Sarcoidosis

This multisystem chronic inflammatory condition is characterised by the formation of non-caseating epithelioid granulomata at various sites in the body. It has a predilection for the lungs and thoracic cavity, but there are protean manifestations that may catch out even the most experienced physicians. Despite having been described since the mid-nineteenth century or so, the underlying aetiology remains uncertain. It appears likely that a genetic susceptibility is combined with a triggering infection, but despite several candidate genes and microorganisms being suggested, there is no definitive evidence in favour of particular ones, as yet.¹ There is considerable variability of the disease in different people and explaining this may help develop new approaches to treatment.²

It largely affects patients in their mid-twenties to mid-forties but cases do appear infrequently in younger and older patients. After the thorax, the skin and eyes are most commonly affected, followed by the liver (not usually clinically relevant), heart and nervous system.

Prevalence

• It is relatively common but figures for exact UK prevalence are hard to come by.
• The overall US prevalence is estimated at 10-40 cases per 100,000 population but its prevalence in Irish- Scandinavian- and Caribbean-origin populations appears to be highest in the US.³
• In the US, the lifetime risk of sarcoidosis in the black population is 2.4% and 0.85% in whites.⁴

Incidence

It is a ubiquitous disease with incidence (varying according to age, sex, race and geographic origin) estimated at around 16.5/100,000 in men and 19/100,000 in women.⁵ It is more common in Scandinavian countries. For example:

• In Denmark incidence is 7-10 cases per 100,000 person years.⁶
• Sweden has the highest reported incidence of sarcoidosis in Europe, ranging from 64 cases per 100,000 (radiographic screening) to 641 cases per 100,000 population (autopsy studies).

Risk factors

• Occupational exposure to beryllium, aluminium and zirconium can cause a granulomatous disease clinically indistinguishable from sarcoidosis.⁴
• Commoner in Scandinavian- and Caribbean-origin populations.
• Quite rare in Indian, Australian aboriginal or South Asian populations.³
• There is a slightly higher prevalence in women.
• There is an increased familial risk with about 5% of UK sufferers having a first, second or third degree relative affected.⁷

This is highly variable depending on ethnicity, duration of illness, pattern and degree of inflammatory organ involvement.

• Up to 50% of sufferers in some series were asymptomatic and diagnosed on the basis of routine CXR.
• There may be non-specific constitutional symptoms or organ-specific symptoms. About a third will have a non-specific presentation with fever, fatigue, cachexia and lassitude and this presentation is more common in people of black or Indian origin.
• An acute presentation is commoner in whites, as is remission of disease about two years after presentation.
• About 10-30% of patients will have a chronic, progressive pattern of disease.
• Black patients have more serious pulmonary involvement with a poorer long-term prognosis and an increased frequency of relapses.

Constitutional upset

• Fever and night sweats, malaise, fatigue,⁸ weight loss.
• Heerfordt's syndrome (inflammation of submaxillary/parotid glands with uveitis and facial nerve palsy) may accompany constitutional presentation.⁹

Lung

• Involved in >90% cases.
• Usual pattern is interstitial lung disease (diffuse parenchymal lung disease).
• Patients may present with dry cough, fever and dyspnoea accompanied by chest discomfort.

Skin¹⁰

• Commonly affected.
• May see papules on face resembling rosacea or maculopapular rashes on body or extremities. Brownish-red infiltrative plaques on extremities and trunk may be present (very similar appearance to plaque psoriasis).
• Erythema nodosum on the legs is a relatively common feature. Löfgren's syndrome refers to the combination of erythema nodosum with arthritis (commonly affecting the ankles) and bilateral hilar or paratracheal adenopathy seen on CXR.
• Lupus pernio is a violaceous, soft infiltration affecting the nose and cheeks that is uncommon but pathognomonic.

The eye

• Affected in >20% cases, most frequently as a granulomatous uveitis.
• Anterior uveitis is frequently of limited duration, but posterior uveitis tends to be more persistent.
• Dry eyes and glaucoma can appear years after other symptoms have disappeared.
• The optic nerve may be affected but blindness is rare.

