Sarcoidosis

Sarcoidosis is a multisystem disease of unknown cause defined pathologically by the accumulation of non-caseating (non-necrotizing) granulomas — organized collections of activated macrophages, epithelioid cells, and lymphocytes — in one or more organs.^[1] It is best understood as a disorder of exaggerated, dysregulated cell-mediated immunity, most likely triggered by an as-yet-unidentified environmental or occupational antigen (or antigens) in a genetically susceptible host, rather than a single specific disease with one identifiable cause.^[1]

Pulmonary-predominant, but genuinely a multisystem disease

The lungs and intrathoracic (hilar and mediastinal) lymph nodes are involved in roughly 90% of patients and dominate the diagnostic and staging discussion in this chapter, but sarcoidosis can involve essentially any organ — and which organs are involved, far more than the radiographic stage alone, is what actually determines how aggressively to treat.^[2]

Epidemiology

In Ontario, a population-based cohort study using health administrative data from 1996 to 2015 found the prevalence of sarcoidosis rose to 143 per 100,000 population by 2015 — a 116% increase from 1996 — with age- and sex-adjusted mortality also rising over the same period, from 1.15% to 1.47%.^[6] Internationally, incidence and prevalence vary substantially by ethnicity: sarcoidosis is roughly three times more common, and tends to run a more severe, more chronic course, in Black populations compared with White populations, and is also disproportionately common in Scandinavian populations.^[6] Most patients are diagnosed between ages 20 and 40, with a second, smaller peak in women older than 50.

Löfgren syndrome — an acute presentation with a genuinely good prognosis

Löfgren syndrome is an acute triad of bilateral hilar lymphadenopathy, erythema nodosum, and periarticular ankle involvement (arthralgia or true arthritis, often with fever) — a distinctive presentation worth recognizing precisely because it changes management: it is self-limited in roughly 80-90% of patients, and biopsy confirmation is often unnecessary when the clinical picture is this classic.^[1] Prognosis tracks HLA-DRB1 genotype closely: up to about 95% of HLA-DRB1*03-positive patients have resolving disease within 2 years, compared with about 51% of HLA-DRB1*03-negative patients.^[7] See Choose Initial Treatment for the watchful-waiting approach this good prognosis supports.

Heerfordt syndrome — a second acute, good-prognosis variant

Also called uveoparotid fever: parotid gland enlargement, anterior uveitis, facial nerve palsy, and fever occurring together. Like Löfgren syndrome, it is a distinctive acute presentation that, once recognized, typically does not require an extensive additional diagnostic work-up.

Pulmonary symptoms

Dry cough, exertional dyspnea, and vague chest discomfort or tightness are the most common respiratory complaints, developing gradually over weeks to months; wheeze can occur with endobronchial granulomatous involvement.^[2]

Constitutional symptoms

Fatigue — often disproportionate to the degree of organ involvement found on investigation — along with low-grade fever, night sweats, and unintentional weight loss are common and can precede a specific organ diagnosis by months.

Cutaneous findings

• Erythema nodosum — tender, erythematous, subcutaneous nodules typically over the anterior shins; nonspecific for sarcoidosis (also seen with infections, other inflammatory diseases, and some medications) but, in the context of Löfgren syndrome, a genuinely reassuring, good-prognosis finding.
• Lupus pernio — violaceous-to-red, indurated plaques and nodules, characteristically on the nose, cheeks, ears, and fingers; unlike erythema nodosum, this is a specific sarcoid skin lesion (not merely reactive), it is disfiguring, and it is strongly associated with chronic, fibrotic, more treatment-refractory disease, including upper respiratory tract and pulmonary fibrotic involvement — a genuinely different prognosis from erythema nodosum despite both being "skin findings."
• Subcutaneous nodules, maculopapular eruptions, and granulomatous infiltration of old scars or tattoos are also recognized cutaneous presentations.

