Changes

January 2024 — minor update. A typographical error has been corrected.

Update

Goals

To support primary health care professionals to:

• Make a working diagnosis of sarcoidosis.
• Offer appropriate information and advice.
• Refer to an appropriate specialist.
• Offer support to people with chronic sarcoidosis.

Outcome measures

No outcome measures were found during the review of this topic.

Audit criteria

No audit criteria were found during the review of this topic.

QOF indicators

No QOF indicators were found during the review of this topic.

NICE quality standards

No NICE quality standards were found during the review of this topic.

QIPP — Options for local implementation

No QIPP indicators were found during the review of this topic.

Definition

Sarcoidosis is a multisystem disease of unknown aetiology.

• It is characterised by the presence of non-caseating granulomas (non-necrotising nodules of inflammation and scarring) in affected organs.
• The most commonly affected organs are the lungs (approximately 90% of people), followed by the skin.
• Other organs such as the eyes, brain, nervous system, liver, and heart may also be affected.

[NICE, 2017; Baughman, 2020; Thillai, 2021; DermNet, 2022; BMJ Best Practice, 2023]

Causes

• The cause of sarcoidosis is unknown, although it may be due to an inflammatory response to an environmental agent or infection.
  • Environmental exposures that have been suggested (but not confirmed) to increase the risk of sarcoidosis include mould, wood stoves, soil, tree pollen, inorganic particulates, insecticides, and silica.
  • Occupational exposures may also be a possible underlying cause in some cases, with healthcare workers, firefighters, and personnel working onboard aircraft carriers being identified as higher-risk groups.
  • Infectious agents that may increase the risk include some viral infections including herpes virus, and bacterial infections including Mycoplasma, Mycobacterium tuberculosis, non-tuberculous mycobacteria, Leptospira, Chlamydia pneumoniae, Borrelia burgdorferi, Pneumocystis jirovecii, and Propionibacterium species
• Genetic factors are also suspected as the disease is more common in certain geographical areas (such as Scandinavia) and among specific populations (such as African-Americans). Individuals whose monozygotic twin has sarcoidosis have an 80% increased risk of developing the disorder.
  • Numerous genetic risk loci have been identified including some HLA alleles.
• Autoimmunity has also been suggested as a potential mechanism.

[Baughman, 2020; DermNet, 2022; BMJ Best Practice, 2023]

Prevalence

Epidemiological studies have demonstrated that the prevalence of sarcoidosis varies across the world [Arkema, 2018; Baughman, 2020; Sikjær, 2021]:

• The peak age of onset appears to be 30–55 years, with studies consistently showing that women tend to be older at diagnosis.
• CKS did not locate any epidemiological data relating to sarcoidosis prevalence in the UK. However, sarcoidosis UK states that 'most specialists agree that around 1 in every 10,000 people have sarcoidosis in the UK' [Sarcoidosis UK, 2023].

Prognosis

• Approximately two-thirds of people with sarcoidosis experience disease remission within 2–5 years.
  • For the majority of people treatment is not required and remission is spontaneous.
  • Spontaneous remission occurs in 55–90% of people with radiographic stage I, and 40–70% of people with radiographic stage II disease — for further information, see the section on Disease staging.
  • Clinical features associated with remission within 2 years include erythema nodosum, hilar adenopathy, and anterior uveitis. 
• Most people with sarcoidosis will continue to live a normal life.
• Approximately 25% of people will develop residual fibrosis in the lungs or elsewhere.
• In 10–30% of people, the disease will become chronic and require prolonged treatment.
  • Factors associated with poor prognosis include the person being over 40 years old at presentation, being of African American or African Caribbean family origin, clinical signs such as lupus pernio, posterior uveitis, CNS involvement, cardiac involvement, severe hypercalcemia, nephrocalcinosis, and radiographic disease stages III and IV (spontaneous remission occurs in approximately 20% of people with stage III disease and is not expected in people with stage IV disease) — for further information, see the section on Disease staging.
• A reduction in life expectancy is observed in 6–8% of people with sarcoidosis. Interstitial lung disease and/or pulmonary hypertension cause up to 70% of sarcoidosis-related fatalities, with cardiac involvement causing most of the remaining deaths.