Neurosarcoidosis

• Infiltrative nerve lesions can affect any part of the central or peripheral nervous system leading to a huge variety of neurological disease.
• Bell's palsy and lymphocytic meningitis are common manifestations of neurological involvement but diabetes insipidus is also seen.
• The following symptoms are encountered relatively commonly as a result of neurological involvement: Facial numbness, dysphagia, hoarseness, headache, visual field defects, polydipsia, hearing impairment, lesions of cranial nerves VII, VIII, IX and X, bitemporal hemianopia due to optic chiasmal involvement, seizures, stroke/TIA, peripheral neuropathic lesions.

Heart disease

Rarely can cause sudden death from arrhythmias or cause symptoms of heart failure in a young patient due to cardiomyopathy.¹¹

Lymphadenopathy

This is commonly picked up on CXR but may be symptomatic and affect axillary, cervical, inguinal nodes and those around salivary glands.

Liver

There may be deranged liver function tests but symptoms are rare, causing significant hepatitis in <10% cases.

Hypercalcaemia and hypercalciuria

• Caused by humoral effect of granulomata on vitamin D3 metabolism.
• Can cause nephrolithiasis, neuropsychiatric disturbance, abdominal pain and bone pain.

Joints

Tends to present as an inflammatory arthritis (often oligoarticular initially) with periarticular soft tissue swelling, tenosynovitis, dactylitis, osteopenia and associated myopathy.¹²

Other organs/systems

Other areas that are more rarely involved and the symptoms they cause are listed here:

• Bone marrow (leading to anaemia, immunosuppression)
• Spleen (causing abdominal discomfort and distension due to splenomegaly)
• Upper respiratory tract (causing nosebleeds, rhinitis, nasal obstruction/masses or tonsillar involvement)
• Salivary glands (causing facial swelling and pain and other symptoms of parotitis)

In a patient who is suspected of suffering from sarcoidosis, the following examination scheme will give a good chance of detecting any relevant signs that may suggest or confirm the diagnosis.

Skin

Carefully examine the skin all over looking for characteristic rashes. Lupus pernio may be seen on the face, and the shins should be looked at to detect erythema nodosum. Old scars or tattoos may show granulomatous infiltrative lesions.

Eyes

Look carefully at the eyes to detect signs of uveitis, dry eyes or conjunctival infiltrates. Consider slit lamp examination if any abnormalities found (usually needs expert input).

Joints and muscles

Examine any painful joints and muscles and characterise the nature of the problem and affected structures.

Head and neck

Check for lymphadenopathy, salivary gland swelling, tonsillar enlargement/inflammation and patency/abnormality of nasal passages if any relevant symptoms.

Abdomen

Check for hepatomegaly and splenomegaly.

Cardiorespiratory

Chest signs of sarcoidosis are usually not detected unless advanced interstitial lung disease present when there may be scattered crackles. Check pulse to detect any rhythm disturbance. Look for signs of heart failure.

Nerves/CNS

Check function of VIIth and other cranial nerves and peripheral sensory/motor nerve function to detect peripheral neuropathy. Formal neurological exam if relevant symptoms.

The differential diagnosis is huge depending on the type of presentation, affected organs, age of patient and ethnic origin/recent travel history. The diagnoses listed below have frequent overlapping clinical and investigational features with sarcoidosis and are important to consider or exclude where relevant.