Lupus pernio — violaceous, indurated plaques concentrated on the nose and cheeks. Unlike erythema nodosum, lupus pernio is a specific sarcoid skin lesion and a marker of chronic, more treatment-refractory disease (see Special Populations). (Image: Sand M, Sand D, Thrandorf C, Paech V, Altmeyer P, Bechara FG, via Wikimedia Commons, CC BY 2.0)

Ocular findings

Anterior uveitis presents with eye redness, pain, and photophobia; posterior uveitis or panuveitis is more likely to present with floaters or blurred/reduced vision and is more likely to threaten sight. Dry eye from lacrimal gland infiltration is also common. Because ocular sarcoidosis can be genuinely silent even when vision-threatening, absence of eye symptoms does not exclude it — see Monitoring & Follow-Up.

Cardiac findings

Palpitations, presyncope, syncope, and symptoms of heart failure can all be presenting features — but cardiac sarcoidosis can also be entirely asymptomatic until a heart block or a sustained ventricular arrhythmia presents as sudden cardiac death, which is exactly why systematic screening (not just symptom-triggered testing) is built into Assessment & Diagnosis and Monitoring & Follow-Up for every patient, not only those with cardiac symptoms.^[3]

Neurologic findings

Cranial neuropathy — most often unilateral or bilateral facial nerve (CN VII) palsy — is the single most common neurosarcoidosis presentation.^[5] Other patterns include an aseptic-meningitis-like picture (headache, meningismus), myelopathy, peripheral or small-fiber neuropathy, and, less commonly, hypothalamic-pituitary involvement (diabetes insipidus and other endocrinopathies) or mass-like intracranial granulomatous lesions.^[5]

Hypercalcemia-related symptoms

Polyuria and polydipsia, constipation, nephrolithiasis (sometimes the presenting complaint), and, in more severe cases, confusion are the clinical clues; because the mechanism is granuloma-driven, symptoms can appear or worsen specifically after increased sun exposure or vitamin D intake — see Special Populations.

Demographic risk factors

• Age — most patients are diagnosed between 20 and 40 years old, with a second, smaller peak in women older than 50.
• Race and ethnicity — incidence and prevalence are substantially higher, and the clinical course tends to be more chronic and severe, in Black populations compared with White populations; Scandinavian populations also have disproportionately high incidence.^[6]
• Sex — sarcoidosis affects both sexes, with a somewhat higher overall prevalence in women, particularly around the second, later-life peak.

Genetic risk factors

HLA class II alleles are the most consistently replicated genetic association. HLA-DRB1*03 is strongly associated with the Löfgren syndrome phenotype and predicts a favourable, self-limited disease course, while HLA-DRB1*15 is a risk factor for chronic, nonresolving disease.^[7] A first-degree relative with sarcoidosis modestly increases risk, consistent with a genuine genetic contribution layered on top of an environmental trigger.

Environmental and occupational risk factors

No single causative antigen has been identified, but epidemiologic studies have linked sarcoidosis risk to specific environmental and occupational exposures, including insecticide/pesticide exposure, mold or mildew exposure, and certain occupational dust exposures — reinforcing that sarcoidosis, like hypersensitivity pneumonitis (see the Interstitial Lung Disease chapter), likely represents an exaggerated immune response to an inhaled antigen or antigens rather than a single specific cause.^[1]

Three diagnostic pillars

The current ATS clinical practice guideline frames the diagnosis of sarcoidosis around three elements that must all be satisfied: (1) a compatible clinical and radiographic presentation, (2) finding non-necrotizing (non-caseating) granulomatous inflammation in one or more tissue samples, and (3) exclusion of other diseases capable of producing a similar clinical and/or histologic picture.^[2] No single test is diagnostic on its own — sarcoidosis remains, genuinely, a diagnosis of compatible findings plus exclusion, not a positive test result.

Biopsy — site selection favours the least invasive accessible option

When tissue confirmation is needed, choose the safest, most accessible site with reasonable diagnostic yield first — a skin lesion, a peripheral or conjunctival nodule, an enlarged peripheral lymph node, or minor salivary gland tissue — before moving to more invasive intrathoracic sampling.^[2] For intrathoracic disease, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) of mediastinal/hilar lymph nodes is preferred over mediastinoscopy given comparable diagnostic yield with meaningfully lower procedural risk.^[2] Biopsy can reasonably be omitted in a patient with a sufficiently classic presentation of Löfgren syndrome (see Recognize the Condition), where the diagnosis is clinical.