[NICE, 2017; Baughman, 2020; Thillai, 2021; DermNet, 2022; BMJ Best Practice, 2023]

Complications

Complications associated with sarcoidosis include:

• Fatigue — present in up to 80% of people with sarcoidosis, regardless of organ involvement.
• Depression, anxiety, and mood disturbance.
• Persistent dyspnoea.
• Pulmonary hypertension — a significant contributor to sarcoidosis morbidity and mortality.
• Pneumothorax.
• Bronchiectasis and Aspergillus colonization — can be complications of cavitary lesions.
• End stage lung disease, cor pulmonale, and respiratory distress — in people with severe, fibrotic pulmonary manifestations.
• Arrythmias and sudden death — in people with cardiac involvement.
• Medication-related complications — due to long-term corticosteroid treatment. For further information, see the CKS topic on Corticosteroids - oral.

[NICE, 2017; Baughman, 2020; Thillai, 2021; DermNet, 2022; BMJ Best Practice, 2023]

When should I suspect sarcoidosis?

• Be aware that although sarcoidosis most commonly affects the lungs (up to 90% of cases), the skin (up to 30% of cases), and/or the eyes (up to 30% of cases), almost any organ can be involved.
  • People with sarcoidosis may exhibit one affected organ system or several.
• Consider a diagnosis of sarcoidosis in a person presenting with:
  • An incidental finding of hilar adenopathy on a chest radiograph.
  • Incidental blood test findings:
    • Abnormal liver function tests (most commonly elevated alkaline phosphatase).
    • Abnormal urea and electrolyte tests.
    • Hypercalcaemia — caused by overproduction of vitamin D by sarcoid granulomas.
  • Clinical features such as:
    • Pulmonary features — dyspnoea, persistent cough, wheezing, and non-cardiac chest pain (characterised by chest tightness or pleuritic discomfort).
    • Skin changes — including hyperpigmentation, hypopigmentation, keloid reaction, lupus pernio, and erythema nodosum. For further details and photographs of skin involvement, please see the DermNet website.
    • Ocular abnormalities  —  most commonly uveitis, but any part of the eye can be involved.
    • Upper respiratory tract symptoms — including hoarseness, nasal obstruction, and persistent or recurrent sinusitis.
    • Peripheral lymphadenopathy — particularly affecting cervical submandibular lymph nodes.
    • Systemic symptoms — including anorexia, weight loss, fever, night sweats, fatigue, and diffuse myalgia.
    • Hepatic features —  hepatomegaly, upper right quadrant pain, fatigue, fever, pruritis, jaundice, and weight loss.
    • Cardiac symptoms — heart failure, arrhythmia, and syncope.
    • Neurological symptoms — facial palsy (caused by paralysis of cranial nerves, particularly VII), headaches, seizures, encephalopathy, and malaise.
    • Musculoskeletal symptoms — acute arthritis affecting the lower legs, ankles, knees, and fingers.
    • Renal features — kidney stones due to abnormal calcium metabolism.

What else might it be?

The features of sarcoidosis (including some X-ray findings) may present similarly to a number of conditions, including:

• Tuberculosis — more common in certain high-risk groups and/or suggested by exposure history. For further information, please see the CKS topic on Tuberculosis.
• Non-small-cell lung cancer — most common in people with a history of smoking. Suggested by pronounced haemoptysis and weight loss. For further information, please see the CKS topic on Lung and pleural cancers - recognition and referral.
• Lymphoma — suggested by cervical and supraclavicular lymphadenopathy. For further information, please see the CKS topic on Haematological cancers - recognition and referral.
• Congestive heart failure — suggested by breathlessness, fluid retention, and fatigue. For further information, please see the CKS topic on Heart failure - chronic.
• Idiopathic pulmonary fibrosis — uncommon in people under the age of 50 years. Suggested by breathlessness, dry cough, fatigue, and finger clubbing.
• Drug-induced fibrosis — suggested by exposure to checkpoint inhibitors and some biologics, including anti-TNFs and anti-interleukins.
• Pulmonary fibrosis caused by connective tissue diseases — such as lupus erythematosus, systemic sclerosis, granulomatosis with polyangitis, and granulomatosis with eosinophilia and polyangiitis (Churg-Strauss syndrome). Suggested by existing diagnoses and/or signs and symptoms of these disorders.
• Berylliosis — most common in people with history of employment in the nuclear and aerospace industries.
• Silicosis — most common in people with history of employment in the mining, quarrying, or stonemasonry industries.
• Hypersensitivity pneumonitis — can be triggered by exposure to a number of agents including birds, compost, peat, moss, metalworking fluids, or mouldy hay.
• Histoplasmosis — suggested by history of living in an endemic area, such as South America, continental Africa, and Madagascar. 

