the major classes of immunosuppressive treatments currently used in the management of severe or refractory Pars planitis.

Pathophysiology and rationale for immunosuppressive therapy

The pathogenesis of Pars planitis is multifactorial but is widely recognized as a T-cell-mediated autoimmune process directed against antigens in the peripheral retina and vitreous base.¹² In response to an unknown trigger, possibly infection, trauma, or molecular mimicry, antigen-presenting cells activate CD4⁺ T cells, which then differentiate into Th1 and Th17 subsets.^10,12 These effector cells release pro-inflammatory cytokines, including interleukin-6 (IL-6), interleukin-17 (IL-17), tumour necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ).^10,11

These mediators perpetuate inflammation by recruiting macrophages, neutrophils, and other immune cells into the eye, while simultaneously disrupting the blood-retinal barrier (BRB).¹⁰ Once the BRB becomes compromised, plasma proteins and fluid leak into the retina, leading to tissue swelling and cystoid macular oedema, a major cause of vision loss in this disease.¹²

In addition to immune dysregulation, genetic predisposition contributes to disease susceptibility. ¹¹ Specific HLA-B27 haplotypes are more common among patients with Pars planitis and are also associated with other autoimmune conditions such as multiple sclerosis, reflecting a shared immunogenetic background.^10,12

Because the inflammation in Pars planitis arises from persistent immune activation, long-term immunomodulation is often required.¹ Corticosteroids provide rapid, nonspecific suppression of cytokine signalling but are limited by systemic and ocular toxicity, glaucoma, cataract, osteoporosis, and hypertension, among them, and by frequent relapse upon tapering.⁹ Immunosuppressive agents, on the other hand, target discrete components of the immune cascade, enabling sustained disease control while minimizing corticosteroid dependence.⁹ For patients who are steroid-dependent, intolerant, or refractory, these agents form the cornerstone of modern management and have dramatically improved visual outcomes in chronic Pars planitis.¹¹

Corticosteroids: First-line but limited

Corticosteroids are highly effective in rapidly suppressing ocular inflammation. They can be delivered systemically, regionally, or intraocularly. The choice depends on disease extent and patient tolerance.¹

In the acute setting, oral prednisone at 1 mg/kg/day often produces dramatic improvement.¹² However, chronic systemic exposure leads to well-known complications, including glucose intolerance, weight gain, mood changes, and bone loss. Local injections reduce systemic effects but can still cause intraocular pressure elevation or cataract progression.¹²

For these reasons, long-term therapy relies increasingly on steroid-sparing immunomodulators.¹⁰ These agents permit lower steroid doses while maintaining control of inflammation, an approach now considered standard for chronic or sight-threatening Pars planitis.¹²

Conventional immunosuppressive agents

Antimetabolites

Methotrexate (MTX) is among the most commonly used first-line immunosuppressive agents for uveitis.³ Administered once weekly, MTX inhibits dihydrofolate reductase, reducing lymphocyte proliferation.³ It has a long track record of safety and efficacy, particularly in pediatric or chronic relapsing cases.^1,3 Side effects include liver enzyme elevation and bone-marrow suppression, so regular monitoring of blood counts and liver function is essential.^1,4

Azathioprine is another antimetabolite that interferes with purine synthesis, thereby limiting immune cell replication.⁷ Although effective, it tends to cause gastrointestinal upset and leukopenia more frequently, leading many clinicians to prefer MTX or newer options.^1,7

Mycophenolate mofetil (MMF) has become increasingly popular as a steroid-sparing drug.⁸ It selectively inhibits inosine monophosphate dehydrogenase, blocking T- and B-cell proliferation.¹⁰ Clinical studies have shown that MMF achieves high rates of inflammation control with relatively mild side effects.⁸ Compared with MTX, it is often better tolerated, though more costly.¹

Calcineurin Inhibitors

Calcineurin inhibitors act by blocking T-cell activation through suppression of IL-2 transcription.^1,12

Cyclosporine was one of the earliest agents used for noninfectious uveitis and remains a cornerstone of therapy.¹ It is particularly useful in combination with antimetabolites such as MTX or MMF, allowing a synergistic effect. The primary concerns with cyclosporine are nephrotoxicity and hypertension, which necessitate close monitoring of kidney function and blood pressure.¹²

Tacrolimus is a more potent analogue that provides similar efficacy at lower doses.^1,12 Some clinicians prefer it due to a more favourable cosmetic side-effect profile. Tacrolimus can be administered orally or topically in certain cases, although systemic monitoring is still required.¹⁰

Alkylating Agents (for refractory cases)

For the most resistant or sight-threatening cases, alkylating agents such as Cyclophosphamide or Chlorambucil may be considered.⁶ These drugs suppress the immune system by cross-linking DNA, preventing cell division. They are generally reserved for short-term use because of their toxicity profile, which includes bone-marrow suppression, hemorrhagic cystitis, infertility, and increased risk of malignancy.⁶

Due to these risks, such agents are now rarely employed except when other treatments have failed.⁶ When used, therapy duration is typically limited to several months under intensive laboratory monitoring.

