blood and immune - dagna

Sarcoidosis

• Sarcoidosis is a multisystem immunological condition that preferentially involves the lungs
• Multisystem diseases are common, differing from organ-specific conditions typically followed by organ-specific specialists
• Hashimoto’s thyroiditis is an example of an organ-specific condition, contrasting with systemic diseases like multiple sclerosis and psoriasis
• Systemic diseases, including sarcoidosis, affect multiple organs and systems
• Sarcoidosis leads to the development of non-caseating granulomas in virtually all organs, with a preference for lung involvement
• Tuberculosis is characterized by caseating granulomas, making it a major differential diagnosis
• The treatment for sarcoidosis involves immunosuppression
• Sarcoidosis is thought to result from an excessive inflammatory response to infectious or environmental agents
• Typical manifestations include pulmonary hilar lymphadenopathy, lung infiltration and inflammation, ocular, and skin lesions

Sarcoidosis Epidemiology

• The average prevalence is 0.2 per 1,000 persons
• Many cases are completely asymptomatic, discovered incidentally during autopsies
• Symptomatic prevalence is often overlooked compared to general prevalence
• It typically affects people of old age with a peak of prevalence between 20 and 60, but also kids and very old people
• Significant variations exist among geographical regions
• It is typically aggregated in families
• More frequent in people of black origin than people that are Caucasian or European
• The lifetime risk of developing sarcoidosis in the black population in the U.S. is 2.4%

Sarcoidosis Pathogenesis

• The pathogenesis is largely unknown
• It likely involves a significant, yet ineffective, response to an antigen, leading to granuloma formation
• Spatial and temporal clustering of cases, along with community outbreaks, suggest an environmental origin
• Specific groups, like healthcare professionals, firefighters, and military personnel are more likely to develop sarcoidosis
• Environmental factors, such as dust, might contribute
• A cluster of sarcoidosis in the Isle of Mann suggested an infectious disease as the key factor
• Analysis of associations reveals both positive and negative correlations with specific conditions

Sarcoidosis Associations

• Negative association means something is opposite to the risk factor
• Tobacco smoking is a negative association with sarcoidosis
• Tobacco smokers are less likely to develop sarcoidosis
• Inflammatory bowel disease is negatively associated with tobacco smoking
• People who smoke have a lower risk of developing inflammatory bowel disease
• Positive associations include having a cat, being/taking care of children, animal dust exposure, and dust in pillows
• Occupational hazards linked to sarcoidosis include agriculture, insecticide/pesticide exposure and mold
• No single infective agent/antigen has been consistently found in people with sarcoidosis
• This suggests a multifactorial etiology, also from an environmental point of view

Sarcoidosis - Granulomas

• Granuloma formation is central to pathogenesis
• Macrophages attempt to eliminate pathogens but, failing that, create a barrier, transforming into epithelioid cells
• Macrophages enter the space where the pathogen is to ingest, but are unable to do so

Sarcoidosis Clinical Aspects

• Roughly 5% of sarcoidosis patients are detected by chest x-ray during unrelated evaluations
• Many cases are asymptomatic and may never be detected

Sarcoidosis Differentials

• Lung carcinoma should be considered
• Tuberculosis should be considered
• Lymphoma is the most common cancer in young people and should be considered

Sarcoidosis Presentation

• Acute presentation includes fever, fatigue, arthralgia, dry cough, and dyspnea
• Subacute presentation includes low-grade fever, dry cough, dyspnea on exertion, or erythema nodosum, fatigue, night sweats, and weight loss
• These symptoms are vague and non-specific

Sarcoidosis Syndromes

• Lofgren syndrome includes fever, arthralgia/arthritis (ankles), erythema nodosum, and hilar lympho-adenopathy
• Complete Lofgren syndrome presentation doesn’t allow you to perform a biopsy
• Heerfordt syndrome is a triad of fever, uveitis or conjunctivitis, and sialadenitis, with or without facial nerve palsy (Bell palsy)

