Sarcoidosis

Summary

Sarcoidosis is a multisystem granulomatous disease of unknown cause that has numerous clinical features, but mostly affects the lungs, eyes, lymph nodes and skin. Sarcoidosis is one of the commonest systemic associations of uveitis.

Aetiology

Sarcoidosis is a multisystem granulomatous disease of unknown aetiology, characterised by formation of non-caseating granulomas that can affect virtually any organ, but most commonly affect the eyes, lungs, skin and lymphatic system. It has a chronic course, but can undergo spontaneous remission.

A biopsy specimen stained with haematoxylin and eosin (HE) demonstrating a typical non-caseating granuloma. The arrow points to Langhans’ multi-nucleated giant cells, and the start points to epithelioid cells, which are surrounded by a ring of leucocytes. Image courtesy of Heinrich's et al.

Epidemiology

The prevalence of sarcoidosis is highest in Northern Europe and colder climates. Generally, people who are of Black ethnic background are affected more frequently and severely than those who are white (10:1).

Females are more commonly affected than males.

The characteristic age of onset is 30-50 years.

It is associated with HLA-DRB1 and DBQ1 alleles.

Presentation

In 20-40% of cases of sarcoidosis, the disease presents incidentally on a chest x-ray. Alternatively, patients present acutely unwell, with fever, polyarthralgia, erythema nodosum and bilateral hilar lymphadenopathy (BHL).

The clinical features of sarcoidosis are numerous, and can be classified into systemic and ocular features.

Systemic features

• General: fever (swinging), anorexia, malaise, weight loss, fatigue, lymphadenopathy

• Upper respiratory: otitis, sinusitis

• Lower respiratory (seen in 90%): dry cough, progressive dyspnoea, chest pain, reduced lung function, pulmonary fibrosis

• Musculoskeletal: polyarthralgia, dactylitis

• Cardiac (5%): restrictive cardiomyopathy (secondary to granulomas and fibrosis), pericardial effusion, arrhythmias

• Neurological: peripheral and cranial polyneuropathy (especially facial nerve palsy, also known as Bell’s palsy), meningitis, transverse myelitis. Pituitary involvement can cause hormonal abnormalities.

• Urological: hypercalcaemia —> renal stones, nephrocalcinosis, diabetes insipidus. The hypercalcaemia is caused by macrophages inside the granulomas metabolising vitamin D to its active form more quickly than usual.

• Abdominal: hepatosplenomegaly

• Dermatological: erythema nodosum (painful erythematous plaques commonly on the shins - caused by lumps of inflamed fat under the skin), lupus pernio (raised, dusky purple plaques on the nose, cheeks and fingers), granulomatous papules and macule

Left, erythema nodosum. Image courtesy of Coyle et al. Right, lupus pernio in a patient with sarcoidosis. Red-purple indurated plaques and nodules are seen on the nose and cheeks. Image courtesy of Sand et al.

Ocular features

Sarcoidosis can involve almost any structure around or within the eye. Moreover, eye disease is often the first clinical manifestation of sarcoidosis.

Granulomatous anterior uveitis is the most common ocular feature, typically affecting patients with acute-onset sarcoidosis. Chronic anterior uveitis (typically granulomatous) tends to affect older patients with chronic lung involvement.

The International Workshop on Ocular Sarcoidosis (IWOS) in 2009 reported 7 key signs for diagnosing intraocular sarcoidosis:

1. “Mutton fat” KPs (keratic precipitates) and/or small granulomatous KPs and/or iris nodules

2. Trabecular meshwork nodules

3. Vitreous opacities: snowballs and/or “strings of pearls”

4. Multiple chorioretinal peripheral lesions (active and/or atrophic). These vary in appearance, but are typically many small pale-yellow infiltrates, sometimes with a punched-out appearance. Retinal granulomas (discrete small yellow-white lesions) can also occur.

5. Nodular and/or segmental periphlebitis (± “candle drippings”) and/or retinal macroaneurysm in an inflamed eye. Periphlebtiis is seen as yellowish or grey-white perivenous sheathing. Perivenous exudates known as “candle wax drippings” indicate severe sarcoid periphlebitis.

6. Optic disc nodule/granuloma and/or solitary choroidal nodule. Optic nerve granulomas do not usually affect vision.

7. Other ocular manifestations including:

• Conjunctival nodules

• Lacrimal gland inflammation, nasolacrimal gland obstruction and dry eye

• Eyelid nodules

• Orbital and scleral lesions

Complications of ocular involvement are the same complications typically seen in idiopathic uveitis:

• Cataract

• Glaucoma

• Band keratopathy

• Vitreous haemorrhage

• Retinal detachment

• Posterior and peripheral anterior synechiae

• Maculopathy (including cystoid macular oedema and choroidal neovascularisation)

A, “mutton-fat” KPs in a patient with sarcoidosis. Image courtesy of Herbort. B, fundus photograph showing peripheral chorioretinal punched-out scars in a patient with sarcoidosis. Image courtesy of Babu. C, fundus photograph showing segmental perivenous sheathing in a patient with sarcoidosis. Image courtesy of Abu El-Asrar et al. D, scleral nodule in a patient with sarcoidosis. Image courtesy of Babu. E, slit lamp photograph showing conjunctival granulomas in a patient with sarcoidosis. Image courtesy of Babu.