Radiographic (Scadding) staging

Chest radiograph staging remains a simple, widely used prognostic framework, even though it is purely descriptive and does not itself establish the diagnosis:

Most spontaneous remissions, regardless of initial stage, occur within the first 2 years after presentation, and the likelihood of remission falls once disease has persisted beyond about 5 years — a genuinely important expectation-setting point for watchful waiting (see Treatment Targets and Choose Initial Treatment).

Bilateral hilar lymphadenopathy with otherwise clear lung fields — the classic Scadding Stage I appearance, the stage with the highest rate of spontaneous remission. (Image: James Heilman, MD, via Wikimedia Commons, CC BY-SA 4.0)

Baseline testing recommended for every newly diagnosed patient

• Serum calcium — a strong recommendation in the ATS guideline, given the genuine and specific risk of granuloma-driven hypercalcemia in this population (see Special Populations).^[2]
• ECG — recommended for every patient at diagnosis, not only those with cardiac symptoms, since cardiac sarcoidosis can be clinically silent (see Special Populations and Monitoring & Follow-Up).^[3]
• Baseline ophthalmologic examination — recommended for every patient, again because ocular sarcoidosis can be silent (see Special Populations and Monitoring & Follow-Up).
• CBC, renal function, and liver function tests as part of the general work-up and as a pre-treatment baseline.
• Pulmonary function testing (spirometry and DLCO) to characterize baseline pulmonary status.

Differential diagnosis

Beyond tuberculosis and other mycobacterial/fungal granulomatous infections, consider lymphoma (especially with asymmetric or bulky lymphadenopathy), berylliosis (a granulomatous lung disease clinically and radiographically similar to sarcoidosis, caused by occupational beryllium exposure — aerospace, electronics, and metal-alloy work are classic exposures, and a targeted occupational history is the only way to catch it), and hypersensitivity pneumonitis (see the Interstitial Lung Disease chapter).

Sarcoidosis has no cure, and a substantial proportion of patients — particularly those with Löfgren syndrome or Stage I disease — will remit spontaneously without any treatment at all (see Assessment & Diagnosis). The treatment goal is therefore not to "clear granulomas" or normalize imaging in every patient, but to:

• Prevent or reverse organ dysfunction in organs where ongoing granulomatous inflammation causes genuine, irreversible harm if untreated — this is the central decision driver, not the radiographic stage or extent of disease (see Choose Initial Treatment).
• Treat high-risk organ involvement aggressively regardless of symptom severity — cardiac, neurologic, and posterior/panuveitic ocular disease carry disproportionate morbidity and mortality risk and change the treatment threshold even when the patient feels reasonably well (see Special Populations).
• Control troublesome symptoms — cough, dyspnea, fatigue, arthralgia — that meaningfully affect quality of life, even when the organ involved is not itself at risk of lasting damage.
• Minimize cumulative corticosteroid toxicity over what is often a multi-year treatment course, by using the lowest effective dose, tapering deliberately, and introducing a steroid-sparing agent proactively rather than only after toxicity has already appeared (see Choose Initial Treatment).
• Support watchful waiting as a genuine, appropriate default for asymptomatic disease without high-risk organ involvement — treatment is not automatically "better" than observation when the disease itself is likely to remit (see Choose Initial Treatment).

Vitamin D and calcium — a genuinely important caution specific to this population

Sun exposure

Because cutaneous vitamin D synthesis feeds the same mechanism, advise patients with a history of hypercalcemia to avoid prolonged, unprotected sun exposure and to mention any planned major increase in outdoor time (for example, a sunny vacation) at a follow-up visit.

Bone health during long-term corticosteroid therapy

Given how often sarcoidosis treatment runs for a year or longer (see Choose Initial Treatment), plan proactively for corticosteroid-related bone loss — but coordinate calcium/vitamin D supplementation decisions specifically with the hypercalcemia caution above rather than applying a standard osteoporosis-prevention protocol unmodified.

