Sarcoidosis

Multifactorial Origin

• Sarcoidosis arises from a complex interplay between environmental, infectious, genetic, and immunological factors.
• No single causative agent has been identified, supporting the theory of variable triggers in genetically susceptible individuals.

Environmental and Occupational Exposures

• Exposure to beryllium can produce chronic beryllium disease, clinically and histologically indistinguishable from sarcoidosis.
• Other implicated exposures include:
  • Silica and inorganic dust
  • Insecticides, moulds, and combustion by-products
  • Rescue and recovery work at the World Trade Center site (increased sarcoidosis risk observed)

Infectious Agents

• Propionibacterium acnes and Mycobacterium tuberculosis DNA have been detected in sarcoid tissues.
• Borrelia burgdorferi and Mycoplasma species have been considered possible triggers in some populations.
• Granulomatous disease resembling sarcoidosis has been reported in transplant recipients, suggesting infective or immune reconstitution mechanisms.

Genetic Susceptibility

• Familial aggregation observed; first-degree relatives have increased risk.
• Strong associations with HLA class II alleles, particularly HLA-DRB1 and HLA-DQB1.
• Non-HLA genetic loci involved include TNF gene polymorphisms and annexin A11.
• Ethnic differences in genetic profiles may influence disease expression and severity.

Immune Dysregulation

• Characterised by a Th1-predominant immune response with elevated IL-2, interferon-gamma, and TNF-α.
• Granulomas form due to localised aggregation of CD4+ T cells and macrophages.
• B cell activation and hypergammaglobulinaemia may contribute to disease activity.

Endogenous Autoantigens and Molecular Mimicry

• Hypothesis suggests self-proteins (e.g., vimentin, heat shock proteins) may trigger immune responses through molecular mimicry.
• Modified autoantigens presented in the context of chronic inflammation could sustain granuloma formation.

Granuloma Formation

• The defining histological feature of sarcoidosis is the presence of tightly organised, non-caseating granulomas.
• These granulomas consist centrally of multinucleated giant cells and epithelioid macrophages, with peripheral infiltration of CD4+ T lymphocytes and scattered CD8+ T cells.
• The local immune response is dominated by T-helper type 1 (Th1) cells producing interleukin-2 (IL-2), interleukin-12 (IL-12), and interferon-gamma, which are critical in promoting and maintaining granulomatous inflammation.

T-cell Mediated Immune Response

• CD4+ T lymphocytes accumulate at sites of granuloma formation, and the CD4/CD8 ratio is often elevated, particularly in bronchoalveolar lavage fluid (BALF), where ratios ≥3.5 are commonly seen.
• However, up to 40% of patients with pulmonary sarcoidosis may exhibit normal or reduced CD4/CD8 ratios, limiting its diagnostic utility.
• Th1 cytokines and tumour necrosis factor-alpha (TNF-α) are essential mediators; elevated TNF-α expression underpins the chronic inflammatory process and supports the rationale for anti-TNF therapies (e.g. infliximab, pentoxifylline) in refractory disease.

Role of Macrophages

• Alveolar macrophages are key effector cells in sarcoidosis, secreting a range of pro-inflammatory cytokines (TNF-α, IL-12, IL-15) and growth factors that perpetuate T-cell activation.
• Macrophages also contribute to granuloma stability and the fibrotic transition in chronic disease.
• The persistent presence of a poorly degradable antigen is believed to drive ongoing macrophage and T-cell activation, leading to oligoclonal immune responses.

B-cell Involvement and Humoral Activity

• Although T-cell responses predominate, B cells are also involved.
• Hypergammaglobulinaemia is common in active sarcoidosis, reflecting polyclonal B-cell activation.
• Soluble HLA class I antigen levels are elevated in serum and BALF and correlate with ACE levels, particularly in active disease.
• A subset of patients has shown clinical benefit from anti-CD20 monoclonal antibody therapy, indicating a pathogenic role for B cells in some cases.

Cellular and Serological Markers of Inflammation

• Biomarkers such as KL-6 (a mucin-like glycoprotein) and surfactant protein D (SP-D), produced by alveolar type II and bronchiolar epithelial cells, are elevated in pulmonary sarcoidosis.
• These markers correlate with lymphocyte percentages in BALF but do not consistently align with chest radiographic findings, ACE levels, or CD4/CD8 ratios.
• Elevated KL-6 levels may predict more extensive pulmonary parenchymal involvement.

Th17 Cells and Immune Regulation

• Th17 cells, a subset of CD4+ T cells producing IL-17, have been implicated in disease progression.
• These cells have been found in the lungs, BALF, and peripheral blood of patients, particularly in those with active sarcoidosis.
• Their presence suggests a broader spectrum of immune dysregulation beyond Th1 responses.

