Sarcoidosis is a chronic granulomatous disease that affects multiple organ systems. It is an autoimmune disease of unknown cause, thought to involve Th1-type cellular immune responses (type IV allergy) to antigenic stimulation, leading to granuloma formation in various organs throughout the body.
Ocular involvement occurs in approximately 25–38% of sarcoidosis cases. 1) In about 20% of cases, ocular symptoms are the first manifestation of the disease. 1) It is relatively common in Japan and is the leading cause of uveitis and endophthalmitis.
Definitive diagnosis requires histological evidence of non-caseating granulomas, but biopsy is not always easily performed. Conjunctival biopsy, as a minimally invasive procedure, contributes to the histological diagnosis of ocular sarcoidosis.
Advantages of Conjunctival Biopsy
Minimally invasive: Can be performed in a short time under local anesthesia.
Direct diagnostic evidence: Histological confirmation of non-caseating granulomas is possible
Avoidance of other invasive procedures: Should be attempted before bronchoscopy or mediastinoscopy
Limitations and Precautions
False negatives during steroid use: May become negative with steroid eye drops before biopsy
Nodules are not always visible: Blind biopsy reduces diagnostic yield
Systemic evaluation is also essential: Diagnosis cannot be made based solely on ocular findings
Characteristic findings of ocular sarcoidosis:
| Site | Typical Findings |
|---|---|
| Anterior chamber | Mutton-fat keratic precipitates, iris nodules (Koeppe/Busacca nodules) |
| Angle | Angle nodules, tent-like peripheral anterior synechiae |
| Vitreous | Snowball/string of pearls opacities |
| Fundus | Waxy chorioretinal exudates, retinal periphlebitis, optic disc granuloma |
| Conjunctiva | Small yellow to light brown nodules (commonly in the inferior fornix) |
Fundus findings are diverse, including diffuse vitreous opacities, chorioretinal atrophy resembling laser photocoagulation scars, cystoid macular edema, and choroidal granulomas. Angle nodules causing elevated intraocular pressure at onset are relatively specific findings.
IWOS diagnostic criteria (7 ocular findings):2)
Diagnostic categories are as follows: 2)
No. There may be only anterior uveitis, but inflammation can also extend to the intermediate, posterior, or panuveitis. In particular, progression to the posterior segment is more common in elderly patients and severe cases. Additionally, ocular symptoms at onset are the first trigger for systemic workup in about 20% of cases.
The cause of sarcoidosis is unknown. It is thought that in susceptible individuals, a pathogenic antigen triggers a Th1-type immune response, leading to the formation of non-caseating granulomas.
Factors suggested to be associated:
Drug-induced sarcoidosis-like reaction (DISR): 4)
TNF-α inhibitors can paradoxically cause sarcoidosis, a condition for which they are indicated (paradoxical adverse events). A review of over 100 cases found that about half of all DISR cases were due to etanercept. This is thought to be because etanercept primarily targets soluble TNF-α and has incomplete effects on membrane-bound TNF-α, leading to insufficient Th1 regulation. 4)
When sarcoidosis is suspected based on ocular findings, perform the following systemic workup and refer to internal medicine/dermatology. Systemic steroid administration should generally be avoided before diagnosis is confirmed (because it may shrink lesions and make diagnosis difficult).
| Test | Significance |
|---|---|
| Serum ACE, soluble IL-2 receptor (sIL-2R) | Indicator of activity |
| Chest X-ray/CT | Confirmation of bilateral hilar lymphadenopathy |
| Gallium scintigraphy | Evaluation of accumulation findings |
| Bronchoalveolar lavage | Increased lymphocyte ratio, CD4/CD8 ratio ≥3.5 |
| Blood test | ESR, CRP, liver enzymes |
Ocular OCT and FAG findings:5)
On OCT, preretinal nodules appear as hyperreflective lesions (with posterior shadowing). Fluorescein angiography shows leakage due to retinal vasculitis and papillitis. Indocyanine green angiography is useful for evaluating choroidal lesions but may be normal in the retinal-limited type. 5)
If the conjunctival nodule is visible, consider directed biopsy; if not visible, consider non-directed biopsy (blind biopsy).