Biologic and targeted immunotherapies

The introduction of biologic agents has revolutionized the treatment of severe or refractory uveitis, including Pars planitis. These drugs specifically target cytokines or immune receptors that drive inflammation, offering potent yet more selective immune modulation.

TNF-α Inhibitors

The TNF-α pathway plays a major role in ocular inflammation. Blocking this cytokine has proven highly effective in controlling uveitic activity.¹⁰

Infliximab, a chimeric monoclonal antibody administered intravenously, was among the first biologics used for uveitis associated with Behçet’s disease and later for idiopathic intermediate uveitis.^2,11 It induces rapid suppression of inflammation, often within weeks.^2,12

Adalimumab, a fully human monoclonal antibody, is now FDA-approved for noninfectious intermediate, posterior, and panuveitis, including Pars planitis.^4,12 Administered subcutaneously every two weeks, it provides convenient long-term control with a well-established safety profile.⁴ Clinical studies demonstrate a significant reduction in relapse rates and improved visual outcomes.¹

However, TNF inhibitors carry risks, including increased susceptibility to infections, demyelinating disease, and injection-site reactions.^10,11

Interleukin pathway inhibitors

When TNF blockade fails or is not tolerated, agents targeting interleukin pathways may be effective.¹¹

Tocilizumab, an IL-6 receptor antagonist, has shown benefit in controlling refractory cystoid macular oedema secondary to Pars planitis.^1,10 By reducing vascular permeability and inflammatory signalling, it can restore macular architecture and improve vision. Intravenous or subcutaneous formulations are available.^10,12

Ustekinumab, targeting IL-12 and IL-23, has been explored in small case series with encouraging results, although its use remains off-label. These biologics illustrate the growing diversity of immune targets in ocular inflammatory disease.¹

Other biologic and emerging options

Rituximab, a monoclonal antibody against CD20, depletes B cells and has been employed in selected autoimmune uveitis cases, particularly those associated with systemic vasculitis or multiple sclerosis.¹

In recent years, JAK inhibitors such as tofacitinib have attracted attention.¹ By blocking intracellular signalling of multiple cytokines, they offer a novel oral approach to immunomodulation.¹² Early data suggest potential efficacy in refractory noninfectious uveitis, but large clinical trials are still underway. 

Treatment strategy and monitoring

Management of severe Pars planitis follows a stepwise, individualised approach:

• Corticosteroids are initiated for rapid inflammation control⁹
• If the disease recurs or requires high steroid doses, antimetabolites (MTX, MMF, or azathioprine) are introduced as steroid-sparing agents¹
• Calcineurin inhibitors may be added for synergistic suppression¹⁰
• In refractory cases, biologic therapy (adalimumab, infliximab, tocilizumab) is employed²
• Alkylating agents remain the final option when all else fails⁶

Monitoring includes both disease activity and drug safety. Clinicians assess visual acuity, anterior chamber and vitreous cell grading, optical coherence tomography (OCT) for macular oedema, and fluorescein angiography when needed.¹

Future directions

Advances in immunology and molecular genetics are driving a shift toward personalized therapy for uveitis. Biomarkers that predict treatment response could allow physicians to tailor immunosuppression more precisely, minimizing toxicity and cost.

Ongoing research is exploring new biologic agents, including inhibitors of IL-17 and IL-1, as well as oral small molecules that block multiple inflammatory pathways simultaneously.¹⁰ Despite these advances, challenges remain, particularly the long-term safety of chronic immunosuppression, limited access in resource-constrained settings, and the need for pediatric-specific data. 

Summary

Severe or refractory Pars planitis represents a complex autoimmune condition requiring more than corticosteroids for lasting control. Immunosuppressive and biologic therapies have transformed outcomes by enabling steroid-sparing, sustained remission, and vision preservation.

A strategic, stepwise approach, starting with traditional agents such as methotrexate or mycophenolate and progressing to biologics like adalimumab or tocilizumab when needed, offers the best balance between efficacy and safety. With continued innovation and closer multidisciplinary collaboration, the prognosis for patients with this once-devastating disease continues to improve.