How should I assess someone with suspected sarcoidosis?

For all people with suspected sarcoidosis:

• Ask about symptoms to determine which organ systems may be affected.
  • Note: many people with incidental chest X-ray findings may be asymptomatic.
• Carry out a respiratory examination. Be aware that:
  • Reported respiratory symptoms may be mild in early disease.
  • Examination findings are often normal and are not considered to be a reliable measure of disease extent or morbidity.
  • Wheeze and stridor are occasionally observed.
  • End inspiratory crackles may occur with fibrotic sarcoidosis.
  • Hypoxaemia is present only in people with extensive fibrotic disease and/or pulmonary hypertension.
• Assess lung function (including spirometry and gas transfer analysis — either in primary care if available, or arrange specialist assessment):
  • Findings may be normal or show a restrictive or obstructive pattern. An isolated reduction in gas transfer may also be observed.
  • Note: breathlessness disproportionate to lung function impairment may suggest pulmonary hypertension or cardiac sarcoidosis.
    • Pulmonary hypertension is also suggested by shortness of breath, fatigue, weakness, angina, and syncope. 
• If there is pulmonary involvement, enquire about the person's employment history — berylliosis and silicosis present similarly to pulmonary sarcoidosis.
• Depending on the clinical features, consider testing to rule out tuberculosis as an alternative diagnosis. For further information, please see the CKS topic on Tuberculosis.
• Enquire about ocular symptoms and examine the eyes if appropriate.
  • Any part of the eye can be affected.
  • Anterior uveitis is the most common observation and is suggested by blurred vision, watery eyes, and photophobia.
  • Optic neuritis and conjunctival nodules are also some of the more common features of eye involvement.
• Ask about skin involvement and consider examining the skin, paying particular attention to the face, hands, and legs.
  
  • Erythema nodosum is the most common non-specific lesion in sarcoidosis. Presents as tender, erythematous nodules, mostly on the shins.
  • Lupus pernio is specific to sarcoidosis and is suggested by large bluish-red and dusky purple infiltrated nodules and plaque-like lesions on the nose, cheeks, ears, fingers and toes.
  • Other cutaneous manifestations include pruritis, purple-red or brown, thickened, circular skin plaques (associated with a chronic course), and sarcoidosis of pre-existing scars and tattoos.
• Enquire about fatigue and mood disturbance — these affect approximately 80% of people with sarcoidosis.
• Carry out an examination, directed by reported symptoms such as palpation of lymph nodes (peripheral lymphadenopathy affects more than 20% of people with sarcoidosis and typically presents with moderately enlarged, and non-tender lymph nodes), abdominal examination (hepatomegaly without tenderness present in approximately 20% of people with sarcoidosis), joint examination (synovial thickening usually absent), and neurological examination (to rule out other causes for any reported neurological features).
• Consider differential diagnoses.

How should I investigate suspected sarcoidosis?

• For people with suspected sarcoidosis:
  • Arrange a chest X-ray (if not already carried out).
    
    • Isolated bilateral hilar lymphadenopathy is the most frequent observation in people with sarcoidosis, while bilateral hilar and right paratracheal lymphadenopathy is the classical presentation. 
    • Diffuse infiltrates and disseminated nodules may also be observed.
    • Fibrosis is most commonly observed in the upper lobes.
    • Note: chest X-ray findings can be used to determine disease staging.
  • Arrange a chest CT scan with contrast and high-resolution cuts of the lungs, if a chest X-ray suggests sarcoidosis.
    • Typical nodal and lung CT findings, such as granulomatous inflammation along lymphatic tracts, support a diagnosis of sarcoidosis.
  • Arrange blood tests — liver function, urea and electrolytes, serum calcium levels, and full blood count should be assessed.
    • Alkaline phosphatase is commonly elevated.
    • Urea and serum creatinine may be elevated if there is renal involvement (uncommon).
    • Hypercalcaemia may also be observed.
    • Full blood count may identify lymphopenia (observed in approximately 50% of people with sarcoidosis), modest leukopenia, and/or anaemia.
  • Arrange a 12-lead ECG — conduction abnormalities may suggest cardiac involvement and/or pulmonary hypertension.

Management of people with suspected sarcoidosis

From age 18 years onwards.

