Sarcoidosis
- DOI:
- 10.1093/med/9780198703860.003.0045
Epidemiology, aetiology, and immunopathology
Definition
• A multi-system disorder of unknown cause, likely resulting from the interplay of environmental and genetic factors
• Characterized by non-caseating granulomata and CD4+ Th1-biased T-cell response in affected organs
• Commonly involves the respiratory system but can affect nearly all organs
• 50–60% of people have spontaneous remissions; others may develop chronic, and sometimes progressive, disease.
Epidemiology
Incidence varies across population studies, from 5 to 100/100, 000, according to geographic distribution. UK incidence is about 5–10/100, 000. Commoner in African Americans, West Indians, and the Irish. Commonly presents between ages of 20 and 40. Unusual in children and the elderly. Typically more aggressive disease in black populations than in Caucasians—higher incidence of skin disease, peripheral lymphadenopathy, bone marrow, and liver involvement; higher relapse rates and worse long-term prognosis.
Aetiology
Sarcoidosis is the result of an abnormal immunological response to a benign environmental trigger(s) or antigen(s). The environmental trigger is likely to be a poorly degradable antigen but not a specific antigen or infectious agent. This abnormal immunology occurs in a genetically predisposed host.
Genetics
Familial and ethnic clustering of cases suggest a genetic predisposition. Best evidence of HLA association comes from large multicentre ACCESS study, showing HLA-DRB1*1101 is associated with susceptibility to disease in blacks and whites; HLA-DRB1*0301 has been associated with acute and remitting disease. Genome-wide association studies have identified polymorphisms in BTNL2, ANXA11, and FAM178A as susceptibility genes in both familial and sporadic cases.
Immunopathology
• Unknown antigen triggers CD4 (helper) T-cell activation and expansion. This response is exaggerated and Th1-biased, with resultant interferon γ and IL2 production from these T-cells
• Activated T-cells proliferate and release mediators, attracting additional inflammatory cells, with concomitant macrophage activation and aggregation
• This leads to immune granuloma formation, which is enhanced by interferon γ
• Granulomata themselves cause increased local fibroblast stimulation and hence eventual fibrosis
• Metabolic activity of macrophages causes raised ACE levels in serum, lung tissue, and bronchoalveolar fluid. Increase in T-cell activity causes B-lymphocyte stimulation, which can cause raised serum immunoglobulins and immune complexes
• In most patients, response resolves over 2–5y.
Delayed-type hypersensitivity reactions are depressed
in sarcoidosis. This is thought to be due to the migration of activated lymphocytes to the active compartment (lungs), with resultant peripheral blood lymphopenia. Seen as a decreased response to tuberculin, mumps virus, and Candida albicans antigens. This is not thought to be clinically significant.
Sarcoid-like reactions
are reported in association with malignancy (mainly lymphoma, cervical, liver, lung, testes, and uterus). Non-caseating pulmonary granulomas are found, but there are no other symptoms or signs of sarcoidosis.
The main differential diagnoses of granuloma on a lung biopsy are shown in Box 45.1.
Further information
Iannuzzi MC. Advances in genetics of sarcoidosis. Proc Am Thorac Soc 2007;4:457–60.Find this resource:
Schurmann M et al. Familial sarcoidosis is linked to the major histocompatibility complex region. Am J Respir Crit Care Med 2000;162:861–4.Find this resource:
Schurmann M et al. HLA-DQB1 and HLA-DPB1 genotypes in familial sarcoidosis. Respir Med 1998;92:649–52.Find this resource:
Chest disease: clinical features
More than 90% of patients with sarcoidosis have thoracic involvement, with an abnormal CXR (see Boxes 45.2 and 45.3). Pulmonary sarcoidosis can be an incidental CXR finding in ~30% of patients. There is spontaneous remission in two-thirds, and 10–30% have a chronic course.
