Sarcoidosis is a Silent Inflammation

What's Sarcoidosis?

Sarcoidosis is a systemic inflammatory illness. Sarcoidosis generates small aggregates of immune system cells throughout the body. Red, swollen granulomas develop from these small collections of immune cells. Most often, the disease affects the lungs and chest lymph nodes, but it can also affect any organ. Not all cases of sarcoidosis require treatment, but some can be fatal and cause irreversible organ damage.

Sarcoidosis affects the lungs

Key features

Cause: Unknown, but probable genetic predisposition and environmental triggers, such as germs, viruses, or chemicals.

• The most commonly affected organ is the lungs.
• The lymph nodes
• Areas of skin and eyes
• Heart, Nervous system

What are the sarcoidosis stages?

For lung sarcoidosis, chest X-rays are used to stage it. These stages help clinicians locate and assess granulomas, but they don't indicate disease severity or progression.

Stages of Pulmonary Sarcoidosis (Siltzbach/Scadding Classification)

Stage 0: Normal chest X-ray, Non-visible lung or lymph node involvement

Stage I: Hilar or mediastinal lymphadenopathy, enlarged chest lymph nodes, normal lungs.

Stage II:  Lymphadenopathy and parenchymal lung diseases. Increased lymph nodes and lung granulomas

Stage III: Parenchymal lung disease, no lymph node enlargement, lung infiltrates.

Stage IV: Pulmonary fibrosis: Permanent lung scarring and honeycomb imaging appearance. 🧠 Important Notes

These stages do not predict progression—patients can improve or move between stages.

Only stage IV is irreversible due to lung scarring.

This stage doesn't account for extrapulmonary sarcoidosis (e.g., skin, eyes, heart) without lung involvement.

How do stages affect treatment choices?

Sarcoidosis treatment is influenced more by organ involvement and symptom intensity than by stage; however, staging still shapes the clinical approach.

Stage-based treatment considerations

Stage 0: Usually untreated. No lung involvement; monitor for symptoms.

Stage I: Observation only. Many cases recover spontaneously; treat extrapulmonary illness or symptoms.

Stage II: Lung involvement and lymphadenopathy frequently necessitate treatment. Corticosteroids may enhance 5-year lung function.

In Stage III:  Treatment becomes more likely. Lung disease without lymphadenopathy; increased fibrosis risk.

Stage IV: Aggressive management. Pulmonary fibrosis: permanent damage; oxygen, immunosuppressants, and anti-fibrotics may help.

Considerations for treatment beyond stage symptoms include:

• Fatigue, dyspnea, visual abnormalities, and arrhythmias.
• Eyes, heart, brain, and kidneys need immediate care to avoid irreversible damage.
• Pulmonary function: FVC or DLCO decline may require earlier intervention.
• Quality of life: Mild disease can be treated if it affects daily life.

Stage-based common therapies

• I–II: Early stages. Oral corticosteroids (prednisone) and inhaled steroids may treat lung problems.
• Moderate to severe: Based on organ involvement, add methotrexate, azathioprine, or hydroxychloroquine.
• Advanced disease (Stage IV): Consider infliximab, oxygen, and anti-fibrotic medicines.

Signs of Sarcoidosis

Sarcoidosis symptoms by organ system are listed below:

• Most common lung symptoms
• A persistent dry cough
• Shortness of breath (particularly when exercising)
• Tightness or chest discomfort
• Less common wheezing

Systemic/General Symptoms

• Often significant fatigue
• Fever/night sweats
• Weight loss
• Swollen neck, armpit, and groin lymph nodes

See Eye Symptoms

• Vision blurred
• Red or painful eyes
• Light sensitivity
• Dry eyes

Symptoms of Skin

• Red spots or nodules (erythema nodosum on shins)
• Lighter or darker skin patches
• Growths or ulcers surrounding scars or tattoos

Cardiac Symptoms

• Palpitations or irregular heartbeat
• Non-lung-related chest discomfort
• Arrhythmia-related fainting
• Heart dysfunction causes leg swelling

Neurological Signs

• Headaches
• Bell's palsy face
• Limb weakness/numbness
• Rare seizures

Signs associated with labs

• High calcium
• A high ACE
• Abnormal liver function tests

Symptoms emerge gradually and vary by organ. Some people are diagnosed inadvertently during imaging without symptoms.

How do doctors diagnose sarcoidosis?

Sarcoidosis diagnosis is like a medical riddle, requiring clues from symptoms, imaging, lab testing, and biopsies. Professionals usually approach it:

Diagnostic Standards

• Medical experts use three pillars:
• Comparable radiologic and clinical results
• Histology of non-caseating granulomas
• Not including other causes

Step-by-Step Test Procedure

1. Clinical Suspicion

• Given persistent cough, weariness, skin sores, or eye inflammation.
• Young to middle-aged folks, notably Black and Scandinavian people, are suspected.

2 Imaging Tests

• First-line chest X-ray: May indicate bilateral hilar lymphadenopathy in over 90% of patients.
• High-resolution CT scan: Finds lung nodules and lymph node calcifications missed by X-ray.
• PET scan: Measures multi-organ inflammation.