Comparison of diagnostic capabilities:1)
Biopsy technique (standard procedure):1)
Multi-level sectioning method:1)
In addition to the standard method (5 sections from 1 level), prepare additional sections from 3 different levels at 15-micron intervals. This allows detection of unevenly distributed granulomas at different depths, improving cumulative diagnostic yield.
For anterior uveitis that cannot be controlled with frequent eye drops, subconjunctival injection of water-soluble steroids is performed. For macular edema, vitreous opacity, and posterior pole inflammation, posterior sub-Tenon injection of triamcinolone is useful.
First-line: Oral steroids (prednisolone)
In mild cases, spontaneous improvement can be expected with eye drops alone, but severe cases and posterior uveitis require systemic steroids. The disease often follows a chronic course, requiring long-term steroid use.
Steroid-sparing therapy:2)
For steroid-dependent or refractory cases, immunomodulatory agents are added.
Biologic agents:
Example of treatment change (PMC11584688):2)
In a 47-year-old male with multisystem sarcoidosis, gradual switching from prednisolone + adalimumab to methotrexate 7.5 mg once weekly to mycophenolate mofetil 1000 mg twice daily led to eventual remission. In the FAST trial, there was no significant difference between mycophenolate mofetil and methotrexate, but treatment success was 74% for methotrexate and 55% for mycophenolate mofetil.2)
Management of drug-induced sarcoidosis (DISR):4)
In etanercept-induced sarcoidosis, discontinuation of the causative drug is fundamental. Systemic steroids (prednisone 50 mg/day) provided partial improvement of inflammation, but in a case with continued steroid dependence, secukinumab (IL-17A inhibitor) was introduced, achieving complete remission for 4 years.4)
Yes. The disease often follows a chronic course, and complications such as cystoid macular edema, epiretinal membrane, secondary glaucoma, and complicated cataract are common. Causes of secondary glaucoma include angle nodules, peripheral anterior synechiae, trabeculitis, and steroid responsiveness. Regular intraocular pressure measurement and slit-lamp microscopy are important for early detection of these complications.
In sarcoidosis, the causative antigen (pathogen-derived or environmental) is phagocytosed and processed by macrophages, activating Th1 lymphocytes. Activated Th1 cells produce IFN-γ and TNF-α, which differentiate macrophages into epithelioid cells. These cells aggregate to form granulomas.
Non-caseating granulomas (aggregates of epithelioid histiocytes) are found within the substantia propria. 1) A minimal “cuff” of lymphocytes and plasma cells is seen around them. Multinucleated giant cells may or may not be present.
Auxiliary microscopic features (not specific): 1)
The choroid is the most common site for posterior segment lesions. Due to high blood flow and the presence of fenestrations in the choroidal vessel walls, lymphocyte-macrophage interactions occur easily. 5) Retina-limited granulomas are rare, as the outer blood-retinal barrier is thought to block most inflammation. 5) However, reported cases of preretinal and intraretinal granulomas suggest an association with neurological symptoms. 5)
Vaccine-induced uveitis is usually mild and responds well to topical steroids. 3) The strong immune response triggered by BNT162b2 (mRNA vaccine) may cause uveitis. 3) In a 35-year-old male with a history of neurosarcoidosis, bilateral anterior and posterior uveitis (anterior chamber cells 2+, periphlebitis, multifocal choroiditis) developed 2 years after Covishield COVID-19 vaccination, which improved within 2 weeks with prednisolone acetate 1% eye drops 4 times/day and timolol eye drops twice/day. 3)
Secukinumab (IL-17A inhibitor) has been reported as a promising option for refractory sarcoidosis ocular lesions with DISR associated with TNF-α inhibitors. 4) In a proof-of-concept study by Hueber et al, secukinumab showed activity in psoriasis, rheumatoid arthritis, and uveitis, and a study by Letko et al confirmed its steroid-sparing effect in non-infectious uveitis (intravenous administration showed superior results to subcutaneous administration). 4) However, secukinumab is not yet approved for uveitis.
OCT enables visualization of preretinal and intraretinal granulomas, and ultra-widefield fundus imaging contributes to the evaluation of peripheral lesions. 5) The diagnostic capability of conjunctival biopsy is expected to further improve with the widespread use of multiplanar sectioning.