Infection screening and vaccination before immunosuppression

Complete tuberculosis and hepatitis B screening before starting a steroid-sparing agent or, especially, a biologic (see Choose Initial Treatment); bring routine immunizations up to date beforehand, and avoid live vaccines once a patient is on a significantly immunosuppressive regimen.

Smoking cessation and general lifestyle

Counsel every current smoker to quit. Regular physical activity and, for patients with more advanced pulmonary involvement, pulmonary rehabilitation can meaningfully improve the fatigue and reduced exercise tolerance that are common even in patients without severe lung function impairment.

Patient education and psychosocial support

Fatigue is one of the most burdensome and most underrecognized symptoms of sarcoidosis, often present independent of measurable organ dysfunction, and deserves acknowledgment and support rather than being dismissed once "the scan looks fine." Direct patients toward reliable, disease-specific resources such as the Foundation for Sarcoidosis Research and the Canadian Lung Association (lung.ca) rather than unfiltered internet searches.

Cardiac sarcoidosis

Screen with a 12-lead ECG in every patient with sarcoidosis at diagnosis, regardless of cardiac symptoms, since clinically silent conduction and rhythm abnormalities are common.^[3] A new abnormality on screening ECG, or any cardiac symptom (see Red Flags & Refer), should prompt further evaluation — echocardiography, ambulatory rhythm monitoring, and advanced imaging (cardiac MRI with late gadolinium enhancement, or FDG-PET) as guided by the specific finding and local availability, per the 2024 AHA scientific statement.^[4]

Immunosuppression is the primary treatment for active cardiac inflammation, generally with higher-dose corticosteroids than for uncomplicated pulmonary disease and a lower threshold to add a steroid-sparing agent (see Choose Initial Treatment); infliximab has a genuine, reported role for cardiac sarcoidosis refractory to corticosteroids and a first-line steroid-sparing agent.^[4]

Device therapy is guided by risk stratification, not by immunosuppression status alone — the two are complementary, not substitutes for one another. ICD implantation carries a Class I (strongest) recommendation for a history of cardiac arrest or sustained ventricular arrhythmia, and for a left ventricular ejection fraction of 35% or less; a Class IIa recommendation applies to inducible ventricular arrhythmia on electrophysiology study, a planned permanent pacemaker, and syncope or near-syncope believed to have an arrhythmic origin; a weaker Class IIb recommendation applies to mild-to-moderate LV systolic dysfunction (ejection fraction 36-49%) and/or right ventricular systolic dysfunction.^[3][4] Antiarrhythmic therapy and catheter ablation both have a role for recurrent ventricular arrhythmia despite device therapy and adequate immunosuppression.

Neurosarcoidosis

The Neurosarcoidosis Consortium Consensus Group's 2018 criteria classify neurosarcoidosis as definite, probable, or possible, based on a combination of compatible clinical presentation, supportive neuroimaging or other neurodiagnostic testing, exclusion of alternative diagnoses, and — for a definite diagnosis — pathologic confirmation from either the nervous system itself or another organ combined with a fully compatible neurologic syndrome.^[5] Cranial neuropathy, especially facial nerve palsy, is the most common presentation; MRI of the brain and spine with contrast is the key imaging investigation, and cerebrospinal fluid findings are typically nonspecific (mildly elevated protein, lymphocytic pleocytosis) rather than diagnostic on their own.^[5] Because neurosarcoidosis carries a genuine relapse risk and can cause permanent neurologic deficit if undertreated, it is generally managed with a higher initial corticosteroid dose and longer duration than uncomplicated pulmonary disease, with earlier introduction of a steroid-sparing agent (methotrexate, azathioprine, or mycophenolate mofetil) rather than waiting for a corticosteroid taper to fail (see Choose Initial Treatment).^[8]

Ocular sarcoidosis

Anterior uveitis is managed acutely with the general principles covered in the Anterior Uveitis chapter (topical corticosteroids and cycloplegia as first-line, urgent ophthalmology involvement); posterior uveitis and panuveitis are more likely to be vision-threatening and generally require systemic corticosteroid or steroid-sparing therapy in addition to, or instead of, topical treatment, coordinated with ophthalmology.^[2] Because ocular sarcoidosis can be entirely silent, every patient should have a baseline ophthalmologic examination at diagnosis regardless of symptoms, with periodic reassessment thereafter (see Monitoring & Follow-Up).

