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
Positive antibodies with dermatomyositis and its associations
Anti Mi2 –> classical DM
Anti SAE –> severe cutaneous disease
Anti MDA5 –> poor outcomes, hypo-amyopathic
Anti TIF-1y/a –> associated with cancers, requires yearly cancer screening
Anti NXP2 –> also associated with cancers, diffuse calcinosis
Features of sine scleroderma
No detectable skin involvement however has other features (i.e. Raynaud’s, digital ulcers, PAH) and positive antibodies specific for systemic sclerosis
Groups of inflammatory myopathies
Group 1 - sporadic IBM
Group 2 - polymyositis
Group 3 - Dermatomyositis
Group 4 - Non-specific myositis
Group 5 - immune mediated necrotising myopathy
Features of IBM
Insidious, asymmetrical onset affecting upper extremities
Quadriceps weakness
Finger flexor weakness
Dysphagia
Features of non-IBM
Acute-subacute
Proximal muscle weakness
Features of immune mediated necrotising myopathy
Resembles polymyositis
Muscle necrosis
Biopsy - paucity of inflammatory infiltrate compared to PM
Autoantibodies associated with IMNM
Anti SRP –> aggressive, severe muscle weakness with lung involvement. Refractory to immunomodulators. Often require rituximab
Anti HMG-CoA reductase –> generally resistant to treatment, purely myopathic phenotype without skin or lung involvement
Myositis associated antibodies
Anti SSA/Ro 60
Anti Ro 52/TRIM21
Anti SSB/La
Anti-PM-Scl75
Anti-PM-Scl100
Anti-ku
Anti-U1RNP
Classification of spondyloarthropathies
Axial spondyloarthritis i.e. non-radiographic axial SpA, ankylosing spondylitis
Reactive arthritis
Psoriatic arthritis
Arthritis associated with IBD
Clinical features of spondyloarthritis
IBD
Arthritis - oligoarticular, lower limb
Sacroiliitis
Enthesitis
Dactylitis
Uveitis
Psoriasis
HLAB27 positive
FHx
IBD
Recent infection
Definition of inflammatory back pain
Chronic > 3 months
Onset before age of 40
Insidious onset
Improvement with exercise
No improvement with rest
Nocturnal pain improving on waking i.e. responds to NSAIDs
Features of ankylosing spondylitis
Radiographic features of sacroiliitis
Inflammatory arthritis of axial skeleton
Extra-axial and extra-articular involvement
Progressive stiffening and fusion of spine
Strong association with HLAB27
Pathogenesis of new bone formation in AS/SpA
Enthesis is primary source of pathology
- insertion of tendons/ligaments onto bone
- annulus fibrosis in spine
- ?mechanical stress
New bone formation
- in sacro-iliac joints, vertebra
- leads to ankylosis
- occurs at site of enthesitis/inflammation
Clinical features of AS
Axial features
- Inflammatory back pain
- Alternating and poorly localised buttock pain
- Restriction in spinal movement
Extra-axial involvement
- Hip arthritis
- Peripheral arthritis/synovitis
- Enthesitis especially at Achilles, plantar fascia, chest wall, pelvic brim
- Acute anterior uveitis
- IBD
- Osteopenia
- Cauda equina
- Increase CVD risk, AR, conduction disturbance
- Chest wall restriction
- Apical fibrosis
- Secondary amyloidosis
Investigations in AS
HLAB27
Inflammatory markers
Imaging of sacro-iliac joints, cervical and thoraco-lumbar spine
Imaging changes in sacro-iliitis
Early - erosions, sclerosis at joint margins
Later - pseudo-widening
Last - joint space narrowing progressing to ankylosis
Radiographic grading of sacroiliitis
Grade 0 - normal
Grade 1- suspicious changes
Grade 2 - minimal abnormality, small areas of erosion/sclerosis, normal joint width
Grade 3- unequivocal abnormality, erosion, sclerosis, joint widening, narrowing or partial ankylosis
Grade 4 - severe abnormality, total ankylosis
Features of sacro-iliitis on MRI
- Bone marrow oedema (active inflammation)
- Erosions detected earlier
- Synovitis, enthesitis
- Features of spinal involvement
Risk factors for more rapid and increased radiographic progression in AS
Rapid
- Men who are HLAB27 positive
- Patients with more damage at baseline
- Patients with higher inflammatory markers
- Higher disease activity states
Increased
- Pts with long standing, advanced AS
