Sarcoidosis

A 35-year-old Afro-Caribbean woman presents with a dry cough, shortness of breath, and bilateral ankle pain. Examination reveals red, tender nodules on her shins. A chest X-ray reveals bilateral hilar lymphadenopathy.

Pathophysiology

Sarcoidosis is thought to be triggered by an unknown antigen. This triggers a cell-mediated immune response, leading to the accumulation of CD4+ T lymphocytes and macrophages in affected organs. A Th1-biased CD4+ response leads to the release of cytokines such as TNF-α, IFN-γ, IL-2, and IL-12, which trigger the formation of non-caseating granulomas. The granulomas can produce 1,25-vitamin D, which causes the hypercalcaemia seen in some patients. There is relative anergy in vivo due to regulatory T cells inhibiting IL-2 and T-cell proliferation.

Aetiology

The exact cause of sarcoidosis is unknown. However, it is thought to be an abnormal immune response to an environmental trigger, such as an inhaled antigen, in a genetically susceptible individual.

Epidemiology & Risk Factors

Sarcoidosis can affect all ages, sexes, races, and places of origin. However, it is more common in:

• people of African-Caribbean and Scandinavian descent
• women
• young adults, with peak incidence in the third and fifth decades of life

The incidence in the UK is 5–10:100,000. The prevalence is highest in Northern Europe.

Clinical Features

Sarcoidosis is a multisystem disorder and, as such, may present in a variety of ways. In 20–40% of cases, it is an incidental finding on a chest X-ray.

• Respiratory - involvement in 90% of patients.
  • Bilateral hilar lymphadenopathy is the most common abnormality seen on chest radiography.
  • Other features include:
    • dry cough
    • shortness of breath
    • chest pain
• Cutaneous - involvement in about 25% of cases and may be the first and only presentation of the disease.
  • Erythema nodosum: most common nonspecific cutaneous manifestation of sarcoidosis after cutaneous sarcoidosis. Presents as painful, red nodules on the shins. Erythema nodosum concurrent with bilateral hilar lymphadenopathy is pathognomonic for sarcoidosis.
  • Lupus pernio: chronic, indurated, purplish lesions on the face, particularly the nose, ears, cheeks and lips, and may ulcerate. Associated with pulmonary sarcoidosis in 75% of cases.
  • Subcutaneous sarcoid (Darier–Roussy sarcoid): multiple firm nodules, most commonly on the arms.
  • Infiltration of pre-existing scars or tattoos may also be seen. These become thickened and red-purple.
  • Other cutaneous manifestations include:
    • red-brown papules and plaques
    • vascular purpura
• Ocular - involvement in 25% of cases.
  • Anterior uveitis is the most common manifestation.
  • Other manifestations include:
    • conjunctivitis
    • keratoconjunctivitis sicca
    • glaucoma
• Constitutional
  • low-grade fever
  • fatigue
  • weight loss
  • night sweats
  • arthralgia
• Other
  • Cardiac:
    • heart block
    • cardiomyopathy
    • arrhythmias
• Renal:
  • renal vasculitis
  • hypercalcaemia
  • nephrocalcinosis
  • renal stones
• Neurological:
  • peripheral nerve lesions
  • cranial nerve lesions (most commonly, lower motor neurone facial nerve palsy, followed by optic nerve involvement)
  • mononeuritis multiplex
  • psychiatric features
  • hypothalamic granulomata
  • meningism
  • ophthalmoplegia
  • pupillary reflex dysfunction
  • seizures
• Gastrointestinal:
  • granulomatous hepatitis
  • hepatomegaly
  • portal fibrosis
  • cirrhosis
  • splenomegaly
  • salivary gland enlargement
  • dry mouth

Löfgren’s syndrome is a mild, acute form of sarcoidosis, which carries a good prognosis (resolving completely in 80% of patients within 1–2 years). It presents with:

• bilateral hilar lymphadenopathy
• fever
• ankle arthritis
• erythema nodosum.