Tissue-Specific Pathophysiology

• In cutaneous sarcoidosis, granulomas also contain mast cells, fibroblasts, and monocytes in addition to typical macrophages and lymphocytes.
• The skin manifestations reflect similar immunological mechanisms but may be influenced by local microenvironmental factors.

Global Incidence and Prevalence

• Sarcoidosis occurs worldwide, but its incidence and prevalence vary significantly by region, ethnicity, and sex.
• In Scandinavian countries, incidence rates range from 11 to 24 per 100,000 individuals per year.
• Japan has one of the lowest reported incidences, approximately 1.3 cases per 100,000 individuals.
• In South Korea, prevalence ranges between 1–5 per 100,000, whereas in Sweden, it may reach 140–160 per 100,000.
• In developing regions like Africa, India, and China, the true burden is likely underestimated due to misdiagnosis—often as tuberculosis.

United States Epidemiology

• Incidence among White Americans is around 11 per 100,000 population, compared to 34 per 100,000 among African Americans.
• African Americans have a 10-fold higher prevalence than Whites and are more prone to chronic and severe disease.
• Among African American patients, approximately 20% report a family history of sarcoidosis versus 5% among White patients.
• First-degree relatives of affected African American patients have a 2.5-fold increased risk.
• Occupational exposure has also been linked to disease: working on the World Trade Center debris pile after 9/11 was associated with increased sarcoidosis risk (odds ratio 9.1), whereas dust cloud exposure alone was not.

Age and Sex Distribution

• Sarcoidosis predominantly affects adults aged 25–35 years, with a secondary peak in women between 45–65 years.
• Overall, women are more frequently affected than men, with a male-to-female ratio of approximately 1:2.
• Women have higher rates of extrapulmonary involvement, especially ocular and neurological manifestations, and are more likely to present with erythema nodosum.
• Men are more frequently hypercalcaemic and may present at an earlier age.

Ethnic and Racial Variations in Clinical Features

• African Americans are more likely to experience extrathoracic organ involvement including skin (excluding erythema nodosum), liver, bone marrow, lymph nodes, and eyes.
• Chronic uveitis is more commonly seen in Black patients in the US.
• Lupus pernio is especially prevalent in individuals of Puerto Rican descent.
• Erythema nodosum is frequently observed among Europeans.
• In Japan, cardiac and ocular sarcoidosis appear to be more prevalent.

Strong Risk Factors

• Age at presentation typically between 20–50 years, though incidence in older adults is increasing.
• Family history significantly raises risk, with studies showing increased incidence in first- and second-degree relatives.
• Scandinavian ancestry is associated with a higher incidence.
• African ancestry is associated with more severe disease and higher mortality.
• Sarcoidosis is more frequent in non-smokers than smokers.
• Female sex is associated with more extrapulmonary involvement, although data on overall sex predilection are mixed.

Pulmonary and Constitutional Symptoms (Common)

• Dry cough is often the initial respiratory symptom.
• Dyspnoea is insidious in onset, potentially progressive.
• Fatigue is common, under-recognised, and may be disproportionate to radiographic or pulmonary function test findings. If severe, pulmonary hypertension or heart failure should be considered.
• Arthralgia, particularly in knees, ankles, and wrists, is frequently reported without synovial thickening.
• Wheezing and rhonchi may occur due to airway hyper-reactivity.
• Lymphadenopathy, especially cervical and submandibular, is non-tender.
• Fever and anorexia can be part of the systemic presentation, reported in up to 45% of cases.

Ocular Symptoms

• Occur in 30–60% of patients; bilateral granulomatous anterior uveitis is most common.
• Symptoms include photophobia, blurred vision, pain, redness, floaters, and dry eyes.
• Periocular mass lesions may result in proptosis or diplopia.
• Uveitis is often associated with elevated CD4/CD8 ratios in vitreous lymphocytes.
• Diagnostic criteria stratify ocular sarcoidosis as definite, presumed, probable, or possible based on biopsy, radiographic, ocular, and laboratory findings.

Cutaneous Symptoms

• Erythema nodosum is a common nonspecific manifestation, more prevalent in European women, and typically self-limiting.
• Lupus pernio, an indurated violaceous facial lesion, is more common in Black women and individuals from Puerto Rico. It is associated with chronic pulmonary and upper airway involvement and portends a poor prognosis.
• Other specific lesions include papular, nodular, scar, plaque, lichenoid, and ulcerative forms.
• Macular or papular lesions are the most frequent type, particularly in Black women, often appearing on the face, neck, and limbs.

Cardiac Symptoms

• Arrhythmias, including ventricular tachyarrhythmias and heart block, may present as initial features.
• Risk of sudden death is heightened in cardiac sarcoidosis.
• Fragmented QRS complexes or bundle branch block on ECG may prompt further work-up.
• Elevated BNP or ANP may support cardiac involvement.
• Cardiac MRI is the preferred imaging modality.