Clinical features
There are probably at least two distinct clinical courses:
• Löfgren’s syndrome Acute disease, which is usually self-limiting. Presents with fever, bilateral hilar lymphadenopathy, erythema nodosum, and arthralgia. Occurs particularly in Caucasians. Has a good prognosis and resolves completely and spontaneously in 80% within 1–2y. A minority may develop lung disease
• Persistent or progressive infiltrative lung disease.
Hilar/mediastinal lymphadenopathy
May be asymptomatic or cause cough or chest pain. Usually bilateral and symmetrical, rarely unilateral and asymmetrical (this would suggest alternative diagnosis more likely). Can be associated with systemic symptoms of malaise and arthralgia, which are helped by NSAIDs. Benign course.
Important to exclude other causes of lymphadenopathy such as TB and lymphoma (see Box 45.3). May need CT and lymph node aspirate or biopsy.
Does not require systemic steroid treatment.
Stage I: 85% resolve spontaneously over 2y; 15% develop lung infiltrates. The average time for bilateral hilar lymphadenopathy resolution is 8 months.
Interstitial lung involvement
May be asymptomatic or cause morbidity and mortality, with dyspnoea, cough, chest ache, or frank pain, malaise, fatigue, and impaired QoL. Rarely have crackles or clubbing on examination. Pulmonary infiltrates on CXR. Can return to normal over time or progress to fibrosis and respiratory failure. Lung function tests may be normal or may show a restrictive defect with reduced transfer factor.
Differential diagnosis: other ILD, malignancy, infection.
Seeing a patient with possible sarcoidosis in clinic
• Make diagnosis—clinically, HRCT ± histology
• Assess extent/severity/presence of extrapulmonary involvement—CXR, PFT, ECG, eyes, rash, renal function, serum calcium, liver function, immunoglobulins, and ACE (last two can be raised in active sarcoidosis)
• Stable or progressive?—CXR, PFT (VC ± kCO), oximetry, ACE, urea (if renal involvement)
• Treatment?
Chest disease: diagnosis and monitoring
Diagnosis
is based on a characteristic clinical picture, plus:
• Histological evidence of non-caseating granuloma in any tissue
• Characteristic picture on imaging (thoracic HRCT scan or gallium scan)
• Lymphocytosis on BAL.
Other diseases capable of producing similar clinical and histological picture, particularly TB and lymphoma, should be excluded.
Investigations
• HRCT Micronodules in a subpleural and bronchovascular distribution. Fissural nodularity and bronchial distortion. Irregular linear opacities, ground-glass shadowing related to bronchovascular bundles, and nodular or ill-defined shadows. Air trapping due to small airway granulomata common. Endobronchial disease in 55%. Minority has UIP pattern, associated with worse prognosis. Hilar and mediastinal lymphadenopathy. CT-guided FNA of subcarinal or mediastinal nodes may be possible and yield a tissue diagnosis
• Bronchoscopy (TBB, TBNA, bronchial biopsy, EBUS, or BAL) may not be necessary if no diagnostic doubt. May be important to exclude infectious agents. Positive yield of bronchial biopsy is 41–57%. Higher if visible abnormal mucosa. Positive yield of TBB is 40–90% (yield still high even if lungs appear normal on HRCT). Initial procedure of choice for suspected pulmonary sarcoidosis. TBNA of mediastinal lymph nodes yields a diagnosis in 63–90% of cases. TBB and TBNA have a higher yield together than either alone. However, presence of non-caseating granulomas on TBB or bronchial biopsy more significant than on lymph node sampling, as granuloma can accompany tumour infiltration of lymph nodes. BAL in sarcoidosis shows a CD4:CD8 ratio of >3.5. A lymphocytosis of >2 × 105cells/mL supports the diagnosis but is not diagnostic (also seen in HP and drug-induced alveolitis)
• Mediastinoscopy for central or paratracheal nodes or open lung biopsy: 90% positive yield. May be necessary to exclude lymphoma. Surgical biopsy is not usually necessary, but, if other procedures have not yielded a definitive diagnosis, it may be required. Lymph node ± lung (usually via VATS) can be biopsied
• Biopsy other affected areas, such as skin, liver, etc., if indicated, as these may be easier to biopsy in order to make a diagnosis
• Mantoux/Heaf test is typically grade 0 in sarcoidosis (peripheral cutaneous anergy to tuberculin due to migration of T-cells to active sites of disease). Positive Mantoux or Heaf test make sarcoidosis a less likely diagnosis although does not necessarily make TB more likely. Heaf testing not widely used now
• Kveim test No longer performed clinically, due to risks of transmissible diseases. It involved injecting homogenized splenic tissue from a patient with sarcoidosis to see if a granulomatous reaction occurred.
