Rheumatology Flashcards
Causes of inherited CTD
Marfan’s syndrome
Ehlers-Danlos syndrome
Osteogenesis imperfecta
Alport’s syndrome
Causes of autoimmune CTD
SLE
RA
Sjogren’s
PM/DM
MCTD
Scleroderma
Overlap/UCTD
HLA region which strongest links with development of autoimmune CTD
HLADRB1
HLA class II sits on what chromosome
Chromosome 6
HLA class I sits on what chromosome
Chromosome 15
HLA class II presents to which cell
CD4 T cells
HLA class I presents to which cell
CD8 T cells
Function of HLA class II
Recognition of self
Presentation foreign peptides to CD4 cells
Role of HLA in SLE
Both HLA-DR and HLA-DQ loci implicated in SLE, particularly HLA-DRB1
Ethnic differences in HLE loci for SLE
Higher risk of SLE in African American and Hispanic for HLA DRB11503 and HLADRB108
Protective risk of SLE in Caucasian for HLA DRB1*0301
Effect of race on clinical manifestations of SLE
Non Caucasian ethnicities significantly higher frequency of lupus nephritis, neuropsychiatric SLE, severe haematologic manifestations and APLS
Asian ethnicities increased prevalence and severity, increased renal disease and increased auto-antibodies
SLE in Australian Indigenous population
Prevalence 2-4x of Caucasians
High disease activity and higher incidence of LN
Tend to have higher morbidity and mortality
Predisposing genes in SLE
HLA genes
STAT 4
Others include IRF5, IRAK1, TNFAIP3, SRP1, TLR7
Environmental factors that contribute to SLE
Oestrogen - can stimulate type 1 IGN pathway (whilst progesterone inhibits it), higher risk of autoimmunity
UV light - higher rate of formation of auto-antibodies
Microbiome
Infection - EBV, CMV, COVID
Major pathways of signalling B and T cells in SLE
Overexpression of IFN (biggest one)
Overexpression of neutrophils
Overexpression of plasmablasts
Role of type I interferon in SLE
Type I IFN is produced in response to a viral infection - acts as an alarm signal
- produced by most cells, but particular APCs
- induced by viral nucleic acid
Recruiter of T cells, B cells and neutrophils
Cytokines involved in SLE
TNF –> neutrophil recruitment, monocyte activation, sustains type I IFN expression
IL-6 –> B cell proliferation
IL-17 –> recruitment of inflammatory cells
IL-10 –> B cell proliferation, loss of tolerance
BAFF –> B cell survival (CD19, CD20), T cell activation
IFN Type 1
Role of Type 1 IFN in SLE
Reduction of Treg cells - loss of tolerance
Increase NETs - IL-17, inflammation
Increase BAFF - B cell proliferation, loss of tolerance
In SLE, type I IFN is initially produced in response to
Production of host nucleic acids
Dermatological and MSK manifestations of SLE
Malar rash
Photosensitive rash
Discoid rash
Subacute cutaneous lupus erythematosus
Periungal erythema/capillary dilatation –> pathogenic Raynaud’s
Alopecia
Mucosal ulcers - PAINLESS
Charcot’s arthropathy - reversible, non erosive arthritis
Classes of lupus nephritis
Class I - mesangial immune deposits without hypercellularity
Class II - mesangial immune deposits with hypercellulary
Class III - focal proliferative (<50% of glomeruli)
Class IV - diffuse proliferative (>50% of glomeruli)
Class V - membranous
Class VI - advanced sclerosing lesions
Indications for treatment of lupus nephritis
Class III-V indicated for treatment (proliferative/membranous)
Class I-II - treatment not required
Class IV - treatment refractory
Clinical manifestations of CNS lupus
Seizures
Headaches
Stroke syndromes
Transverse myelitis
Coma
Dementia
Ataxia
Rigidity, tremor
Chorea
Aseptic meningitis
Psychiatric disorders
SAH
Hemiballismus
Cranial neuropathy
Peripheral neuropathy
Mononeuritis multiplex
MS-like disorder
GBS
MRI findings on CNS lupus
T2 white matter lesions
- sensitive but not specific
- does not correlate to disease activity
Antibodies/serology in SLE
ANA - all patients
anti-dsDNA
anti-Sm - higher risk of patients
anti-Ro/La - higher risk of neonatal heart block
Complement
Marker of disease activity in SLE
Complement level - though not for all patients
Not dsDNA
Findings of serologically active SLE
High dsDNA and/or low complement levels
Diagnosis of APLS
Presence of at least 1 of 3 antibodies (on multiple occasions)
- Beta 2 glycoprotein, anticardiolipin, lupus anticoagulant
Thrombotic event
Target for SLE management
Aim for remission
If not possible, aim for low disease activity state
Treatment for SLE
Treat the lesion not diagnosis
Hydroxychloroquine - standard of care
Anti-malarials
- skin and joint disease
Steroids
- Low dose for skin, joint or musculocutaneous disease
- Medium dose for serosal, moderate haem disease
- High dose for renal, significant haem disease
MTX
- skin and joint disease
Azathioprine
- for everything
Mycophenolate mofetil
- Class III-IV GN
- Or if azathioprine intolerant
Cyclophosphamide
- severe proliferative GN and if other management fails
Toxicity of hydroxycholoquine
Ocular toxicity
- requires annual review after 5 years of therapy
Management of lupus nephritis
Induction therapy
- IV glucocorticoids (e.g., methylprednisolone)
PLUS other immunosuppressants (e.g., mycophenolate or cyclophosphamide)
Maintenance of remission
- Oral prednisone
PLUS mycophenolate OR azathioprine
- Refractory or relapsing disease: Rituximab may be considered.