Neurological and Endocrine Symptoms

• Facial palsy, especially in the setting of parotitis and uveitis (Heerfordt’s syndrome), may be an early sign.
• Seizures, headache, and hypopituitarism may reflect central nervous system sarcoidosis.
• Diabetes insipidus is the most common endocrine complication, followed by hyperprolactinaemia.
• Myelitis, leptomeningitis, and neuropsychiatric symptoms (e.g. encephalopathy, mood disorders) may also occur.

Other Historical Features (Uncommon but Relevant)

• Chest wall pain due to costochondritis may mimic musculoskeletal causes.
• Haemoptysis is rare and usually mild unless complicated by mycetoma in advanced disease.
• Weight loss and low-grade fever may mimic malignancy or tuberculosis.
• Hepatomegaly, when present, is typically non-tender.
• History of beryllium exposure should raise suspicion for chronic beryllium disease as a differential.

Psychiatric and Quality-of-Life Considerations

• High burden of fatigue and psychiatric morbidity, including major depressive disorder, anxiety, bipolar disorder, and panic disorder, has been reported.
• One randomised trial demonstrated that dexmethylphenidate hydrochloride may reduce sarcoidosis-associated fatigue.

Pulmonary Examination

• Chest examination is frequently unremarkable, especially in early stages.
• Wheezing may be heard in cases of significant airway involvement or extrinsic bronchial compression from enlarged lymph nodes.
• Crackles (rales) are atypical and should prompt consideration of alternative or coexisting diagnoses (e.g., pulmonary fibrosis or infection).
• Signs such as clubbing or hypoxaemia are rare and typically indicate advanced pulmonary disease.

Cutaneous Findings

• Erythema nodosum presents as tender, erythematous nodules, most often on the anterior shins. It is non-specific but strongly associated with acute sarcoidosis and is considered a favourable prognostic marker.
• Lupus pernio appears as violaceous, indurated plaques or nodules, particularly on the nose, cheeks, lips, ears, and digits. It is strongly associated with chronic pulmonary and upper respiratory tract involvement and indicates a poorer prognosis.
• Other specific skin lesions include:
  • Papular and maculopapular eruptions—often on the face, neck, or scars/tattoos
  • Nodular sarcoidosis, plaque-like lesions, and subcutaneous nodules
  • Hypopigmented or hyperpigmented lesions, especially in patients with darker skin
• Lesions may mimic other dermatological disorders (e.g., granulomatous rosacea).

Ocular Signs

• Anterior uveitis is the most frequent ocular manifestation, often bilateral and granulomatous.
• Key findings may include:
  • Photophobia
  • Redness and pain
  • Blurred vision
  • Keratitic precipitates or iris nodules
  • Conjunctival nodules
• Orbital involvement may present with proptosis, diplopia, or periocular disfigurement.
• Ocular inflammation is associated with an elevated CD4/CD8 ratio in vitreous lymphocytes.

Lymphatic and Abdominal Examination

• Peripheral lymphadenopathy is common, particularly in the cervical and submandibular regions. Nodes are generally non-tender and mobile.
• Hepatomegaly and/or splenomegaly may be palpable in some cases, though are typically asymptomatic and non-tender.

Neurological Findings

• Facial nerve palsy is the most common cranial neuropathy. When combined with parotitis and uveitis, it is characteristic of Heerfordt syndrome.
• Seizures, headache, visual field defects, or other signs of CNS involvement may be present in neurosarcoidosis.
• Diabetes insipidus and hyperprolactinaemia suggest hypothalamic-pituitary involvement.
• A full neurological examination may detect sensorimotor neuropathies, cranial nerve deficits, or gait disturbances.

Cardiac Examination

• Findings are often subtle or absent unless significant cardiac sarcoidosis is present.
• Irregular heart rhythm, bradycardia, or syncope should prompt further investigation.
• In advanced disease, signs of heart failure or pericardial effusion may be evident.
• Electrocardiographic abnormalities may precede auscultatory findings.

Psychiatric and Cognitive Features

• Although not detectable through routine physical exam, clinicians should be attentive to signs of depression, anxiety, and cognitive impairment.
• Formal neuropsychiatric assessment may be warranted in patients with significant fatigue or behavioural changes.

Chest X-ray

• First-line imaging; essential for detecting intrathoracic involvement (>90% of cases).
• Classifies disease using modified Scadding stages:
  • Stage 0: Normal
  • Stage I: Bilateral hilar lymphadenopathy
  • Stage II: Hilar lymphadenopathy + pulmonary infiltrates
  • Stage III: Pulmonary infiltrates without lymphadenopathy
  • Stage IV: Fibrosis with architectural distortion
• Bilateral hilar adenopathy is the most frequent finding. Pleural effusions and calcified nodes are rare.