Heerfordt’s syndrome (uveoparotid fever) is an acute presentation of sarcoidosis with fever, uveitis, and bilateral swelling of the parotid and other salivary and lacrimal glands. Other features of sarcoidosis may coexist, such as skin lesions and pulmonary involvement. Facial nerve palsy (lower motor neurone type) may be seen. As it is a form of neurosarcoidosis, other neurological features may also be present, for example:

• meningism
• ophthalmoplegia
• pupillary reflex dysfunction

Investigations

There is no single diagnostic test for sarcoidosis. Diagnosis is based on a combination of the clinical picture, supporting investigations and exclusion of other diagnoses. It should ideally be confirmed with histology.

• Chest X-ray: abnormal in 85% of cases of pulmonary sarcoidosis, but 30–60% are asymptomatic (that is, an incidental finding). Bilateral hilar lymphadenopathy is the most common finding. The Scadding radiological classification of thoracic sarcoidosis is as follows:
  • Stage 0: normal
  • Stage I: hilar lymphadenopathy only
  • Stage II: hilar lymphadenopathy and parenchymal infiltrate
  • Stage III: parenchymal infiltrate
  • Stage IV: fibrosis
• High-resolution CT (HRCT): more sensitive than CXR for detecting pulmonary involvement. It may reveal:
  • micronodules in a subpleural and bronchovascular distribution
  • fissural nodularity and bronchial distortion
  • irregular linear opacities
  • ground-glass shadowing related to bronchovascular bundles
  • nodular or ill-defined shadows
  • air trapping due to small airway granulomata
  • endobronchial disease (seen in 55% of patients)
  • hilar and mediastinal lymphadenopathy
  • minority of patients have a usual interstitial pneumonia (UIP) pattern
• Serum angiotensin-converting enzyme (ACE) levels: elevated in about 40–90% of patients with active sarcoidosis. However, ACE is also elevated in other conditions, such as hyperthyroidism, Gaucher’s disease, silicosis, TB, hypersensitivity pneumonitis and pneumocystosis. It is therefore not a reliable diagnostic test, although it can be used to monitor disease activity. Elevated ACE levels in CSF may help diagnose CNS sarcoidosis, even when serum ACE is normal.
• Blood tests: FBC, ESR, CRP, U&Es, LFTs, calcium, vitamin D, and PTH. Hypercalcaemia is seen in 10% of patients. Lymphopenia is also common.
• ECG: may show arrhythmias or bundle branch block.
• Pulmonary function tests (PFTs): may show a restrictive picture with reduced lung volumes and impaired gas transfer. All patients with suspected sarcoidosis should undergo PFTs.
• Slit lamp examination: Mild, asymptomatic eye involvement is common. If there is no evidence of sarcoidosis elsewhere, a conjunctival biopsy may be necessary.
• Tuberculin skin test: The tuberculin test is usually negative in chronic sarcoidosis. However, most patients with sarcoidosis who develop tuberculosis become tuberculin-positive.
• 24-hour urinary calcium: All patients with suspected sarcoidosis should undergo a 24-hour urinary collection to assess for hypercalciuria.

Further Investigations:

• Tissue biopsy: diagnostic and will reveal non-caseating granulomas. The biopsy may be taken from the lung, liver, lymph nodes, skin nodules, or lacrimal glands. Transbronchial lung biopsy is the initial procedure of choice for suspected pulmonary sarcoidosis. A CT-guided biopsy of mediastinal or hilar lymph nodes seen on CT may also be possible and yield a tissue diagnosis. A biopsy may also be required to exclude other diagnoses, such as lymphoma or tuberculosis. The presence of non-caseating granulomas on transbronchial biopsy or bronchial biopsy is more significant than on lymph node sampling because granulomas can accompany tumour infiltration of lymph nodes.
• Bronchoscopy: may not be necessary if there is no diagnostic doubt. However, it may be important for excluding infectious agents. The positive yield of endobronchial biopsy is 40–60%. This is higher if there is visible abnormal mucosa. Transbronchial lung biopsy has a positive yield of 40–90%. The yield is still high even if the lungs appear normal on HRCT. Transbronchial needle aspiration (TBNA) of mediastinal lymph nodes yields a diagnosis in 60–90% of cases. Transbronchial biopsy and TBNA together have a higher yield than either alone.
• Bronchoalveolar lavage (BAL): shows a CD4:CD8 ratio of >3.5. A lymphocytosis of >2 × 10^5 cells/mL supports the diagnosis but is not diagnostic, as it is also seen in hypersensitivity pneumonitis and drug-induced alveolitis.