• Rheumatoid arthritis
• Lymphoma
• Metastatic malignancy
• TB
• Multiple sclerosis
• Lung cancer
• Systemic Lupus Erythematosus
• Other causes of interstitial (parenchymal) lung disease
• Multiple myeloma
• Churg-Strauss syndrome

• FBC may show raised white count/eosinophilia or lymphopenia. Anaemia may be seen.
• ESR often raised (~65% cases).
• Check U&E (renal impairment quite rare) and serum calcium (elevated in 10% to15% of cases). Phosphate and alkaline phosphatase may be increased. LFTs may show derangement.
• If calcium elevated then 24-hour urinary collection can prove hypercalciuria.
• Serum angiotensin converting enzyme (ACE) levels are elevated in around 60% of patients with acute disease and reduce in response to treatment or resolution of the disease. ACE is produced by the granulomata themselves. It is a relatively non-specific finding but can help to make the diagnosis in line with the clinical context and other investigations.
• Plain chest X-ray may show bilateral hilar or paratracheal lymphadenopathy. High-resolution CT scanning is often used to detect interstitial lung disease.
• Lung function tests show restrictive defect in severe, progressive cases (shrinking lung syndrome).
• Bronchoalveolar lavage findings: increased lymphocytes, especially raised CD4:CD8 ratio can help to clinch diagnosis in correct circumstances.
• Transbronchial biopsy can demonstrate presence of non-caseating granulomata giving a more accurate diagnosis.
• Gallium scanning may be used to detect extra-pulmonary disease and tends to reveal a 'lambda' pattern.
• ECG important to check for early signs of rhythm disturbance due to conducting system disease or effects of hypercalcaemia. 24-hour ECG may be used to detect paroxysmal rhythm disturbance.
• Formal ophthalmological examination is recommended for all newly diagnosed cases.
• Diagnosis may be achieved by biopsy of any suspicious skin lesions or accessible lymph nodes. There will be multiple non-caseating epithelioid granulomata.
• The Kveim test (intra-dermal injection of splenic material from a confirmed case of sarcoidosis, and histological examination of any nodule formed) has fallen out of favour due to the risk of transmission of new-variant CJD12, and the several weeks it takes to get a diagnosis.

Traditionally, pulmonary involvement has been classified into 5 stages based on CXR findings. The prognostic value of this classification in children is uncertain. Note that CXR may also demonstrate pleural involvement, such as a pneumothorax or pleural effusion.

• Stage 0 - Normal findings on chest radiograph
• Stage I - Bilateral hilar lymphadenopathy (which may be accompanied by paratracheal adenopathy)
• Stage II - Bilateral hilar adenopathy with pulmonary infiltrates (parenchymal involvement or reticular opacities)
• Stage III - Parenchymal infiltrates without hilar adenopathy
• Stage IV - Parenchymal involvement turns into volume loss (pulmonary fibrosis) and may be other features (cavitations, calcifications, hilar retraction, bullae, cysts, and emphysema)

Pulmonary disease

Treatment is mainly symptomatic and the mainstay remains the use of oral corticosteroids:¹³

• Patients with early disease (hilar lymphadenopathy only) do not require any therapy.
• Systematic reviews have demonstrated evidence of benefit from use of steroids in the short-term, in terms of symptoms and x-ray appearances, but there is no real convincing proof of benefit in the long-term.¹⁴
• Consensus guidelines state that steroids should be continued for 12 months but not beyond 2 years in those who respond, with dose tapered down as low as possible and given on alternate days if feasible.
• Consideration of prophylaxis against osteoporosis with bisphosphonate drugs is recommended but calcium and vitamin D are usually avoided due to the risk of hypercalcaemia in sarcoidosis.
• Given the significant morbidity attributable to long-term use of steroids, they should be given with extreme caution and under expert monitoring in patients with pulmonary sarcoidosis.
• There is no current evidence of any efficacy for inhaled corticosteroids.

As of yet, systematic reviews have not revealed that immunosuppressant drugs have benefits that outweigh their significant toxic effects in this scenario.¹⁵ Examples of these and other drugs that are being investigated include:

• Methotrexate¹⁶ and azathioprine. These are used in expert hands in individual cases.
• Leflunomide appears to be as effective as methotrexate, with less toxicity, in patients with chronic sarcoidosis. It should be considered as an alternative in chronic sarcoidosis patients who cannot tolerate methotrexate.¹⁷
• Immunomodulatory agents that affect the TNF-alpha axis such as chloroquine, pentoxifylline, thalidomide and infliximab are being used with some initial evidence of efficacy but no robust trial data to support their use as yet.^18,4,19,20

Surgical intervention may be considered in extreme cases of fibrotic lung disease with life-threatening haemoptysis. Lung transplantation has also been rarely used.