Full Blood Count (FBC)

• May reveal anaemia, leukopenia, eosinophilia, or lymphopenia.
• Haematologic abnormalities suggest possible splenic or marrow involvement.

Renal and Liver Function Tests

• Serum urea and creatinine: Assess for renal involvement.
• Liver enzymes (AST, ALT, ALP): Screen for hepatic sarcoidosis. Elevated ALP suggests granulomatous liver disease.

Serum Calcium

• Hypercalcaemia and hypercalciuria may result from overproduction of calcitriol by granuloma macrophages.

Pulmonary Function Tests (PFTs)

• May show restrictive, obstructive, or mixed patterns.
• FVC decline suggests progression; may be normal in early disease.

Electrocardiogram (ECG)

• Screens for arrhythmias or conduction defects suggestive of cardiac involvement.

Eye Examination

• Evaluates for uveitis, conjunctival nodules, and retinal vascular changes.

Interferon-Gamma Release Assay (IGRA)

• Preferred over tuberculin skin test for ruling out latent tuberculosis due to reduced sensitivity in sarcoidosis-related anergy.

Serum ACE

• Often elevated, but with limited specificity or reliability as a diagnostic marker.

High-Resolution CT (HRCT)

• Superior for identifying parenchymal disease: nodules, fibrosis, ground-glass opacities, bronchiectasis.
• Helps differentiate between active inflammation and chronic scarring.

Bronchoalveolar Lavage (BAL)

• Assesses lymphocytic alveolitis; CD4/CD8 ratio >3.5 supports diagnosis.
• BAL cell analysis helps exclude alternative diagnoses (e.g., infection, malignancy, chronic beryllium disease).

Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration (EBUS-TBNA)

• Standard for evaluating mediastinal lymphadenopathy.
• High diagnostic yield for non-caseating granulomas.
• Preferred over mediastinoscopy.

Endobronchial and Transbronchial Lung Biopsy

• Provides histological confirmation if other tests are inconclusive.
• Endobronchial mucosal biopsy improves diagnostic yield when lesions are visible.

Skin Biopsy

• Non-caseating granulomas may confirm diagnosis in patients with cutaneous lesions.

24-hour Urine Calcium

• Detects hypercalciuria in patients with renal calculi or suspected nephrocalcinosis.

Gallium-67 Scintigraphy

• Panda (lacrimal/parotid) and lambda (hilar/mediastinal) uptake patterns are suggestive.
• Limited by low specificity and long scan time.

Vitamin D Metabolism Assessment

• Elevated 1,25-dihydroxyvitamin D with suppressed 25-hydroxyvitamin D indicates dysregulated macrophage-driven synthesis.

MRI

• Reserved for cardiac or neurological sarcoidosis. Detects myocardial granulomas, meningeal enhancement, and parenchymal lesions.

18F-FDG PET Scan

• Detects metabolically active lesions and is helpful for evaluating cardiac involvement, treatment response, or inaccessible sites for biopsy.
• Positive in inflammation, malignancy, and infection—non-specific.

Emerging Imaging Modalities

18F-FLT PET and 11C-thiothymidine PET/CT

• Identify cellular proliferation in granulomas.
• May aid in treatment response assessment without dietary restrictions required for FDG PET.

Tissue Diagnosis and Invasive Testing

• Diagnosis is based on:
  • Compatible clinical and radiological features
  • Exclusion of mimicking conditions
  • Histological identification of non-caseating granulomas
• Biopsy Site Selection: Prioritise accessible tissues (e.g. skin, conjunctiva, lymph nodes).
• Avoid biopsy in pathognomonic syndromes (e.g. Löfgren syndrome) or asymptomatic stage I cases.
• Invasive sampling (EBUS-TBNA, transbronchial biopsy) is indicated when the diagnosis is unclear or extrathoracic access is unavailable.

Histopathology

• Non-necrotising granulomas composed of epithelioid histiocytes, multinucleated giant cells, and surrounding lymphocytes.
• Schaumann and asteroid bodies may be seen but are not pathognomonic.
• Necrosis suggests infection or necrotising sarcoid granulomatosis.

Infectious Causes

Tuberculosis (TB)

• May present with similar symptoms: cough, weight loss, fever, night sweats.
• Both caseating and non-caseating granulomas may be seen on biopsy.
• Positive tuberculin skin test or interferon-gamma release assay.
• Acid-fast bacilli on sputum smear or culture confirm diagnosis.

Nontuberculous Mycobacteria (NTM)

• Often produce non-caseating granulomas and airspace inflammation.
• Culture and special stains required as histology is indistinguishable from sarcoidosis.
• Frequently associated with organizing pneumonia and cavitating lesions.

Fungal Infections (Histoplasmosis, Blastomycosis, Coccidioidomycosis)

• Mimic sarcoidosis with mediastinal lymphadenopathy and pulmonary nodules.
• Confirmed via fungal culture, urinary antigen (Histoplasma), or biopsy with fungal stains.
• Disseminated forms may cause erythema nodosum and multisystem involvement.