3. Blood Tests ACE levels: Elevated in ~60% of patients, but not conclusive.

• Calcium and vitamin D: Granulomas interrupt metabolism, causing hypercalcemia.
• CBC, liver enzymes, and renal function: Organ involvement detection.

4. Lung Function Exams

• Assesses lung damage using spirometry and DLCO.

5. Gold Standard Biopsy

• Identifies non-caseating granulomas to confirm diagnosis.
• Common sites: skin, lymph nodes, lung.
• Endobronchial ultrasound-guided biopsy (EBUS-TBNA) is accurate and minimally invasive.

6. Other Conditions Excluded

• Eliminate tuberculosis, cancer, and autoimmune illnesses that mimic sarcoidosis.

A prognosis

• Many recover without complications.
• Chronic cases can harm the lungs and heart.

The latest sarcoidosis treatments?

Sarcoidosis treatment is changing, with promising novel medicines beyond corticosteroids and immunosuppressants. Here are 2025's most interesting developments:

1. Efzofitimod (ATYR1923)

• First-in-class immunomodulator targeting immune cell neuropilin-2 (NRP2) receptor.
• Reduces inflammation without weakening the immune system by modulating macrophage activity.
• Clinical Trials: Fully enrolled Phase 3 EFZO-FIT trial with mid-2025 outcomes.
• Lung function and steroid dependency improved in earlier trials.
• IV infusion monthly.
• Orphan drug and fast-track status in the U.S., EU, and Japan.

2. HARS WHEP Protein Therapy

• This ancient aminoacyl-tRNA (this complex is essential for protein synthesis, as it delivers the correct amino acid to the ribosome during translation) synthetase protein controls immunological responses.
• Mechanism: Binds NRP2 to reduce macrophage inflammation.
• Possible pulmonary sarcoidosis, fibrosis, and inflammation reduction.
• Status: Early clinical development, promising gentle immune modulator.

3. Targeted Synthetic Therapies

• This includes JAK inhibitors and other pathway-specific drugs.
• Tofacitinib: Potential treatment for cutaneous sarcoidosis.
• Targets the granuloma-forming JAK-STAT pathway.
• Using Sirolimus (mTOR inhibitor) systemically in a limited trial for cutaneous sarcoidosis.
• Some patients achieved complete remission.

4. Biologic Therapies

• Anti-TNF infliximab: Decently effective in pulmonary sarcoidosis.
• Adalimumab: Might affect skin.
• Limitations: Rituximab and sarilumab have shown poor efficacy.

Also, read https://journals.lww.com/lungindia/fulltext/2022/05000/new_sarcoidosis_guidelines__are_we_near_to.1.aspx.

Possible Risks

Sarcoidosis can affect anyone; however, risk factors increase the probability of acquiring the disease or severe symptoms. The overview is structured as follows:

• Genetic and family factors

• Family history: Sarcoidosis increases with close relatives.
• Genetic predisposition: HLA-DRB1, BTNL2, and ANXA11 gene variations increase vulnerability.
• Environmental and occupational exposure
• Workplace risks:
• Chemical, pesticide, mold, or dust exposure
• Typical in agriculture, firefighting, automotive, and healthcare.
• Biological aerosols and nanoparticles: Industrially-associated immunological activation.
• Silica exposure: Generates granulomas.

Infectious Causes

• In genetically sensitive people, bacteria or viruses can cause an aberrant immunological response.
• Mycobacteria: Some studies show the link, although it is not established.

 Demographics

• Age: Most common 20–40; risk rises after 55.
• A bit more common in women.
• Race/Ethnicity:
• African Americans and Scandinavians have higher rates and severity.
• Of Japanese descent: More likely cardiac or ocular involvement

The Risks of Medication

• Certain HIV drugs
• Cancer or autoimmune monoclonal antibodies

Related Conditions

• Autoimmune overlap: Sjögren's syndrome, thyroid illness, and systemic sclerosis can occur with sarcoidosis.
• Lymphoma: Only rarely can it cause sarcoidosis-like inflammation.

When and who to see a specialist.

Sarcoidosis symptoms that intensify or involve vital organs require medical attention. This guide is clear:

When to See a Doctor

Treatment is needed if you experience:

• Chronic dry cough or breathlessness
• Tightness or chest discomfort
• Unusual weight loss, fatigue, or fever
• Skin discolouration or painful red lumps (erythema nodosum)
• Blurred vision, discomfort, redness, or light sensitivity
• Neurological symptoms: facial palsy, numbness, weakness, headaches
• Heart symptoms: palpitations, fainting, leg swelling
• Swollen neck, armpit, or groin lymph nodes

Consult a doctor if minor symptoms linger more than a few weeks or affect everyday living.

Select Specialists for Sarcoidosis. Sarcoidosis sometimes necessitates a multidisciplinary team. The organs involved may require:A An 

• Specialist Pulmonologist manages lung issues predominantly.
• Rheumatologist treats joint and systemic inflammation
• A cardiologist assesses cardiac involvement.
• Neurologist examines nerve system symptoms
• Dermatologist treats skin issues
• Ophthalmologist Controls eye inflammation
• Immunologists regulate the immune system.

Conclusion.

The immune system creates granulomas in organs—usually the lungs, but also the skin, eyes, heart, and nervous system—with this chronic inflammatory disease. Possible causes include genetic predisposition and environmental factors.