Title

From age 18 years onwards.

Search strategy

Scope of search

A literature search was conducted for guidelines, systematic reviews and randomized controlled trials on primary care management of sarcoidosis. 

Search dates

Unrestricted - July 2023

Key search terms

Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline.

• exp sarcoidosis, sarcoid.tw., Schaumanns.tw., Boeck.tw., Besnier.tw.

Sources of guidelines

• National Institute for Health and Care Excellence (NICE)
• Scottish Intercollegiate Guidelines Network (SIGN)
• Royal College of Physicians
• Royal College of General Practitioners
• Royal College of Nursing
• NICE Evidence
• Health Protection Agency
• World Health Organization
• National Guidelines Clearinghouse
• Guidelines International Network
• TRIP database
• GAIN
• NHS Scotland National Patient Pathways
• New Zealand Guidelines Group
• Agency for Healthcare Research and Quality
• Institute for Clinical Systems Improvement
• National Health and Medical Research Council (Australia)
• Royal Australian College of General Practitioners
• British Columbia Medical Association
• Canadian Medical Association
• Alberta Medical Association
• University of Michigan Medical School
• Michigan Quality Improvement Consortium
• Singapore Ministry of Health
• National Resource for Infection Control
• Patient UK Guideline links
• UK Ambulance Service Clinical Practice Guidelines
• RefHELP NHS Lothian Referral Guidelines
• Medline (with guideline filter)
• Driver and Vehicle Licensing Agency
• NHS Health at Work(occupational health practice)

Sources of systematic reviews and meta-analyses

• The Cochrane Library:
  • Systematic reviews
  • Protocols
  • Database of Abstracts of Reviews of Effects
• Medline (with systematic review filter)
• EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

• NIHR Health Technology Assessment programme
• The Cochrane Library:
  • NHS Economic Evaluations
  • Health Technology Assessments
• Canadian Agency for Drugs and Technologies in Health
• International Network of Agencies for Health Technology Assessment

Sources of randomized controlled trials

• The Cochrane Library:
  • Central Register of Controlled Trials
• Medline (with randomized controlled trial filter)
• EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

• Bandolier
• Drug & amp; Therapeutics Bulletin
• TRIP database
• Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

• Department of Health
• Health Management Information Consortium(HMIC)

Patient experiences

• Healthtalkonline
• BMJ - Patient Journeys
• Patient.co.uk - Patient Support Groups

Sources of medicines information

The following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content.

• British National Formulary(BNF)
• electronic Medicines Compendium(eMC)
• European Medicines Agency(EMEA)
• LactMed
• Medicines and Healthcare products Regulatory Agency(MHRA)
• REPROTOX
• Scottish Medicines Consortium
• Stockley's Drug Interactions
• TERIS
• TOXBASE
• Micromedex
• UK Medicines Information

Stakeholder engagement

Our policy

The external review process is an essential part of CKS topic development. Consultation with a wide range of stakeholders provides quality assurance of the topic in terms of:

• Clinical accuracy.
• Consistency with other providers of clinical knowledge for primary care.
• Accuracy of implementation of national guidance (in particular NICE guidelines).
• Usability.

Principles of the consultation process

• The process is inclusive and any individual may participate.
• To participate, an individual must declare whether they have any competing interests or not. If they do not declare whether or not they have competing interests, their comments will not be considered.
• Comments received after the deadline will be considered, but they may not be acted upon before the clinical topic is issued onto the website.
• Comments are accepted in any format that is convenient to the reviewer, although an electronic format is encouraged.
• External reviewers are not paid for commenting on the draft topics.
• Discussion with an individual or an organization about the CKS response to their comments is only undertaken in exceptional circumstances (at the discretion of the Clinical Editor or Editorial Steering Group).
• All reviewers are thanked and offered a letter acknowledging their contribution for the purposes of appraisal/revalidation.
• All reviewers are invited to be acknowledged on the website. All reviewers are given the opportunity to feedback about the external review process, enabling improvements to be made where appropriate.