Cutaneous sarcoidosis

Erythema nodosum requires no specific treatment beyond symptomatic care (NSAIDs, leg elevation) and resolves with the underlying disease (see Choose Initial Treatment's Löfgren syndrome discussion). Lupus pernio and other specific cutaneous sarcoid lesions are a different story: limited disease can be managed with topical or intralesional corticosteroids, but extensive or disfiguring lupus pernio — which is itself a marker of chronic, more fibrotic, more treatment-refractory disease — typically needs systemic therapy, with hydroxychloroquine, methotrexate, and infliximab (which has a particularly well-reported track record specifically for lupus pernio) all reasonable options depending on severity.^[8]

Hypercalcemia and renal involvement

Beyond the acute management in Choose Initial Treatment, ongoing hypercalcemia and hypercalciuria increase the risk of nephrolithiasis and nephrocalcinosis, and can, over time, contribute to chronic kidney disease — reasons to monitor serum and, where feasible, 24-hour urine calcium periodically in any patient with a history of hypercalcemia (see Monitoring & Follow-Up), and to revisit the vitamin D/calcium supplementation caution (see Non-Pharmacologic Treatment) at every relevant visit rather than only at diagnosis.

Pregnancy

Sarcoidosis often improves during pregnancy, plausibly related to physiologic changes in maternal immune tolerance and endogenous corticosteroid production, with a recognized risk of flare in the postpartum period. Prednisone is the preferred agent if treatment is needed during pregnancy. Methotrexate and mycophenolate mofetil are both teratogenic and contraindicated; azathioprine is generally considered the better-tolerated immunosuppressive option in pregnancy when a steroid-sparing agent is genuinely needed, though the decision should be individualized with obstetric and specialist input.

• Routine follow-up every 3-6 months for most patients, more frequently around diagnosis, during a corticosteroid taper, or for actively progressing/high-risk organ disease.
• Pulmonary function testing (spirometry, DLCO) and chest imaging periodically to track pulmonary disease trajectory, with frequency individualized to severity and stability.
• Serum calcium at diagnosis and periodically thereafter, more frequently during any period of increased sun exposure, vitamin D intake, or immobilization, and always before initiating or increasing vitamin D/calcium supplementation (see Non-Pharmacologic Treatment).^[2]
• Baseline ECG for every patient at diagnosis and periodically thereafter, with a low threshold to repeat or escalate to advanced cardiac imaging for any new cardiac symptom (see Special Populations).^[3]
• Baseline ophthalmologic examination for every patient at diagnosis, with periodic reassessment (commonly annually, more often if abnormal or symptomatic), given how often ocular sarcoidosis is clinically silent.
• Methotrexate/azathioprine: baseline CBC, renal function, and liver function tests, then periodically (for example, every 4-8 weeks initially, spacing out once stable) for the duration of therapy.
• Infliximab: confirm negative TB/hepatitis B screening before starting (see Choose Initial Treatment), and monitor clinically for infusion reactions and infection at each visit.
• Hydroxychloroquine: baseline and periodic ophthalmologic monitoring specifically for retinal toxicity — a distinct surveillance requirement from the ocular sarcoidosis monitoring above.
• Bone density assessment for patients on a prolonged corticosteroid course, coordinated with the vitamin D/calcium caution specific to this population (see Non-Pharmacologic Treatment).
• Screen for adrenal insufficiency symptoms when tapering corticosteroids after a prolonged course, and taper gradually rather than stopping abruptly.