Sarcoidosis Physical Findings

• Virtually any organ could be involved, including pulmonary, dermatological, ocular, cardiac, and neurological manifestations
• Pulmonary findings are present in over 90% of patients
• Endocrine system or gastrointestinal tract involvement is very uncommon

Sarcoidosis Pulmonary Involvement Stages

• Stage 1: Bilateral hilar lymphadenopathy without lung infiltration
• Stage 2: Bilateral hilar lymphadenopathy with lung infiltration
• Stage 3: Lung infiltration without lymphadenopathy (paradoxically a negative prognostic factor)
• Stage 4: Lung is almost destroyed

Sarcoidosis Cutaneous Involvement

• Skin involvement is not life-threatening, but can be emotionally devastating
• Erythema nodosum is extremely typical
• Lupus pernio is a typical lesion; biopsies reveal granulomas, violaceous rash is also observed and also macropapular area of blood
• Inflammation of tattoos may occur due to immune system overreaction to foreign bodies

Sarcoidosis Organ Involvement

• Liver and spleen: Granulomas may be present without specific damage to function; liver function tests can assess involvement
• Neurologic Granulomas can develop in the brain, leading to neurological symptoms
• Bell palsy may occur
• Manifestations can occur in the central nervous system, brain, and spinal cord (paralysis and other symptoms)
• Sarcoidosis can cause liver fibrosis, though it is uncommon
• Ophthalmological Uveitis is a major manifestation; Bechet’s disease and B27+ uveitis should be ruled out
• Cardiac: Granulomas can infiltrate the heart, causing muscular problems and heart failure
• Arrhythmias are a significant concern when infiltration occurs in the wrong place
• Hypercalcemia and renal Macrophages hydroxylate vitamin D, leading to hypervitaminosis D and hypercalcemia
• Elevated calcium is seen in the urine (hypercalciuria) before hypercalcemia develops, potentially leading to kidney calcification and damage
• Bone and Joint: Granulomas in bones may mimic metastasis

Sarcoidosis Diagnosis

• Imaging is important
• Histological demonstration of non-caseating granulomas in biopsies
• Key differential is tuberculosis; tests should rule out mycobacterium tuberculosis

Sarcoidosis Lab Tests

• Routine evaluations may be normal
• Hypercalcemia or hypercalciuria may be present
• Elevated transaminase suggests hepatic involvement
• Angiotensin-converting enzyme (ACE) may be elevated
• An X-ray can disclose lymphadenopathy
• A high-resolution CT scan of the chest more accurately studies lung involvement

Sarcoidosis Biopsy

• Biopsy is important, deferrable with Lofgren syndrome
• Rule out lymphoma, tuberculosis, fungal infection, lung cancer
• Berylliosis should be ruled out

Sarcoidosis Differential Diagnoses

• Lymphoma
• Tuberculosis, infection
• Fungal infection
• Lung cancer

Sarcoidosis Prognosis

• Not tremendously severe
• Depends on the extent of organ involvement and severity of lung involvement
• Stage 1 sarcoidosis has a high probability of remission
• Stage 4 has low probability of getting better and significant mortality
• 5% of patients with sarcoidosis will die from the disease

Autoinflammatory Diseases

• The immune system has two parts: innate (macrophages and phagocytes) and adaptive
• Autoimmune diseases affect the adaptive immune system
• Autoinflammatory conditions affect the innate immune system
• Characterized by hyperactivity of the immune system without antibodies or antigen-specific T cells
• May involve HLA imbalance or gender imbalance
• Often involve the pattern-recognition receptor pathway

Periodic Fever

• Can be infectious, immune, cancerous, or hematopoietic
• Genetic mutations can lead to anti-inflammatory conditions

Periodic Inflammatory Fever

• Genetically associated, appears early in life
• Sudden onset with specific signs

Auto Inflammatory Associated Fever

• Sometimes it is periodic: sometimes normal, and has a fever on another
• Those last features are suggesting of an auto inflammatory condition

Familial Mediterranean Fever

• First reported in 1908
• Associated to an autosomal recessive gene mutation only in 1997
• Has a higher prevalence in the middle east
• Characterized by a short 2/3 days
• Recurrent fever
• Up to once a month
• Linked to a spiking patter
• With peaks of even 40 degrees ⁃ Erysipelas like erythema ⁃ Sierositis ⁃ Amyloid kidney deposition
• The patient will experience excruciating pain in the chest and/or abdomen

Amyloid in Tissues

• What is the main problem associated to inflammation?
• Production of acute phase proteins, amyloid being one of those.
• During relapses, the high production of amyloid in an auto inflammatory condition, could lead to deposition in tissues, ultimately destroying it
• The most affected tissues are kidneys, lung and heart

Mevalonate kinase deficiency

• Hyperimmunoglobulinemia D
• First case published in lancet in 1984
• Family of Dutch origin affected by recurrent attack of fever
• Similar to FMF
• Kids are mostly affected
• Present symptoms similar to FMF, but with longer fever time ⁃ Spleno/hepatomegaly ⁃ Arthritis and arthralgia, myalgia ⁃ Growth retardation
• Skin manifestations ⁃ Neurological and intestinal involments

TNF receptor associated periodic syndrome

• TRAPS aka Familial Hibernian Fever
• Latin for Ireland
• Discovered in 1982
• Described in a group of kids in a family where myalgias and painful erythema was common
• Similar to FMF
• Autosomal dominant mutation in the TNF receptor 1 gene Main manifestions are: ⁃ Abdominal/thoracic pain ⁃ Arthralgia/arthritis ⁃ Testicular pain ⁃ Monocytic fasciitis ⁃ Amyloidosis ⁃ Centrifugal migratory rash

PFAPA syndrome

• Periodic fever, aphthous stomatitis, pharyngitis
• With an early onset, patients develop recurrent fever accompanied by one between: aphthous stomatitis, recurrent pharyngitis and cervical adenitis.
• Patients will be mostly young, under 5 years, even because growing up the disease might get better
• Not linked to genetic predisposition
• From an hyper activation of some throat tissues

Cryopyrin associated periodic syndromes

• CAPS
• Autosomal dominant disease
• Familial cold urticaria (1940)
• Autosomal dominant disease
• Familial cold urticaria is a familial disease associated to recurrent relapse of cortical rash with conjunctivitis and arthritis

Mackle Wells syndrome (1962)

• Discovered in the uk
• Associated to similar symptoms of familial cold urticaria, but all patients affected by this syndrome became also deaf
• Starting from adolescence, patients would develop progressively deafness, nephropathy and amyloidosis, accompanied by the classic urticaria symptom
• Chronic infanta and neurological cutaneous articular syndrome syndrome (Cinca, 1981)
• All the diseases explained above are actually different spectra of the same syndrome
• Due to a mutation in the protein cryopyrin.
• It is a protein involved in inflammasome formation Due to temperature variation

Auto-inflammatory syndromes diagnosis

• By using classification criteria published some years ago
• Recurrent fever
• Recurrent rash
• Arthritis

Still Disease (sJIA)

• San Raffaele is the referral center worldwide for this disease
• Professor and his team just published the first guidelines for treating this condition

Systemic JIA

• Known as disease with multiple organs in the body and extreme inflamation.

• A list of symptoms include

• high grade fever

• rash

• acute phase proteins All those findings are associated to growth retardation, disability and risk of severe infections Different manifestations are associated to Still, such as disseminated intravascular coagulopathy, purpura, shock Elevated ferritin A normal body if IL-1 is injected, would respond shivering, increasing glycemia and temperature

• Macrophage activation syndrome: The same that led to death after Sars-Cov-2 infection

• a bone marrow biopsy is performed to prove it.

• AA amyloidosis

The most worrying manifestation associated is the Different manifestations are associated to Still, such as disseminated intravascular coagulopathy Macrophage activation syndrome: The same that led to death after Sars-Cov-2 infection

Auto-inflammatory diseases affected patients will get better if treated with IL-1 blockers: either blocking it directly or indirectly (receptor). Anakinra is a receptor antagonist, Canakinumab is an antibody directed against IL-1 molecule