Management

The majority of patients with sarcoidosis improve without treatment. In fact, most patients with sarcoidosis remain asymptomatic and do not require treatment. Patients with asymptomatic stage 2 or 3 disease and only mildly abnormal lung function do not require treatment. This includes those with bilateral hilar lymphadenopathy alone, as most will recover spontaneously. For acute sarcoidosis, bed rest and NSAIDs are usually sufficient. Observation, with regular monitoring to assess for disease progression, is appropriate for these patients.

Indications for Treatment:

• Respiratory:
  • increasing symptoms
  • deteriorating lung function
  • worsening changes on chest X-ray
• Cardiac involvement
• Neurological involvement
• Hypercalcaemia
• Sight-threatening ocular sarcoidosis
• Lupus pernio

Treatment Options:

• Corticosteroids: mainstay of medical treatment for sarcoidosis. A typical regimen is prednisolone 40 mg/day for 4–6 weeks, then tapered slowly over a period of months according to clinical response.
• Other Immunosuppressants: For severe illness or steroid-refractory disease, other immunosuppressants may be used.
  • Methotrexate may be used in place of, or in addition to, low-dose prednisolone. It is given once weekly at a dose of 10–15 mg orally for a 6-month trial. It is useful for chronic sarcoidosis and cutaneous disease. It should be avoided in patients with hepatic or renal impairment. Side effects include gastrointestinal upset, stomatitis, pneumonitis, myelosuppression, and teratogenicity. Bloods (FBC, MCV, AST, ALT) should be monitored every 2 weeks for the first 3 months and then monthly. It should not be used for more than 2 years without review.
  • Hydroxychloroquine at a dose of 200 mg once or twice daily may be used as a steroid-sparing agent. It is particularly useful for cutaneous disease and hypercalcaemia. It can be given with steroids and other immunosuppressants in severe sarcoidosis. Side effects are rare but include ocular toxicity.
  • Other options include leflunomide, ciclosporin, thalidomide, and TNF-α inhibitors (etanercept, infliximab, adalimumab, golimumab). These should be used in conjunction with specialist centres.
• Lung transplantation: Lung transplantation may be considered in patients with refractory disease.

Complications & Prognosis

The majority of patients with sarcoidosis have a good prognosis. About 60% of patients with thoracic sarcoidosis will resolve spontaneously within 2 years. About 20% will respond to steroid therapy. However, improvement is unlikely for the remaining 20%, even with treatment. Mortality in the UK from sarcoidosis is <5%.

Complications:

• Respiratory:
  • progressive pulmonary fibrosis
  • respiratory failure
• Cardiac:
  • heart block
  • cardiomyopathy
  • arrhythmias
  • sudden death
• Neurological:
  • facial nerve palsy
  • optic nerve involvement
  • mononeuritis multiplex
  • psychiatric features
  • hypothalamic granulomata
• Ocular:
  • uveitis
  • conjunctivitis
  • keratoconjunctivitis sicca
  • glaucoma
• Renal:
  • hypercalcaemia
  • hypercalciuria
  • renal stones
  • nephrocalcinosis
  • renal failure
• Other:
  • bone cysts, especially of terminal phalanges
  • splenic rupture
  • bone marrow infiltration
  • liver failure
  • portal hypertension
  • diabetes insipidus

Factors Associated with a Good Prognosis:

• Löfgren’s syndrome
• HLA-B8
• HLA-DQB1*0201

Factors Associated with a Poor Prognosis:

• Insidious onset of disease; symptoms for >6 months (chronic pulmonary involvement)
• Absence of erythema nodosum
• Extrapulmonary manifestations, for example:
  • lupus pernio
  • nasal mucosa involvement
  • chronic uveitis
  • chronic hypercalcaemia
  • nephrocalcinosis
  • neural involvement
• Age >40 years
• Black race
• Stage III disease on chest X-ray. Only 30% of these patients show significant improvement.
• Usual interstitial pneumonia (UIP) pattern on HRCT.

Anxiety and depression are also associated with sarcoidosis, and may be exacerbated by oral steroid use. This can contribute to fatigue. Treatment for anxiety and depression may be necessary.