1. Inadequate response to, or relapse on tapering, corticosteroid monotherapy: add methotrexate as the preferred first steroid-sparing agent rather than simply increasing or prolonging the corticosteroid dose (see Choose Initial Treatment).^[8]
2. Methotrexate contraindicated or not tolerated (renal impairment, significant hepatotoxicity, pregnancy, or genuine intolerance): switch to azathioprine or mycophenolate mofetil rather than abandoning the steroid-sparing strategy altogether.
3. Refractory disease after an adequate trial (generally several months) of a steroid-sparing agent: add infliximab, having first confirmed TB and hepatitis B screening (see Choose Initial Treatment and Monitoring & Follow-Up).^[9]
4. Active cardiac or neurologic involvement not responding promptly to initial therapy: escalate directly to a steroid-sparing agent and/or infliximab and involve the relevant specialist urgently, rather than working sequentially through the same step-up ladder used for uncomplicated pulmonary disease — the mortality/morbidity stakes justify moving faster (see Special Populations).
5. Hypercalcemia not controlled by corticosteroids alone: add hydroxychloroquine, reconfirm strict avoidance of vitamin D/calcium supplementation, and involve nephrology for persistent or severe cases.
6. Lupus pernio refractory to topical therapy and hydroxychloroquine: escalate to methotrexate or infliximab — infliximab in particular has a well-reported track record for this specific, often disfiguring and treatment-resistant lesion (see Special Populations).^[8]

• Starting corticosteroids for presumed sarcoidosis before genuinely excluding tuberculosis and other granulomatous infections — this is the single most consequential error in the entire chapter (see Assessment & Diagnosis and Red Flags & Refer).^[2]
• Treating radiographic stage or extent of disease alone, in an asymptomatic patient with no high-risk organ involvement, rather than basing the treatment decision on actual organ dysfunction and risk (see Treatment Targets).
• Recommending routine, unmonitored vitamin D and/or calcium supplementation to a patient with sarcoidosis — including for standard corticosteroid-associated bone-health prevention — without first checking serum calcium (see Non-Pharmacologic Treatment and Special Populations).^[2]
• Using a thiazide diuretic for a sarcoidosis patient with hypercalcemia — thiazides reduce renal calcium excretion and will worsen, not treat, hypercalcemia; use a loop diuretic instead, and only after volume repletion (see Choose Initial Treatment).
• Assuming a sarcoidosis patient without cardiac symptoms does not have cardiac involvement — clinically silent cardiac sarcoidosis is common and can present first as sudden cardiac death; a baseline ECG is recommended for every patient regardless of symptoms (see Assessment & Diagnosis and Special Populations).^[3]
• Skipping the baseline ophthalmologic examination in an asymptomatic patient — ocular sarcoidosis, like cardiac sarcoidosis, can be clinically silent until vision is already threatened.
• Substituting etanercept for infliximab or adalimumab under the assumption that all anti-TNF agents work equally well for sarcoidosis — etanercept has not shown efficacy and has been reported to induce granulomatous disease (see Choose Initial Treatment).^[8]
• Stopping a prolonged corticosteroid course abruptly rather than tapering — both disease relapse and adrenal insufficiency are real risks.
• Starting infliximab or another biologic without first completing TB and hepatitis B screening (see Choose Initial Treatment and Monitoring & Follow-Up).
• Misclassifying erythema nodosum and lupus pernio as interchangeable "sarcoid rashes" — they carry essentially opposite prognostic implications and need different management (see Recognize the Condition and Special Populations).

Systemic Corticosteroids

First-line therapy for symptomatic, progressive, or organ-threatening sarcoidosis. See Choose Initial Treatment for organ-specific dosing intensity and tapering detail.

Steroid-Sparing Antimetabolites

Introduced proactively for disease expected to need a prolonged corticosteroid course, or for relapse on tapering — not only after corticosteroid toxicity has already appeared.

Biologic Therapy — Anti-TNF Agents

For disease refractory to corticosteroids and a first-line steroid-sparing agent. Confirm latent TB and hepatitis B screening before starting either agent below (see Assessment & Diagnosis and Choose Initial Treatment).

Antimalarial — Hypercalcemia and Cutaneous Disease

A steroid-sparing option specifically useful where its mechanism — reducing macrophage 1,25-dihydroxyvitamin D production — directly addresses the problem.