Pneumocystis jirovecii

• Rarely causes granulomatous inflammation but must be considered in immunocompromised individuals.
• Detected using silver stains or PCR.

Non-Infectious Granulomatous Disorders

Hypersensitivity Pneumonitis (HP)

• Caused by inhalation of organic antigens (e.g., mould, avian proteins, hay).
• Features include poorly formed granulomas near bronchioles, CD8-dominant lymphocytosis in BAL.
• History of relevant environmental exposure is crucial.
• Radiology shows mid-zone predominant ground-glass opacities and mosaic attenuation.

Chronic Beryllium Disease (Berylliosis)

• Clinically and histologically identical to sarcoidosis.
• Requires a history of exposure (aerospace, nuclear, electronics industries).
• Diagnosed by a positive beryllium lymphocyte proliferation test in blood or BAL.

Drug-Induced Sarcoid-Like Reactions

• Reported with TNF inhibitors (etanercept, infliximab), checkpoint inhibitors, interferons, antiretrovirals, and several chemotherapeutics.
• Reactions usually resolve after discontinuation of the causative agent.
• Methotrexate and BCG therapy may also induce pulmonary granulomatosis.

Primary Immunodeficiencies (e.g., CVID)

• Present with sarcoid-like granulomas in the lung, liver, or lymph nodes.
• Suspected in patients with recurrent infections, autoimmune conditions, and hypogammaglobulinaemia.
• GLILD (granulomatous and lymphocytic interstitial lung disease) is a characteristic pattern.

Neoplastic Disorders

Lymphoma (Hodgkin’s and Non-Hodgkin’s)

• Frequently present with mediastinal lymphadenopathy.
• Systemic B symptoms may overlap with sarcoidosis.
• Diagnosis requires lymph node biopsy showing malignant cells.
• PET imaging may be indistinguishable in some cases.

Lymphomatoid Granulomatosis

• Angiocentric and angiodestructive lymphoproliferative disorder.
• Often EBV-driven, with necrotic granulomatous inflammation.
• May involve lungs, skin, and CNS. Requires biopsy with immunophenotyping.

Sarcoid-Like Reactions to Malignancy

• Non-caseating granulomas may occur near primary tumours or metastatic lymph nodes.
• Common with lung, breast, renal cell, and testicular cancers.
• Diagnosis relies on exclusion and careful pathology to detect adjacent tumour cells.

Other Granulomatous Disorders

Pulmonary Langerhans Cell Histiocytosis

• Affects young smokers.
• HRCT shows nodules and cysts predominantly in upper lobes.
• Biopsy reveals CD1a-positive, S-100-positive Langerhans cells.

Erdheim-Chester Disease

• Rare histiocytic disorder with systemic involvement.
• Cells are CD68-positive, CD1a-negative, S-100-negative.
• Diagnosis often delayed due to protean manifestations.

Foreign Body Granulomatosis

• Caused by intravenous injection or aspiration of particulate matter.
• Granulomas contain polarizable foreign material on microscopy.

Vasculitic Diseases

Granulomatosis with Polyangiitis (GPA)

• Features necrotising granulomas, systemic vasculitis, and c-ANCA positivity.
• Presents with upper/lower respiratory tract disease and glomerulonephritis.

Eosinophilic Granulomatosis with Polyangiitis (EGPA)

• Associated with asthma, eosinophilia, and p-ANCA.
• Vasculitic component with eosinophilic-rich granulomas.

Bronchocentric Granulomatosis

• Necrotising granulomas centred around airways.
• Associated with asthma and allergic bronchopulmonary aspergillosis.

Treatment Strategy Overview

• Sarcoidosis is often self-limiting, particularly in early-stage pulmonary disease; not all patients require therapy.
• Treatment decisions are based on the severity of symptoms, risk of organ damage, and impact on quality of life.
• A stepwise approach is used, beginning with corticosteroids and escalating to immunosuppressants or biologics in refractory disease.
• Multidisciplinary input is often necessary for extrapulmonary involvement, especially ocular, cardiac, neurological, or renal.

When to Initiate Treatment

• Indicated for symptomatic organ-threatening disease, such as ocular inflammation, cardiac conduction abnormalities, CNS lesions, hypercalcaemia, or progressive pulmonary decline.
• Asymptomatic patients with radiographic stage I disease (bilateral hilar lymphadenopathy) are generally monitored without intervention due to high rates of spontaneous remission.
• Treatment may be deferred in patients with mild pulmonary symptoms and preserved lung function, especially if stable over time.