Extra-pulmonary disease²¹

• Ocular disease:
  • Usually resolves spontaneously but if sight-threatening can be treated with topical steroids under expert guidance and follow up.
  • Adjunctive immunosuppressives or immunomodulators are used but there is no real supportive trial data.
  • Surgery is usually delayed until disease is inactive or healing may be problematic.
• Cutaneous disease:²²
  • Most cutaneous manifestations resolve spontaneously or respond to NSAIDs in a matter of weeks.⁴
  • However, lupus pernio usually requires therapy with systemic corticosteroids (it is a harbinger of chronic, poorly-responsive sarcoidosis).
  • Other treatment modalities used by dermatologists include intra-lesional or occlusive steroid dressings.
  • Adjunctive therapy with immunosuppressants is often used to treat large or slowly responding lesions that need systemic steroids.
  • Thalidomide appears to be beneficial in unresponsive cases, but must be given with careful attention to its potential toxic and teratogenic effects and only in expert centres in protocol-driven programs.²³
• Neurosarcoidosis:
  • Is usually treated with high-dose oral steroids as first-line therapy.
  • Refractive cases of neuropsychiatric disturbance or aggressive CNS granulomata formation may be given adjunctive therapy with immunosuppressants such as azathioprine or ciclosporin.
  • Neurosurgery is used to treat large mass lesions or obstructive hydrocephalus.
• Cardiac disease:
  • Steroids are often used but there is no convincing evidence-base for this.
  • Pacemakers and implantable cardioverter-defibrillators are used in cases of dangerous cardiac arrhythmia.
  • Electroablation, cardiac resection and transplantation may be used in severe cases.
  • Standard pharmacotherapy is employed to treat arrhythmias and cardiac failure.
  • Treatment of pulmonary hypertension with pulmonary vasodilators improved clinical status and dyspnoea in a small study.²⁴

About two-thirds of cases will resolve in the long term. The remaining third tend to run a chronic course which may be progressively disabling (particularly if lungs badly affected) or relapse and remit. Mortality is estimated at 1 to 5% depending on the ethnic group affected. Prognosis in white patients is better than in black sufferers.

• Good prognostic indicators: Acute presentation, erythema nodosum, minimal lung disease with only hilar lymphadenopathy.
• Poor prognostic indicators: Advanced interstitial lung disease, chronic iritis, lupus pernio, tracheal disease, increasing number of extra-pulmonary manifestations.

Complications occur according to the organ affected, but are subject to variability in incidence and severity.

• Pulmonary:
  • Infections
  • Progressive fibrotic lung disease leading to death
  • Pulmonary hypertension²⁴
• Cardiac:
  • Cardiac arrhythmia and sudden death
  • Cardiac failure
• Ocular:
  • Uveitis and conjunctivitis
  • Blindness (rare)
  • Ocular sicca syndrome
• Skin:
  • Chronic refractory skin disease
• Liver:
  • Commonly involved but rarely clinically significant
• Nervous system:
  • Cranial and peripheral nerve damage
  • Neuropsychiatric illness
  • Permanent CNS impairment
  • Stroke/TIA
• ENT:
  • Salivary gland dysfunction
  • Nosebleeds, nasal obstruction
• Others:
  • Lymphatic (evidence of hypersplenism)
  • Hypercalcaemia
  • Nephrolithiasis
  • Arthritis and joint damage

Although sarcoidosis cannot be prevented, some preventive measures may reduce complications. For example:

• Influenza vaccination
• Osteoporosis prophylaxis (steroid usage)
• Patient education (early treatment of extrapulmonary complications such as uveitis and arrhythmias)
• Smoking cessation advice (although evidence lacking to show it causes deterioration in pulmonary sarcoidosis)