There is no single measurement to assess all the aspects of patients with sarcoidosis. Clinical examination and serial measurements are key.
• PFT Pulmonary sarcoidosis gives a restrictive defect with decreased TLC and VC. TLCO provides the most sensitive measurement of change, although many use a properly performed VC as an alternative. Likely to improve with steroids. Airflow obstruction may also occur
• CXR may improve with time or treatment
• HRCT can help with determining burden of active disease
• ACE levels increased in up to 80% of patients with acute sarcoidosis although can be normal in active disease. It may be a surrogate marker of the total granuloma burden. Levels become normal as disease resolves. Can be useful to monitor the clinical course, if activity is uncertain, but levels should not be used in isolation to determine treatment. Levels suppressed by steroids, and, when steroids are stopped, levels usually increase, unrelated to sarcoidosis activity. This is not a specific test. False positives include TB
• Calcium may rise with active sarcoidosis or in the summer months. This may cause renal impairment, so urea or creatinine should also be checked
• BAL not performed routinely to assess progress of sarcoidosis, but reduction in lymphocytosis would indicate improvement
• PET scan may be positive in areas of disease activity. Not reliable for studying brain or heart. Limited studies of serial data
• Gallium scan rarely used now, as non-specific and expensive. Areas of active inflammation are positive, with a classic ‘panda pattern’. Positive areas soon become negative with steroid use. Bowel and liver positive anyway, so disease cannot be charted in these areas.
Most patients with pulmonary sarcoidosis do not require treatment. Asymptomatic CXR infiltrates are usually just monitored. The BTS have recently issued guidelines (see Box 45.4).
Starting drug treatment
• When required, treatment is usually with steroids initially. Good evidence for short- to medium-term improvement in symptoms, respiratory function, and radiology, but long-term benefits less clear
• Give high doses, such as 30mg prednisolone/day, to control active disease. Rarely need >40mg/day. Usually give this high dose for 2–3 weeks, and then reduce if there has been a response
• Maintenance dose of around 5–20mg to control symptoms and prevent progression of disease. Leave on this dose for a few months, and then slowly reduce steroid dose further. Maintain on low dose of prednisolone (5–7.5mg/day or alternate days) for prolonged period of up to 12 months to consolidate resolution, before considering complete withdrawal. Remember bone protection
• Some patients, e.g. with progressive pulmonary sarcoidosis, may require longer treatment (years) of low-dose prednisolone to prevent relapse
• Inhaled steroids are of limited efficacy in sarcoidosis but may be useful if there is cough or bronchial hyperreactivity
• Relapses often occur when treatment is stopped and may require the reintroduction of steroids or the increase of steroid dose. Duration and dose of steroids is dictated by site and response to treatment
• If steroid treatment fails or sarcoidosis life-threatening, other immunosuppressive regimes may be indicated (see Box 45.5), e.g. pulsed high-dose IV methylprednisolone, especially for neurosarcoidosis
• In cases where prolonged immunosuppression is required, or if steroid side effects cannot be tolerated, other immunosuppressive drugs should be considered. Possibilities include azathioprine and methotrexate. There are limited data for their use in sarcoidosis
• Patients who have troublesome symptoms related to sarcoidosis, such as arthralgia, skin disease, fever, sweats, ocular symptoms, systemic symptoms such as fatigue, may require symptomatic steroid treatment. Lower initial doses, such as 20mg/day, are likely to be sufficient to gain symptomatic control, and doses can then be reduced
• Prescribe gastric and bone protection with steroids when necessary.