Corticosteroids as First-line Therapy

• Oral prednisone is the mainstay for symptomatic pulmonary or extrapulmonary sarcoidosis.
• Starting doses of 20–30 mg/day are effective for most patients; response is reassessed after 4–6 weeks.
• The dose is then tapered gradually to a maintenance level and eventually discontinued over several months.
• Long-term corticosteroid use is associated with significant adverse effects, warranting early tapering or steroid-sparing strategies where possible.

Pulmonary Sarcoidosis

• Observation is appropriate for asymptomatic stage I disease.
• Stages II–IV with symptoms (e.g., dyspnoea, cough, fatigue) are typically treated with oral corticosteroids.
• Inhaled corticosteroids may be used for cough or bronchial hyperresponsiveness but do not alter disease progression.
• Oxygen therapy is indicated for hypoxaemic patients.
• Lung transplantation is considered in end-stage pulmonary fibrosis refractory to medical therapy.

Cardiac Sarcoidosis

• High-dose corticosteroids are typically initiated at diagnosis to reduce inflammation and prevent arrhythmias.
• Immunosuppressants such as methotrexate, azathioprine, or leflunomide are introduced early to minimise steroid burden.
• Cardiology input is critical; implantable devices (e.g., pacemaker, ICD) are used for heart block or ventricular arrhythmias.
• Infliximab may benefit selected refractory cases but requires monitoring due to potential cardiotoxicity.

Ocular Sarcoidosis

• First-line therapy for anterior uveitis includes topical corticosteroids and mydriatic agents.
• Posterior segment or optic nerve involvement requires systemic corticosteroids.
• In corticosteroid-refractory cases, agents like methotrexate, mycophenolate, or azathioprine are introduced.
• Biologics, especially infliximab, are reserved for vision-threatening or treatment-resistant ocular disease.
• All patients should be referred early to an ophthalmologist for monitoring and complication management.

Neurosarcoidosis

• CNS involvement often presents with cranial neuropathies, seizures, endocrinopathies, or encephalopathy.
• High-dose corticosteroids are the initial treatment.
• Methotrexate is the preferred second-line agent; alternatives include azathioprine or mycophenolate.
• Biologic agents are reserved for resistant cases.
• MRI and CSF analysis guide diagnosis and disease monitoring.

Cutaneous Sarcoidosis

• Topical and intralesional corticosteroids manage limited lesions.
• Extensive or disfiguring skin involvement may require systemic therapy.
• Methotrexate or hydroxychloroquine is considered for steroid-sparing purposes.
• Lupus pernio often necessitates systemic therapy and may respond to infliximab if resistant to other agents.

Renal Sarcoidosis

• Manifestations include granulomatous interstitial nephritis and hypercalcaemia-induced nephropathy.
• Oral corticosteroids are used for both indications.
• Hydroxychloroquine and ketoconazole can reduce calcitriol synthesis in hypercalcaemia.
• Azathioprine or mycophenolate are considered for interstitial nephritis unresponsive to steroids.
• Monitor renal function, calcium levels, and review medications for nephrotoxicity.

Immunosuppressive Therapy and Biologics

• Methotrexate is the preferred steroid-sparing agent across pulmonary and extrapulmonary sarcoidosis.
  • Typically started at 10–15 mg weekly, with folic acid co-administration.
  • Requires monitoring of liver enzymes, blood counts, and renal function.
  • Contraindicated in pregnancy, advanced liver disease, and renal impairment.
• Azathioprine, leflunomide, and mycophenolate are suitable alternatives.
• Infliximab is the most studied biologic, reserved for cases failing standard immunosuppression.

Supportive and Preventive Care

• Bone health is essential in patients on chronic corticosteroids.
  • Avoid routine calcium and vitamin D supplementation without checking for hypercalcaemia.
  • Bisphosphonates may be needed to prevent glucocorticoid-induced osteoporosis.
• Assess for fatigue, mood disorders, and physical limitations.
• Pulmonary rehabilitation and patient support groups are beneficial adjuncts.
• Routine vaccinations and monitoring for infections are important due to immunosuppression.

Monitoring and Evaluation of Response

• Regular assessments with PFTs, chest imaging, and clinical review every 3–6 months.
• Symptom improvement, radiographic resolution, and stabilisation of lung function indicate treatment success.
• Serum ACE levels are not reliable for monitoring and are not routinely recommended.
• Long-term follow-up includes screening for relapse, particularly during or after corticosteroid tapering.

Management of Relapse and Refractory Disease

• Relapses are managed by resuming previous effective corticosteroid dose or adding immunosuppressants.
• Flare symptoms alone without radiographic progression may be treated with a short course of prednisone.
• Refractory disease requires a reassessment of diagnosis and escalation to agents like methotrexate or infliximab.
• Referral to a specialist centre is advised for multisystem or relapsing disease.

General Outlook

• Sarcoidosis is often a self-limiting condition, particularly in early radiographic stages.
• Many patients experience spontaneous resolution and do not require treatment.
• The most reliable prognostic factor is the initial chest radiograph stage, which correlates with remission likelihood, symptom persistence, and mortality.
• Overall 5-year mortality is low, typically around 5–7%, with most deaths due to advanced pulmonary or cardiac sarcoidosis.