Stakeholders

• Key stakeholders identified by the CKS team are invited to comment on draft CKS topics. Individuals and organizations can also register an interest to feedback on a specific topic, or topics in a particular clinical area, through the Getting involved section of the Clarity Informatics website.
• Stakeholders identified from the following groups are invited to review draft topics:
  • Experts in the topic area.
  • Professional organizations and societies (for example, Royal Colleges).
  • Patient organizations, Clarity has established close links with groups such as Age UK and the Alzheimer’s Society specifically for their input into new topic development, review of current topic content and advice on relevant areas of expert knowledge.
  • Guideline development groups where the topic is an implementation of a guideline.
  • The British National Formulary team.
  • The editorial team that develop MeReC Publications.
• Reviewers are provided with clear instructions about what to review, what comments are particularly helpful, how to submit comments, and declaring interests.

Patient engagement

Clarity Informatics has enlisted the support and involvement of patients and lay persons at all stages in the process of creating the content which include:

• Topic selection
• Scoping of topic
• Selection of clinical scenarios
• First draft internal review
• Second draft internal review
• External review
• Final draft and pre-publication

Our lay and patient involvement includes membership on the editorial steering group, contacting expert patient groups, organizations and individuals.

Evidence exclusion criteria

Our policy

Scoping a literature search, and reviewing the evidence for CKS is a methodical and systematic process that is carried out by the lead clinical author for each topic. Relevant evidence is gathered in order that the clinical author can make fully informed decisions and recommendations. It is important to note that some evidence may be excluded for a variety of reasons. These reasons may be applied across all CKS topics or may be specific to a given topic.

Studies identified during literature searches are reviewed to identify the most appropriate information to author a CKS topic, ensuring any recommendations are based on the best evidence. We use the principles of the GRADE and PICOT approaches to assess the quality of published research. We use the principles of AGREE II to assess the quality of published guidelines.

Standard exclusions for scoping literature:

• Animal studies
• Original research is not written in English

Possible exclusions for reviewed literature:

• Sample size too small or study underpowered
• Bias evident or promotional literature
• Population not relevant
• Intervention/treatment not relevant
• Outcomes not relevant
• Outcomes have no clear evidence of clinical effectiveness
• Setting not relevant
• Not relevant to UK
• Incorrect study type
• Review article
• Duplicate reference

Organizational, behavioural and financial barriers

Our policy

The CKS literature searches take into consideration the following concepts, which are discussed at the initial scoping of the topic.

• Feasibility
  • Studies are selected depending on whether the intervention under investigation is available in the NHS and can be practically and safely undertaken in primary care.
• Organizational and Financial Impact Analysis
• Studies are selected and evaluated on whether the intervention under investigations may have an impact on local clinical service provision or national impact on cost for the NHS. The principles of clinical budget impact analysis are adhered to, evaluated and recorded by the author. The following factors are considered when making this assessment and analysis.
  • Eligible population
  • Current interventions
  • Likely uptake of new intervention or recommendation
  • Cost of the current or new intervention mix
  • Impact on other costs
  • Condition-related costs
  • In-direct costs and service impacts
  • Time dependencies
• Cost-effectiveness or cost-benefit analysis studies are identified where available. 

We also evaluate and include evidence from NICE accredited sources which provide economic evaluations of recommendations, such as NICE guidelines. When a recommended action may not be possible because of resource constraints, this is explicitly indicated to healthcare professionals by the wording of the CKS recommendation.

Declarations of interest

Our policy

Clarity Informatics requests that all those involved in the writing and reviewing of topics, and those involved in the external review process to declare any competing interests. Signed copies are securely held by Clarity Informatics and are available on request with the permission of the individual. A copy of the declaration of interest form which participants are asked to complete annually is also available on request. A brief outline of the declarations of interest policy is described here and full details of the policy is available on the Clarity Informatics website. Declarations of interests of the authors are not routinely published, however competing interests of all those involved in the topic update or development are listed below. Competing interests include:

• Personal financial interests
• Personal family interest
• Personal non-financial interest
• Non-personal financial gain or benefit

Although particular attention is given to interests that could result in financial gains or losses for the individual, competing interests may also arise from academic competition or for political, personal, religious, and reputational reasons. An individual is not obliged to seek out knowledge of work done for, or on behalf of, the healthcare industry within the departments for which they are responsible if they would not normally expect to be informed.

Who should declare competing interests?

Any individual (or organization) involved in developing, reviewing, or commenting on clinical content, particularly the recommendations should declare competing interests. This includes the authoring team members, expert advisers, external reviewers of draft topics, individuals providing feedback on published topics, and Editorial Steering Group members. Declarations of interest are completed annually for authoring team and editorial steering group members, and are completed at the start of the topic update and development process for external stakeholders.

Competing interests declared for this topic:

None.