Sarcoidosis: recognising and managing a multisystem granulomatous disease

Sarcoidosis is a multisystem granulomatous disease of uncertain aetiology that can involve virtually any organ. In Australia, incidence is estimated at approximately 10 per 100,000 per year, though this is likely an underestimate given diagnostic delay. The lungs and mediastinal lymph nodes are the most commonly affected sites, but the skin, eyes, liver, heart, and nervous system are all recognised targets. For most patients the disease is self-limiting; for a minority it follows a chronic, progressive course requiring long-term immunosuppression. The GP’s role spans initial recognition, urgent triage of red-flag presentations, and long-term co-management alongside respiratory, rheumatological, or other specialist teams.

A. Core clinical assessment

Presentations that should prompt consideration of sarcoidosis

• Bilateral hilar lymphadenopathy on chest X-ray (incidental or symptomatic)
• Persistent dry cough, dyspnoea, or chest tightness with no alternative explanation
• The Löfgren syndrome triad: bilateral hilar adenopathy + erythema nodosum + periarticular ankle arthritis (± fever)
• Unexplained uveitis, particularly bilateral or recurrent
• Lupus pernio (indurated violaceous facial plaques) — pathognomonic for sarcoidosis
• Unexplained hypercalcaemia or hypercalciuria
• Cranial nerve palsies, particularly facial nerve palsy, without another cause

History

Ask about constitutional symptoms (fatigue, night sweats, weight loss), duration, and whether the onset was acute (Löfgren syndrome tends to acute onset) or insidious. Occupational history matters: exposure to silica, beryllium, or organic antigens can cause granulomatous disease that mimics sarcoidosis — berylliosis in particular is histologically indistinguishable. A family history is relevant; a first-degree relative with sarcoidosis increases risk approximately five-fold. African American descent confers higher risk and more severe disease; this is less frequently encountered in Australia but remains relevant in communities with African or Caribbean heritage.

Physical examination

Systematic examination should cover: skin (erythema nodosum, lupus pernio, plaques), eyes (conjunctival nodules, anterior uveitis signs — ask about red eye, photophobia, floaters), lymph nodes (peripheral adenopathy), lungs (auscultation for crackles or decreased air entry), heart (rhythm, murmurs, signs of heart failure), liver and spleen (organomegaly), and the nervous system (cranial nerve function, signs of raised intracranial pressure in suspected neurosarcoidosis).

Baseline investigations

Every patient with suspected sarcoidosis requires:

• Chest X-ray (CXR) — Scadding staging: Stage 0 = normal, Stage I = bilateral hilar adenopathy alone, Stage II = bilateral hilar adenopathy + parenchymal infiltrates, Stage III = parenchymal infiltrates without hilar adenopathy, Stage IV = pulmonary fibrosis
• High-resolution CT chest when CXR is abnormal or when parenchymal disease is suspected
• Full blood count (lymphopenia is common; eosinophilia suggests alternative diagnosis), renal function, liver function
• Serum calcium — elevated in 10–20% due to granulomatous 1α-hydroxylase activity (see Special populations)
• 24-hour urinary calcium if serum calcium is borderline
• ECG — mandatory at every assessment to screen for conduction disease (PR prolongation, bundle branch block, heart block)
• Spirometry and DLCO when pulmonary involvement is likely
• Ophthalmology referral for slit-lamp examination, even without ocular symptoms
• Serum ACE — note that this has limited diagnostic utility (sensitivity ~60%; specificity ~83%) and is not recommended as a primary diagnostic tool by ATS 2020 guidelines; it is sometimes used to monitor disease activity in patients with elevated baseline SACE

Confirming the diagnosis

Diagnosis requires: (1) compatible clinico-radiological presentation, (2) histological demonstration of non-caseating granulomas, and (3) exclusion of alternative diagnoses — particularly mycobacterial and fungal infection, lymphoma, and occupational granulomatous disease. The most accessible biopsy sites are skin lesions, peripheral lymph nodes, and, when required, endobronchial mucosa or transbronchial biopsy via bronchoscopy.

Löfgren syndrome is the one clinical diagnosis exception. When a patient presents with the complete Löfgren triad and no features suggesting infection, lymphoma, or another systemic disease, biopsy is not required. Documentation of the clinical rationale for not biopsying should be made in the records.

B. Evidence appraisal — treatment and prognosis

Natural history and Scadding stage prognosis

The prognosis correlates broadly with radiological stage at presentation. Stage I disease remits spontaneously in approximately 60–80% of cases within two years; Stage II in 50–60%; Stage III in under 30%; Stage IV fibrosis is irreversible. Löfgren syndrome remits in around 80% without immunosuppression. Chronic or progressive disease is more common in older patients, those of African descent, and those with insidious rather than acute onset.