Other drugs used in sarcoidosis
(See 
p. [link] for more information regarding immunosuppressive drugs.)
If there is progressive pulmonary sarcoidosis refractory to steroids, consider:
• Methotrexate Given once/week 10–15mg PO for 6-month trial. Use instead of, or in addition to, low-dose prednisolone. Avoid if hepatic or renal failure. Side effects: GI upset, stomatitis, pneumonitis, myelosuppression. Teratogenic. Monitor FBC and MCV, AST, ALT every 2 weeks for 3 months, then monthly. Do not use for >2y without review. Useful for chronic sarcoidosis and cutaneous disease
• Azathioprine Used in neurosarcoidosis and stages II/III pulmonary sarcoidosis with partial/no steroid response. 100–150mg/day. Use instead of, or in addition to, low-dose prednisolone. Side effects: myelosuppression, GI upset, stomatitis, idiosyncratic reaction—fever, rash. Low oncogenic potential. No gonadal toxicity. Check FBC every 2 weeks for 3 months, then monthly. Thiopurine methyltransferase (TPMT) testing should be performed prior to commencement (see
pp. [link]–[link])• Anti-malarials Hydroxychloroquine 200mg od/bd. For skin and particularly hypercalcaemia. Steroid-sparing. Can be given with steroids and other immunosuppressant in severe sarcoidosis. Side effects: rarely ocular toxicity
• Others Leflunomide, ciclosporin, thalidomide, TNF-α inhibitors (etanercept, infliximab, adalimumab, golimimumab), to be used in conjunction with specialist centres.
Prognosis
There are no prognostic markers in sarcoidosis, apart from:
• Good prognosis Löfgren’s syndrome has complete resolution in 80% of people. Associated with HLA-DQB1*0201
• Poorer prognosis with chronic disease Lupus pernio, nasal mucosa involvement, chronic uveitis, chronic hypercalcaemia, nephrocalcinosis, neural involvement, age >40, and black race
• Prognosis according to CXR appearance:
• Stage II: 50% cases recover spontaneously in 2y; 30–40% require systemic steroids; 10–15% require long-term steroids
• Stage III: worse prognosis. Only 30% show significant improvement with steroids
• Gene expression from mRNA profiling has shown early promise in differentiating progressive from non-progressive disease.
Systemic symptoms
are common, such as fever, sweats, loss of appetite, weight loss, fatigue, malaise, chest pain, dyspnoea, and cough. Polyarthralgia often affects the knees, ankles, wrists, and elbows and can be improved by NSAIDs.
Hypercalcaemia
Granulomata convert vitamin D3 to active 1, 25-dihydroxycholecalciferol. This causes enhanced calcium absorption from intestine. Sunlight also increases levels of vitamin D and calcium. High calcium may cause systemic effects and is often associated with renal damage and hypercalciuria. Commoner in Caucasians and in men.
Treatment
If mildly raised, limit dietary calcium intake; avoid sun exposure, and drink plenty of fluids. Otherwise, steroids, often low dose once calcium level controlled (should be within 2 weeks—if not, investigate for other cause for hypercalcaemia). Decrease dose when calcium level satisfactory. Some patients may only need steroids during the summer months. Hydroxychloroquine can also be used.
Skin
Erythema nodosum
Raised papules, nodules, or plaques, usually on shins. Also tender, indurated, or bruised appearance. Firm and often have shiny appearance. Nodular change involving different tattoo colours recognized and is characteristic of sarcoidosis. Sarcoid tissue may arise in old scars or cause scar hypertrophy.
Eye
Uveitis (acute or chronic), episcleritis, scleritis, glaucoma, conjunctivitis, and retinal involvement
can occur. May be asymptomatic or cause painful red eye, with photophobia, lacrimation, and blurred vision. Pupil irregular or constricted. Untreated, can cause visual impairment.
Lacrimal involvement in sarcoidosis gives keratoconjunctivitis sicca—dry eye with diminished tear secretion. Painful red eyes. Treat with artificial tears.