Indication for biologic therapy in SLE
Persistently active disease, frequent flares despite adequate treatment
Biologic therapy used in SLE
Rituximab - CD20 antibody –> effective if high dsDNA, low complement
Belimumab - anti-BAFF –> add on therapy for lupus nephritis
Voclosporin - calcineurin inhibitor –> add on therapy for lupus nephritis, not PBS supported yet
Other therapies not PBS supported yet - Anifrolumab (anti-TFN1) and eculizumab
Preventative management in SLE
Annual CVS risk factor screening
Immunisations
Bone health
BP in lupus nephritis
Cancer screening
Reproductive health
B cell therapy works best in which group of SLE patients
Serologically active patients
Clinical features of Sjogren’s
Sicca symptoms (all patients)
Dental disease
Non-erosive arthritis
Lymphocytic infiltration into skin and organs - renal, respiratory, mucocutaneous, MSK, risk of NHL
Indication for lymphoma annual screening
If more than 2 risk factors, do annual screening
Management for Sjogren’s disease
Sicca symptoms
- education, artificial tears, secretagogues, treatments for complications
Systemic manifestations
- HCQ, MTX, leflunomide, mycophenolate
- +/- glucocorticoids
Scleroderma definition
Slow initial inflammation leading to fibrosis of connective tissues
Division of scleroderma disease and relevance to mortality
Limited - below elbow and knee, face involvement, truncal sparing
Diffuse - everywhere else
Diffuse disease related to higher mortality
CREST symptoms
Calcinosis
Raynaud’s
Oesophageal dysmotility
Sclerodactyly
Telangiectasia
Hand clues for scleroderma
Early - oedematous “puffy fingers”
Induration phase - some damage present
Late - sclerodactyly, lots of damage present
Findings of Raynaud’s
Primary
- not associated with tissue damage - no signs present
- no underlying disease
Secondary
- Due to underlying disorder
- Structural microvascular abnormalities present
Pulmonary involvement in scleroderma
Limited skin disease - higher chance of primary PAH
Diffuse skin disease - higher risk of ILD and secondary PAH
Autoantibodies present in scleroderma
Scl-70
- associated with diffuse skin disease
- higher risk of ILD
Centromere staining pattern
- associated with limited skin disease
- higher risk of primary PAH
RNA polymerase III
- rapidly progressing skin disease
- high risk of renal crisis
Indications for systemic immunosuppressive therapy in SLE patients
- Severe and progressive diffuse skin involvement
- ILD
- Myocarditis
- Severe inflammatory myopathy and/or arthritis
Features of myopathies
Weakness
Painless
Arthritis
Raynauds
ILD
Classical skin features of DM
Heliotrope rash
Shawl/V sign
Gottron’s papules
Treatment principle of myopathies
Glucocorticoids + steroid sparing agent +/- IVIg
If rapidly progressing variant, use cyclophosphamide or MMF + steroid + IVIg
Anti-synthetase syndrome clinical features
Myositis
ILD
Arthropathy
Fever
Raynaud’s
Mechanic’s hands
Positive autoantibody in anti-synthetase
Anti-Jo1
Features of amyopathic dermatomyositis
Classic DM skin findings + more cutaneous features i.e. ulceration
Risk of rapidly progressive ILD particularly in MDA-5 disease