Observation versus treatment

Not all sarcoidosis requires treatment. The ATS/ERS/WASOG 2020 guidelines support active surveillance for asymptomatic Stage I and Stage II disease with preserved lung function. Treatment is indicated for: progressive loss of lung function, symptomatic pulmonary disease, cardiac or neurological involvement, hypercalcaemia refractory to conservative measures, ocular disease not controlled by topical therapy, disfiguring skin disease, or significantly impaired quality of life from fatigue or systemic symptoms.

Prednisolone — first-line treatment

Prednisolone remains the cornerstone of treatment. Initial doses are typically 20–40 mg/day for pulmonary disease, with gradual reduction over 6–12 months. Relapse on dose reduction is common; the minimum effective dose for the individual should be sought. Bone protection (calcium supplementation is used cautiously given the hypercalcaemia risk — see below; bisphosphonate therapy is typically added early), blood glucose monitoring, and infection prophylaxis should be co-managed as for any chronic corticosteroid course.

Methotrexate — preferred steroid-sparing agent

The ERS 2021 guidelines recommend methotrexate as the preferred steroid-sparing agent when corticosteroid dose cannot be reduced below an acceptable maintenance threshold, or when corticosteroid-related toxicity accumulates. WASOG multicentre data support its effectiveness across pulmonary and extrapulmonary manifestations. Typical dosing is 10–15 mg/week with folate supplementation; liver function and full blood count monitoring apply. Methotrexate takes 3–6 months to reach full effect, so bridging prednisolone is usually maintained initially.

Infliximab — for refractory or organ-threatening disease

Infliximab has the best RCT evidence for refractory sarcoidosis (the RPC trial) and is particularly preferred for cardiac and neurosarcoidosis by the ERS 2021 guidelines. In Australia, PBS Authority is required. Screening for latent tuberculosis (QuantiFERON-TB or TST) is mandatory before initiation.

Antifibrotic therapy for progressive fibrosing ILD

A subset of sarcoidosis patients with Stage IV fibrosing disease follow a progressive fibrosing ILD (PF-ILD) phenotype. Nintedanib and pirfenidone are PBS-listed under Authority Required for PF-ILD that includes progressive fibrosing sarcoidosis, based on INBUILD and other trial data. This is typically initiated and monitored by a respiratory physician.

C. Multisystem manifestations and red flags

Cardiac sarcoidosis — urgent

Cardiac sarcoidosis is estimated to occur in 5–10% of patients with systemic sarcoidosis but is the leading cause of sarcoidosis-related death in developed countries. The HRS 2014 Expert Consensus and ERS 2021 guidelines recommend ECG as a minimum screen at every assessment. Red flags requiring same-day or next-day cardiology referral include:

• High-grade AV block or bundle branch block in a patient under 60 without another cause
• Unexplained ventricular tachycardia or non-sustained VT
• Syncopal episodes in any patient with known sarcoidosis
• Unexplained cardiomyopathy with reduced ejection fraction

Cardiac MRI and FDG-PET are the imaging modalities of choice for suspected cardiac sarcoidosis. An implantable cardioverter-defibrillator may be required; electrophysiology input is essential.

Neurosarcoidosis — urgent

Neurosarcoidosis occurs in 5–15% of patients and can manifest as cranial nerve palsy (facial nerve most common), leptomeningitis, hypothalamic–pituitary dysfunction, peripheral neuropathy, or encephalopathy. Any cranial nerve palsy or neurological symptom in a patient with sarcoidosis warrants urgent neurology referral and MRI brain with gadolinium. Neurosarcoidosis is notoriously treatment-refractory; infliximab is often required.

Ocular sarcoidosis — urgent

Uveitis is present in up to 25% of patients. Sight-threatening complications include posterior uveitis, cystoid macular oedema, and secondary glaucoma. Every patient with known sarcoidosis requires slit-lamp examination at diagnosis and regular ophthalmology follow-up. Any new visual symptoms (floaters, photophobia, blurred vision) require same-week ophthalmology review.

Hypercalcaemia — moderately urgent

Granulomatous 1α-hydroxylase converts 25-OH vitamin D to the active 1,25-dihydroxyvitamin D unregulated by PTH feedback, risking hypercalcaemia and nephrolithiasis. Check serum calcium and 24-hour urinary calcium. Mild asymptomatic hypercalcaemia may resolve with sunlight restriction and hydration; prednisolone rapidly normalises calcium in most cases. Severe hypercalcaemia (>3.0 mmol/L) or nephrocalcinosis requires urgent management.