Heart
Cardiac sarcoidosis occurs in 5% of patients with pulmonary disease. Post-mortem studies show cardiac sarcoidosis is present in 25% so is often undiagnosed. Patients may present with chest pain or, more commonly, are found to have conduction defects on the ECG. These may be benign and asymptomatic, like first-degree heart block, but more significant arrhythmias can occur, the first indication of which may be sudden death. Myocardial granulomata can occur in any part of the heart. Commonly, they occur in the interventricular septum where they can affect nodal and conducting tissue. The LV wall can be affected, with fibrosis causing reduced compliance and contractile difficulties, leading to cardiac failure. Aneurysms can form, and pericarditis can occur. Valvular dysfunction due to infiltration of the papillary muscles is rare. The clinical course can be uncertain.
Diagnosis
Echo may show signs of cardiomyopathy—usually restrictive. MRI, technetium scan, or gallium scan show non-segmental fixed defects. Biopsy is diagnostic but can be difficult, as sarcoidosis is patchy. Not recommended in general. ECG and 24h tape may be helpful in identifying potentially fatal arrhythmias and conduction defects.
Treatment
Must be treated with systemic steroids 20–40mg prednisolone/day, which improve symptoms and ECG and echo features. These should be slowly reduced, but intractable arrhythmias may need continued high dosage. May need other immunosuppressants. Investigate with 24h tape and electrophysiological studies if uncertain. Amiodarone, a pacemaker, implantable defibrillator, or heart transplant may be necessary.
Kidney
A degree of renal involvement is found in 35% of patients with sarcoidosis. Rarely can present with renal failure (especially following onset of hypercalcaemia), obstructive uropathy, nephrolithiasis, or urinary tract disorder. Nephrocalcinosis is a common cause of chronic renal failure. Often associated hypercalcaemia or other manifestation of sarcoidosis.
CNS
Involved in 4–18% of patients. Can affect any part of the peripheral or central nervous system. Can present as a peripheral nerve or cranial nerve lesion. Most common is lower motor neurone facial nerve palsy, with optic nerve involvement being next most common. Mononeuritis multiplex recognized. May be less specific, with psychiatric features. Hypothalamic granulomata may cause diabetes insipidus, appetite disturbance, or hypersomnolence.
Musculoskeletal
Arthralgia is common in sarcoidosis, but arthritis is unusual. Arthralgia commonly affects the ankles and feet in men, but also hands, wrists, and elbows. A subacute proximal myopathy can occur as well as bone cysts, especially of terminal phalanges. The latter show little response to systemic steroids.
GI
Haematological
Splenomegaly can occur and may be massive, causing abdominal discomfort. A massive spleen may require splenectomy to avoid rupture. Associated anaemia, neutropenia, and thrombocytopenia. Lymphopenia often seen.
ENT
Nasal or laryngeal granuloma. Sinus invasion. Parotid and other salivary gland enlargement, dry mouth.
Further information
Baughman RP et al. A concise review of pulmonary sarcoidosis. Am J Respir Crit Care Med 2011;183:573–81.Find this resource:
Dempsey OJ et al. Sarcoidosis. BMJ 2009;339:620–5.Find this resource:
American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders statement on sarcoidosis. Eur Respir J 1999;14:735–7.Find this resource:
BTS interstitial lung disease guideline 2008. http://www.brit-thoracic.org.uk/portals/0/guidelines/dpldguidelines/thorax%20sept%2008.pdf.
Judson MA et al. Two year prognosis of sarcoidosis: the ACCESS experience. Sarcoidosis Vasc Diffuse Lung Dis 2003;20:204–11.Find this resource:
World Association of Sarcoidosis and other Granulomatous Disorders website. http://www.wasog.org/.
Lockstone HE et al. Gene set analysis of lung samples provides insight into pathogenesis of progressive, fibrotic pulmonary sarcoidosis. Am J Respir Crit Care Med 2010;181:1367–75.Find this resource:
