BOTTOM LINE

Autoinflammatory Disease generally refers to a broad spectrum of diseases related to inappropriate antigen-independent activation of the innate immune system. Autoinflammatory diseases are often (but not always) characterized by periodic fever; other inflammatory lesions may present as arthritis, osteomyelitis, rashes, enterocolitis/mucositis, serositis, vasculitis, lymphadenopathy, conjunctivitis, meningitis, or  basal ganglia calcifications. Many patients present at young age or have family history of consanguinity or affected family members. Diagnosis requires recognition of innate immune system activation and pattern-recognition of specific diseases supported by concordant ESR/CRP elevations and careful interpretation of genetic testing. Treatment is guided by blocking the underlying primary aberrant pathway; this includes colchicine, IL-1i, IL-6i, IL-18i, TNFi, and JAKi.
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CONTINUUM OF AUTOINFLAMMATORY AND AUTOIMMUNE DISEASES

	Innate Immunity	Adaptive immunity
Specificity	“Hard-wired” recognition of molecular patterns shared by pathogens and by damaged host cells	“Learned” recognition of microbial and non-microbial antigens
Response	Rapid initial response (minutes-hours)	Slow initial response (days-weeks)
Memory	None/limited memory: identical subsequent responses	Memory: subsequent responses more rapid and intense
Blood proteins	Complement, various lectins and agglutinins	Antibodies
Cellular effectors	Phagocytes (macrophages, neutrophils), dendritic cells, NK cells, mast cells, innate lymphoid cells	B- and T-cell lymphocytes
Disease	“Auto-inflammatory” Antigen-independent inappropriate activation. No MHC association, no antibodies, equal sex effected	“Auto-immune” Self/non-self inappropriate lack of discrimination MHC association, auto-antibodies, female predominance

In reality: complex interplay between Innate/Adaptive immune system and Auto-Immune/Auto-Inflammatory disease

Auto-inflammatory diseases can be divided into 4 main categories based on pathogenesis and response to empiric treatment

1. Inflammasomopathies:
   Diseases caused by inappropriate activation of the inflammasome; often respond to IL-1i, TNFi, IL-18i
2. Interferonopathies:
   Diseases caused by inappropriate activation of Type 1 interferon; often respond to JAKi
3. NF-κB-opathies/aberrant TNF activity/Relopathies:
   Diseases caused by dysregulation of NF-κB; often responds to IL-1i, IL-6i, TNFi
4. Other:
   Other diverse mechanisms, some diseases do not neatly fit above; our understanding of disease is evolving over time.

INFLAMMASOMOPATHIES

—The Normal Inflammasome

• Inflammasomes are a complex of proteins that assemble in response to pathogenic or physiological stimuli:
• Damage-associated molecular patterns (DAMPs, from cell or tissue damage)
• Pathogen-associated molecular patterns (PAMPs, like lipopolysaccharide from micro-oganisms)
• DAMPs/PAMPs are detected by pattern recognition receptors, including Pyrin and NLRs (nucleotide-binding domain-like receptor)
• Pattern recognition receptors combine with other proteins, including ASC (apoptosis-associated speck-like proteins) and pro-caspase-1 to assemble The Inflammasome
• Multiple different inflammasomes are defined based on their nucleating proteins:
  • Pyrin
  • Cryopyrin (NLRP3/NALP3)
  • NLRC4
  • LRP1
• Inflammasomes active caspase-1, and thus activate IL-1β and IL-18, causing pyroptosis: inflammatory cell death

—Inflammasomopathies

• Mutations affect genes encoding inflammasome regulators, leading to inappropriate nucleation of the inflammasome complex
• Clinical differences in inflammasomopathies relate to nature/severity of mutation and distribution of inflammasome, for example
  • Pyrin and Cryopyrin activate IL-1β,  are expressed widely, resulting in widespread disease mediated through IL-1β
  • NLRC4 activates IL-18, is expressed in the gut, resulting in colitis mediated through IL-18 (IL-1β  plays a role)
  • NLRP1 is expressed in the skin, resulting in skin pathology

• FMF: Familial Mediterranean Fever, FCAS: Familial Cold Autoinflammatory Syndrome, MWS: Muckle-Wells Syndrome
• AR = Autosomal recessive. AD = Autosomal dominant.
• Some name  inflammasomopathies by genetic mutation, ex: NRP3-AID (AutoInflammatory Disease), NLRP12-AID
• Diseases with amyloid risk (FMF, MWS) require routine urinalyses to screen for renal amyloid involvement

INTERFERONOPATHIES

—Normal Interferon (IFN) function:

• IFNs are cytokines released by cells in response to viral nucleic acid (viral DNA or RNA)

—Interferonopathies:

• Due to aberrant activation of Type I IFN caused by abnormality in:
  • Nucleic acid handling: nucleic acid sensing, accumulation of host nucleic acid, intracellular debris mimicking viral nucleic acid
  • Type I IFN signaling

Type I IFNs	IFN-α, IFN-β, others; involved in anti-viral defense. Signals through Type I IFN-receptor and JAK1, TYK2
Type II IFNs	IFN-ɣ; involved in innate and adaptive immunity. Signals through Type II IFN-receptor and JAK1, JAK2
Type III IFNs	IFN-λ. Signals through receptor that shares kinases with Type I IFN-receptor.

NF-κB DISORDERS and/or ABERRANT TNF ACTIVITY

—Normal NF-κB and TNF function

• NF-κB integrates multiple cell surface and intracellular danger signals to trigger production of proinflammatory cytokines like TNF, IL-6
• NF-κB regulation is complex; involves different sensor proteins, inhibitor proteins, and ubiquitin-dependent functional modifications

—NF-κB-opathies (aka “Relopathies”)

• Caused by a disorder in the complex regulation of NF-κB , including TNF (TNF regulates NF-κB and is also produced by NF-κB)
• Hallmarks: fever, systemic inflammation, sometimes granuloma

OTHER AUTO-INFLAMMATORY DISORDERS

(that are more prevalent in adult than paediatric patients)

—Schnitzler’s

• Patient
  • Median age 55-years, slight male predominance.
• Features
  • Recurrent fever (72%), urticaria, bone/joint pain (40%), lymphadenopathy (25%), paraprotein (IgM>IgG)
  • Urticaria may precede other symptoms by years
• Treatment
  • IL-1i, IL-6i

—CNO/CRMO, SAPHO

CNO (Chronic nonbacterial osteomyelitis), aka CRMO (Chronic Recurrent Multifocal Osteomyelitis). Preferred terminology is CNO.

SAPHO (Synovitis acne pustulosis hyperostosis osteitis) is likely on the same disease spectrum as CNO.

Adult CNO overlaps with features of spondyloarthritis (psoriatic arthritis, axial spondyloarthritis); however vast majority of adult CNO present with isolated osteomyelitis.

• Mechanism
  • IL1RN mutation leading to NLRP3 activation and expression of IL-1β, TNF, IL-18
• Patient
  • May affect adults or children
  • Adults: 29-46 years-old
  • Female predominance 60-73%
• Features
  • Bone:
    Swelling and bone pain due to uni- or multi-focal aseptic osteitis commonly at
    • Metaphyses/epiphyses of long bones
    • Shoulder girdle (clavicle and sternum)
    •  Vertebral bodies
    • Mandible (rare)
  • Musculo/cutaneous (20%):
    • Palmoplantar pustulosis, cystic acne,
    • Inflammatory arthritis (more in SAPHO)
  • Spondyloarthropathy features:
    • IBD (10%), Psoriasis, hidradenitis suppurativa
    • Association of CNO with seronegative spondyloarthropathy may be stronger in adults than in children
• Imaging
  • Diagnostic confirmation of osteitis usually by
    • X-ray: osteolytic or hyperostotic features
    • MRI whole-body or regional with STIR: for bone marrow edema signifying osteitis
    • Can evaluate for fracture, sarcoma, metastases, infarction; bone biopsy and culture may be required
• Differential
  • Infectious osteomyelitis
  • Malignancy: primary bone tumour or metastases
  • Spondyloarthritis: axial spondyloarthritis or psoriatic arthritis
  • Rheumatoid arthritis
  • Mechanical/degenerative: Osteoarthritis, anterior SC joint subluxation, local trauma
  • Metabolic: Paget’s disease, osteomalacia, hypophosphatasia
  • Other: Tietze syndrome, Fibrous dysplasia
• Treatment of osteitis
  • First line:
    • NSAIDs
  • Refractory
    • Methotrexate, sulfasalazine (±NSAIDs, steroids), or
    • TNF-inhibitors: adalimumab, etanercept, other TNFi (±methotrexate), or
    • Bisphosphonates: Pamidronate (first choice), zoledronate (±NSAIDs, steroids)
    • Referral to expert centre.

—VEXAS

VEXAS: Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic; associated with UBA1 mutation

• Mechanism
  • Mutation of UBA1, X-linked gene, causes treatment-refractory myeloid-drive autoinflammation
• Patient
  • Men, 55-65 years-old (range 40-85 years); few cases of female VEXAS identified
• Features
  • Systemic
    • Recurrent fever
  • Cutaneous
    • Neutrophilic dermatoses (30-46%), livedo, panniculitis, urticaria, ulcer
  • Chondritis
    • Chondritis (46-65%): airway, costochondritis, vestibular symptoms
  • Pulmonary
    • Dyspnea (95%), dry cough (55%), pleural effusion, lymphadenopathy, ground-glass changes
  • Vascular
    • DVT/PE, superficial thrombophlebitis
    • Variable-vessel vasculitis: leukocytoclastic vasculitis (28-38%), urticarial or bullous vasculitis
    • May resemble polyarteritis nodosa clinically, but lack classic arteriographic findings
  • Arthritis
    • Oligo– or Polyarticular inflammatory arthritis
  • Ocular
    • Ocular inflammation (22%): episcleritis, uveitis, iritis, scleritis, blepharitis.
    • Orbital/periorbital inflammation (12%): can mimic cellulitis
  • Other
    • Reported: pericarditis, myocarditis, hearing loss, interstitial nephritis, mononeuritis, diarrhea
    • Associated diseases: Relapsing polychondritis
• Labs
  • Basic
    • CBC: macrocytic anemia, thrombocytopenia, neutropenia
    • ESR, CRP: elevated
  • Genetic
    • Must have UBA1 mutation
• Treatment
  • Prednisone 20-40mg/d; may have difficulty remaining below 10-15mg/d
  • csDMARDs: do not appear to be helpful (methotrexate, azathioprine, mycophenolate)
  • tsDMARDs: May benefit from JAKi
  • bDMARDs: may benefit from TNFi, IL-6i. N.B.: Avoid IL-1i, can cause severe cutaneous reaction.
  • Stem cell transplant: may help autoinflammation or be necessary if MDS or myelofibrosis (if candidate)

—PFAPA

PFAPA: Periodic fever with aphthous stomatitis pharyngitis and adenitis

• Patient
  • Usually pediatric disease, adult cases reported
• Features
  • Every 4-6 weeks: fever with aphthous stomatitis, pharyngitis, cervical adenitis lasting 3-6 days
  • 41% of adults have all 4/4 features, 60% of adults of 2/4 features
  • Adults may develop exudative pharyngitis
• Treatment
  • Single dose of prednisone 0.5mg/kg/d
  • Colchicine, IL-1i if frequent flares

—Idiopathic recurrent pericarditis (IRP)

• Definitions
  • Recurrent pericarditis: pericarditis with relapse after at least 4 weeks
  • Chronic pericarditis: symptoms persisting >3 months without symptom-free interval for 4 weeks
• Features
  • Chest pain (100%), pleurisy (36%), fever (30%), ALT elevation (8%), peritonitis (5%)
  • Recurrence rate: 20-30% after first episode, 20-50% after first relapse
  • Investigations: ESR/CRP elevation, compatible ECG, echocardiographic evidence of effusion
• Treatment
  • Colchicine
  • If refractory: low-dose corticosteroids
  • If steroid dependent: methotrexate, azathioprine, anakinra, rilonacept, pericardectomy

Adult Onset Still’s disease: has auto-inflammatory and auto-immunity features

See dedicated chapter.

GENERAL APPROACH TO AUTO-INFLAMMATORY DISEASES

—STEP ONE

Recognize features suggesting auto-inflammatory disorder

• Periodic fever (common, but not always present)
• Age: May onset at younger age, especially if onset in a child
• Family: May have consanguinity or family history of auto-inflammatory disease
• Multi-organ: may include joints, skin, GI mucosa, serosa, vasculopathy, lymphadenopathy, eye, brain
• Flares: reflect innate immune system activity (quick onset, each flare stereotypically the same)
• Labs: Should have objective elevations in ESR and CRP concordantly with flares; antibodies negative (except for interferonopathies, where multiple antibodies can be positive.)

—STEP TWO

Recognize pattern suggesting specific auto-inflammatory disease

Complete patient profile, history, exam, and baseline investigations may suggest defined disorder

• FMF:
  Fever, 6-72h serositis, erysipelas-like rash in patient of Mediterranean/Middle-Eastern heritage
• MKD/HIDS:
  Fever, 3-6 days of rash, vomiting/diarrhea, lymphadenopathy with frequent infections
• FACS, MWS:
  Fever, urticaria ±cold-induced, with deafness, conjunctivitis, and inflammatory arthritis
• TRAPS:
  Fever x1-4 weeks with abdominal pain, myagias, rash, conjunctivitis, periorbital edema
• DADA2:
  Fever, PAN-like vasculitis, young-onset stroke, livedo, cytopenias, hypogammaglobulinemia
• Schnitzler:
  Fever, urticaria, bone/joint pain with paraproteinemia in patient ~50 years-old
• CNO/SAPHO:
  Bone pain/swelling in axial skeleton (SC joint), long bones, IBD, pustular rash or psoriasis
• VEXAS:
  Fever, polychondritis, neutrophilic dermatoses, joint swelling, ↓Hb/↑MCV, ↓PTL, men >40y

—STEP THREE

Investigations to support hypothesis

• Full baseline panel including CBC, creatinine, urinalysis/ACR, SPEP, immunoglobulins, ESR/CRP, ferritin
• Other markers if accessible, ex: IL-6, IL-18, IgD, IgA, CXCL, MKD, ADA2 activity, interferon signature
• NGS panel of specific genes for defined mutations in recurrent fever/autoinflammatory syndromes
• Whole-exome or genome sequencing of patient/affected family members, interpreted by experts

—STEP FOUR

Diagnosis and differential diagnosis

• Probability of autoinflammatory disease increases in patients presenting with a syndrome of
  inflammation and end-organ dysfunction plausibly explained by innate immune system activation in a pattern compatible with a known disease supported by genetic testing or other markers of disease.
• Consider possible underlying disease mechanism: inflammasomopathy, interferonopathy,  or
  NF-κB-opathies/aberrant TNF activity
• Differentials to consider include infection, malignancy, systemic autoimmune rheumatic diseases

—STEP FIVE

Treat empirically if high enough clinical suspicion

• NSAID and steroid response is non-specific, though PFAPA flares resolve with a single dose of steroid
• Colchicine response supports diagnosis of an inflammasomopathy
• IL-1i response is safe, even with active infection, and supports inflammasomopathy or NF-κB-opathies
• JAKi response supports relevance of interferon or IL-6 (interferonopathy, NF-κB-opathies)
  but must be used with caution if empirically used due to broad effect
• TNFi may be helpful for empiric use, though with caution given immunosupression

REFERENCES

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