Stage I (bilateral hilar lymphadenopathy only)

• Remission rates: 60–90%
• Asymptomatic at 5 years: 95%
• Chest radiograph clearing: 54%
• Mortality: 0%

Stage II (hilar lymphadenopathy and pulmonary infiltrates)

• Remission rates: 40–70%
• Asymptomatic at 5 years: 58%
• Chest radiograph clearing: 31%
• Mortality: 11%

Stage III (pulmonary infiltrates without lymphadenopathy)

• Remission rates: 10–20%
• Asymptomatic at 5 years: 25%
• Chest radiograph clearing: 10%
• Mortality: 18%

Stage IV (extensive fibrosis and distortion)

• Remission rates: 0%
• Chest radiograph clearing: 0%
• Pulmonary hypertension: 30%
• Long-term oxygen therapy required: 12%
• 10-year survival: 84%
• Cause of death: 75% due to respiratory complications

Functional Impairment and Recovery

• Long-term functional impairment is seen in 15–20% of cases and may resolve spontaneously.
• The likelihood of functional recovery is inversely proportional to the degree of parenchymal lung disease.
• Persistent dyspnoea, reduced diffusing capacity (DLCO), and radiographic fibrosis indicate a worse prognosis.

Complications and Mortality Drivers

• Most fatalities result from respiratory failure, pulmonary hypertension, or cardiac sarcoidosis.
• Neurosarcoidosis, although less common, can lead to severe neurological dysfunction or death.
• Advanced parenchymal disease is closely associated with both reduced survival and functional disability.

Mortality Trends

• Sarcoidosis-related mortality has increased in the United States between 1988 and 2007.
• The rise was particularly pronounced among Black females aged ≥55 years.
• In most cases, sarcoidosis itself was the primary recorded cause of death.

Pulmonary Hypertension

• May occur in the context of fibrotic lung disease or independently.
• Can be disproportionate to the extent of parenchymal involvement.
• Associated with reduced exercise tolerance and increased mortality.
• Limited data support vasodilator therapies such as sildenafil, iloprost, and bosentan in selected cases.

End-Stage Lung Disease

• Represents the final phase of progressive pulmonary fibrosis.
• Characterised by severe restriction, hypoxaemia, and impaired gas exchange.
• Lung transplantation is the only definitive treatment in eligible patients.

Severe or Life-Threatening Haemoptysis

• Occurs in patients with aspergillomas or severe bronchiectasis, particularly in stage IV disease.
• Bronchial artery embolisation is the first-line intervention for high-risk surgical candidates.
• Rigid bronchoscopy with endobronchial balloon tamponade may be used acutely.
• Surgical resection may be required if embolisation fails.

Corticosteroid-Related Hyperglycaemia

• Long-term corticosteroid use can exacerbate pre-existing diabetes or unmask latent disease.
• May lead to complications such as hyperosmolar hyperglycaemic state.

Corticosteroid-Induced Osteoporosis

• Risk increases with steroid use beyond 3–6 months.
• Lifestyle advice should include smoking cessation, limiting alcohol, increasing weight-bearing exercise, and fall prevention.
• Monitor serum calcium and 24-hour urinary calcium, especially when initiating vitamin D or calcium.
• Use of bisphosphonates is effective for preventing fractures and reducing bone loss.

Corticosteroid-Related Infection

• Immunosuppression increases the risk of opportunistic infections including fungal pathogens such as histoplasmosis, cryptococcosis, blastomycosis, and aspergillus.

Corticosteroid-Related Cataracts and Glaucoma

• Long-term corticosteroid exposure increases the risk of cataract formation and intraocular pressure elevation.
• Prompt referral to ophthalmology is essential when ocular symptoms develop.

Hydroxychloroquine-Related Retinal Toxicity

• Risk increases with prolonged use.
• Baseline and annual ophthalmologic screening is recommended.

Immunosuppressant-Related Hepatotoxicity

• Methotrexate and azathioprine can cause elevations in liver enzymes or fibrosis.
• Routine monitoring of liver function is required.

Immunosuppressant-Related Bone Marrow Toxicity

• Manifested as anaemia, leukopenia, or thrombocytopenia.
• Regular blood count monitoring is essential.

Congestive Heart Failure

• May occur due to sarcoid involvement of the myocardium.
• Requires standard heart failure management and consideration of advanced therapies.

Arrhythmias and Heart Block

• Conduction abnormalities such as atrioventricular block may necessitate pacemaker placement.
• Ventricular arrhythmias can be life-threatening and require defibrillator implantation.
• Cardiac involvement may present with palpitations, syncope, or sudden death.