Diagnosis

Sarcoidosis is adiagnosed histopathologically, with a biopsy typically from the lung, lymph nodes, liver or skin nodules, showing non-caseating granulomas. It is also important to rule out other differentials, and to rule out alternative causes of uveitis by appropriate investigation:

• Blood tests: ↑ESR, ↑ calcium (in 10%), lymphocytopaenia, deranged LFTs, ↑ serum ACE (angiotensin converting enzyme), ↑ serum lysozyme

• Urine: ↑ calcium

• Imaging: chest x-ray (abnormal in 90%), high-resolution CT (if chest x-ray is negative), cardiac MRI

• Fibreoptic bronchoscopy with biopsy

• ECG: may show arrhythmias or bundle branch blood

• Lung function testing: may show a restrictive pattern (due to reduced lung volumes) and a reduced transfer factor (due to impaired gas transfer)

• Negative tuberculin skin test (to rule out tuberculosis)

Staging

Sarcoidosis is staged according to the findings on chest x-ray.

Stage	​Features
0	Normal
1	BHL
2	​BHL + interstitial infiltrates
3	Diffuse interstitial infiltrates only
4	Diffuse fibrosis, honeycombing (due to bullae) and pleural involvement

Management

BHL alone with no symptoms:

• No treatment required, recovers spontaneously

Acute illness:

• Usually resolves spontaneously

• Bed rest + NSAIDs

• Corticosteroids - oral prednisolone for 6 weeks, then taper over 1 year. Indications for steroids: (1) patients with stage 2 or 3 disease on chest x-ray who are symptomatic; (2) hypercalcaemia; (3) ocular, cardiac or neurological involvement

• Oxygen therapy if needed

Long-term:

• For pulmonary disease: oral/inhaled corticosteroids, anti-TNF⍺, possibly lung transplantation

• Additional immunosuppression can be considered: methotrexate, cyclosporin, cyclophosphamide

Treating ocular disease:

• Anterior and intermediate uveitis: steroid drops and cyclopentolate (see our ‘Classification of Uveitis’ notes)

• Posterior uveitis: systemic steroids ± immunosuppressive agents

• Cystoid macular oedema: topical NSAID

• Peripheral retinal neovascularisation: scatter photocoagulation to ischaemic areas

• Inflammation should ideally be suppressed for ≥3 months prior to cataract surgery

References

1. Salmon, John F., and Jack J. Kanski. Kanski’s Clinical Ophthalmology: A Systematic Approach. Ninth Edition, Elsevier, 2020.

2. Pasadhika, Sirichai, and James T. Rosenbaum. ‘Ocular Sarcoidosis’. Clinics in Chest Medicine, vol. 36, no. 4, Dec. 2015, pp. 669–83. PubMed Central, https://doi.org/10.1016/j.ccm.2015.08.009.

3. Henrichs, Marcel-Philipp, et al. ‘Scar Sarcoidosis on a Finger Mimicking a Rapidly Growing Soft Tissue Tumour: A Case Report’. BMC Research Notes, vol. 5, Oct. 2012, p. 545. PubMed Central, https://doi.org/10.1186/1756-0500-5-545.

4. Coyle, Christopher, et al. ‘Erythema Nodosum as a Result of Estrogen Patch Therapy for Prostate Cancer: A Case Report’. Journal of Medical Case Reports, vol. 9, Dec. 2015, p. 285. PubMed Central, https://doi.org/10.1186/s13256-015-0776-4.

5. Sand, Michael, et al. ‘Cutaneous Lesions of the Nose’. Head & Face Medicine, vol. 6, June 2010, p. 7. PubMed Central, https://doi.org/10.1186/1746-160X-6-7.

6. Herbort, Carl P. ‘Appraisal, Work-up and Diagnosis of Anterior Uveitis: A Practical Approach’. Middle East African Journal of Ophthalmology, vol. 16, no. 4, Oct. 2009, pp. 159–67. PubMed, https://doi.org/10.4103/0974-9233.58416.

7. Babu, Kalpana. ‘Sarcoidosis in Tuberculosis-Endemic Regions: India’. Journal of Ophthalmic Inflammation and Infection, vol. 3, no. 1, June 2013, p. 53. PubMed, https://doi.org/10.1186/1869-5760-3-53.

8. Abu El-Asrar, Ahmed M., et al. ‘Differential Diagnosis of Retinal Vasculitis’. Middle East African Journal of Ophthalmology, vol. 16, no. 4, 2009, pp. 202–18. PubMed Central, https://doi.org/10.4103/0974-9233.58423.