D. Australian health system operations

PBS and MBS access

Prednisolone and methotrexate are unrestricted PBS items and accessible from general practice. Infliximab for refractory sarcoidosis requires specialist initiation and Authority Required PBS access (form submitted online via HPOS). Antifibrotic agents (nintedanib, pirfenidone) are PBS Authority items restricted to respiratory physicians. MBS item 11035 (flow volume loop spirometry) and item 11024 (DLCO) are relevant to monitoring pulmonary function. Bronchoscopy with transbronchial biopsy (MBS item 41892) is used when endobronchial tissue is needed.

Specialist referral pathways

Respiratory physician is the primary specialist for most patients with pulmonary-predominant sarcoidosis. Rheumatologist, dermatologist, ophthalmologist, cardiologist, and neurologist are engaged based on organ involvement. Public hospital chest clinics across major Australian cities see sarcoidosis regularly; the Lung Foundation Australia provides patient resources and can help with specialist access information.

Disability and work capacity

Severe sarcoidosis with significant fatigue, pulmonary impairment, or multisystem involvement can impair work capacity. NDIS may be relevant for patients with severe neurological or systemic disease. Workplace modifications or social security support may be appropriate. The Australasian Sarcoidosis Collaboration (via TSANZ) provides resources for clinicians managing complex cases.

E. Special populations

Women of childbearing age

Sarcoidosis in pregnancy is complex. Disease often improves during pregnancy (due to immunological shifts) but may flare post-partum. Prednisolone is acceptable in pregnancy at the lowest effective dose; methotrexate is teratogenic and contraindicated. Infliximab can be continued in the second trimester with specialist input; timing of cessation before delivery requires multidisciplinary discussion. A sarcoidosis specialist and maternal-fetal medicine collaboration is recommended.

Vitamin D supplementation in sarcoidosis

Patients with sarcoidosis are at risk of vitamin D deficiency from sun avoidance and immunosuppression; paradoxically, supplementation risks exacerbating hypercalcaemia. Measure 25-OH vitamin D and serum calcium before supplementing. If supplementation is required (severe deficiency, bone protection), start at conservative doses (500–1000 IU/day, rather than high-dose weekly regimens) and monitor serum calcium and 24-hour urinary calcium at 4–6 weeks. Specialist advice is preferred when baseline calcium is borderline.

Occupational exposures

Patients who work with silica (mining, sandblasting, tunnelling), beryllium (aerospace, electronics), or organic antigens (farmers, bird-keepers) may have occupational granulomatous lung disease that mimics sarcoidosis. Berylliosis is histologically indistinguishable from sarcoidosis; beryllium lymphocyte proliferation test (BeLPT) is required to exclude it. Refer to an occupational physician and consider WorkSafe/workers’ compensation if occupational disease is likely.

Older patients

The clinical presentation in older adults is more often insidious, with higher rates of hypercalcaemia, bone involvement, and cutaneous disease than in younger cohorts. Drug interactions are more common (prednisolone–antidiabetics, methotrexate–NSAIDs/trimethoprim). Older patients are at higher fracture risk on corticosteroids; bone protection should be initiated early.

When to escalate

Refer urgently (same day or next day) for:

• Suspected cardiac sarcoidosis: syncope, high-grade AV block, VT, unexplained cardiomyopathy in a patient with known or suspected sarcoidosis
• Suspected neurosarcoidosis: new cranial nerve palsy, seizure, or encephalopathy
• Uveitis or new visual symptoms in a patient with known sarcoidosis (same-week ophthalmology)
• Severe symptomatic hypercalcaemia (>3.0 mmol/L, confusion, renal impairment)
• Rapidly progressive dyspnoea with worsening spirometry

Refer semi-urgently (within 2–4 weeks) to respiratory physician for:

• New diagnosis requiring tissue confirmation
• Stage II–IV disease with pulmonary symptoms or functional impairment
• Any patient for whom treatment decisions exceed routine GP scope

What this article is and is not

This article provides educational information to support general practitioners in recognising, investigating, and co-managing sarcoidosis in the Australian health system. It summarises published guidelines and clinical evidence; it does not replace specialist assessment for individual patients. Diagnosis, treatment initiation, and long-term monitoring of complex or organ-threatening sarcoidosis require respiratory, rheumatological, cardiac, neurological, or ophthalmological specialist involvement as appropriate. Drug doses cited are indicative starting points and must be individualised by the treating clinician.

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Sources cited