Neurosarcoidosis-Related Complications

• Meningeal involvement may present as aseptic meningitis.
• CNS parenchymal disease includes mass lesions, encephalopathy, endocrinopathy, and seizures.
• Spinal canal disease may lead to cauda equina syndrome.
• Neuropathy may be sensorimotor, motor, or demyelinating; Guillain-Barré–like presentations are rare.
• Myopathy includes muscle weakness, polymyositis, and muscle atrophy.
• Differentiation from steroid-induced myopathy is required.
• Pituitary involvement can result in diabetes insipidus or hypopituitarism.

Ocular Complications

• Includes vascular retinitis, optic atrophy, and vision loss.
• Require urgent ophthalmologic evaluation and long-term monitoring.

Infection Risk in Advanced Pulmonary Sarcoidosis

• Patients with stage IV disease are particularly susceptible to respiratory infections.
• Vigilance is needed for atypical pathogens and consideration of local antibiotic resistance.

Hypercalcaemia

• Caused by unregulated synthesis of calcitriol by sarcoid granulomas.
• Risk increases with vitamin D supplementation; both 25- and 1,25-dihydroxyvitamin D levels should be assessed prior to initiating supplementation.
• Monitoring of calcium levels is crucial, particularly in those receiving corticosteroids.

Cranial Neuropathies

• Facial nerve palsy is the most common presentation.
• May occur as part of uveoparotid fever, which has a favourable prognosis.
• Other cranial nerves may also be affected, necessitating neurological evaluation.

1. Bokhari SR, Zulfiqar H, Mansur A. Sarcoidosis. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023.
2. Celada LJ, Kropski JA, Herazo-Maya JD, et al. PD-1 up-regulation on CD4 T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production. Sci Transl Med. 2018;10(460).
3. Dubaniewicz A. The diagnostic algorithm of practice in pulmonary and extrapulmonary sarcoidosis. Pol Merkur Lekarski. 2018;44(261):101–109.
4. Facco M, Cabrelle A, Teramo A, et al. Sarcoidosis is a Th1/Th17 multisystem disorder. Thorax. 2011;66(2):144–150.
5. Gupta D, Hansell A, Nichols T, Duong T, Ayres JG, Strachan D. Epidemiology of pneumothorax in England. Thorax. 2000;55(8):666–671.
6. Kobak S, Yildiz F, Semiz H, Orman M. Elderly-onset sarcoidosis: A single centre comparative study. Reumatol Clin (Engl Ed). 2020;16(3):235–238.
7. Landi C, Carleo A, Cillis G, Rottoli P. Sarcoidosis: proteomics and new perspectives for improving personalised medicine. Expert Rev Proteomics. 2018;15(10):829–835.
8. Light RW. Pleural Diseases. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2013.
9. Ma Y, Gal A, Koss M. The pathology of pulmonary sarcoidosis: update. Semin Diagn Pathol. 2018;35(5):324–333.
10. Matsou A, Tsaousis KT. Management of chronic ocular sarcoidosis: challenges and solutions. Clin Ophthalmol. 2018;12:519–532.
11. Møller J, Hellmund V, Hilberg O, Løkke A. Sarcoidosis. Ugeskr Laeger. 2018;180(34).
12. Niederer RL, Al-Janabi A, Lightman SL, Tomkins-Netzer O. Serum angiotensin-converting enzyme has a high negative predictive value in the investigation for systemic sarcoidosis. Am J Ophthalmol. 2018;194:82–87.
13. Petek BJ, Rosenthal DG, Patton KK, et al. Cardiac sarcoidosis: Diagnosis confirmation by bronchoalveolar lavage and lung biopsy. Respir Med. 2018;144S:S13–S19.
14. Salama A, Abdullah A, Wahab A, et al. Sarcoidosis: Pathophysiology, diagnosis and treatment. Med Sci (Basel). 2018;6(3):74.
15. Sohn DW, Park JB, Lee SP, et al. Viewpoints in the diagnosis and treatment of cardiac sarcoidosis: Proposed modification of current guidelines. Clin Cardiol. 2018;41(10):1386–1394.
16. Swigris JJ, Olson AL, Huie TJ, et al. Sarcoidosis-related mortality in the United States from 1988 to 2007. Am J Respir Crit Care Med. 2011;183(11):1524–1530.
17. West SG. Current management of sarcoidosis I: pulmonary, cardiac, and neurologic manifestations. Curr Opin Rheumatol. 2018;30(3):243–248.
18. Wills AB, Adjemian J, Fontana JR, et al. Sarcoidosis-associated hospitalisations in the United States, 2002 to 2012. Ann Am Thorac Soc. 2018;15(12):1490–1493.
19. Yoon HY, Kim HM, Kim YJ, Song JW. Prevalence and incidence of sarcoidosis in Korea: a nationwide population-based study. Respir Res. 2018;19(1):158.