- early axial SpA (radiographic and non-radiographic)
First line treatment for AS
Physiotherapy
NSAIDs
Can consider sulfasalazine or MTX for peripheral arthritis (though not effective for axial disease)
Indications and examples of biologic treatment for AS
Indicated for those with inadequate response to NSAIDs and physiotherapy
TNF inhibitors i.e. Infliximab, adalimumab, etanercept
IL-17A inhibitors - secukinumab
Certolizumab
Upadacitinib
Pathogenesis of psoriatic arthritis
Genetic risk factors - first degree relative
Tissue specific factors
Obesity
Psoriasis
Clinical features of psoriatic arthritis
Distinct patterns of joint involvement
- Asymmetric oligoarthritis/monoarthritis
- Polyarthritis - symmetric
- Spondyloarthritis - axial, AS-like
- DIP joint with nail disease
- Arthritis mutilans
Dactylitis (40-50%)
Enthesitis (30-50%)
Skin disease
Nail changes - pitting, onycholysis, nail plate crumbling
Comorbidities of PsA
Increased CVD
Higher prevalence of metabolic syndrome
Obesity
Investigation findings in PsA
Elevated inflammatory markers
RF and CCP NEGATIVE
Imaging
- Erosion with new bone formation - “Pencil in cup”
- Ankylosis
Treatment options for psoriatic arthritis
NSAIDs + CSI for symptomatic treatment
csDMARDs
Anti-TNF
Anti-IL17A
Anti-p40 subunit IL12/23
Anti-IL23
JAK inhibitors
Treatment considerations for psoriatic arthritis
MSK manifestations
- peripheral arthritis
- axial involvement
- enthesitis
- dactylitis
Psoriasis manifestations
- skin and/or nails
Co-morbditis
- IBD, uveitis
- metbolic syndrome
Nomenclature of vasculitis
Immune complex small vessel vasculitis
- Cryoglobulinemic vasculitis
- IgA vasculitis (Henoch-Schnolein)
- Hypocomplementemic urticarial vasculitis
Medium vessel vasculitis
- Polyarteritis nodosa
- Kawasaki disease
Large vessel vasculitis
- Takayasu arteritis
- Giant cell arteritis
ANCA-associated small vessel vasculitis
- Microscopic polyangiitis
- Granulomatosis with polyangiitis
- Eosinophilic granulomatous with polyangiitis
Pathogenesis of GCA
Unclear aetiology - associated with genetic factors and possible triggering event
Two key cytokine influences
- IL-6 –> inflammatory response
- IFN-y –> produced by Th1 cells (under IL-12 and IL-18), local vascular effect
Clinical features of GCA
Constitutional symtoms
- fever, malaise, anorexia, weight loss
Cranial symptoms
- new heaadache (could be temporal, occipital or frontal)
- jaw/tongue claudication
- scalp tenderness
Associated with PMR
- inflammatory shoulder and pelvic girdle symptoms
Ocular symptoms
- temporary vision loss (amaurosis fugax, monocular)
- permanent vision loss
- diplopia
Extra-cranial/large vessel disease
- Aortic and branches involvement
- Cough
Causes of ocular complications in GCA
AION
Central retinal artery occlusion
Intracerebral (posterior circulation)
Investigation findings of GCA
Inflammatory markers
Temporal artery biopsy
- gold standard test though this is flawed (may have skip lesions)
- intimal hyperplasia, inflammatory cell infiltrate, disruption of internal elastic lamina, giant cells
Temporal artery US
Imaging of large vessel/extra cranial disease
PET/MRI scans
Management of GCA
Steroid management
- GCA without visual Sx: Pred 40-60mg daily
- GCA with visual Sx: IV methylpred for 3 days then pred
Tocilizumab
Definition of GPA
Necrotising granulomatous inflammation, usually involving upper and lower respiratory tract, small to medium vessels or necrotising GN
Positive PR3-ANCA (65-75%)
Positive MPO-ANCA (20-30%)
ANCA ~5%
Definition of MPA
Necrotising vasculitis with few or no immune deposits, predominantly affecting small vessels
Necrotising arterties and necrotising GN may be present
Positive MPO-ANCA (55-65%)
Positive PR3 ANCA (20-30%)
ANCA 5-10%
Definition of eosinophilic GPA
Eosinophil-rich and necrotising granulomatous inflammation often involving respiratory tract, associated with asthma and eosinophilia
Similarities of GPA and MPA
Small-medium sized necrotising vasculitis
Predilection for renal involvement - pauci-immune necrotising GN
Pulmonary involvement - cough, haemoptysis
Constitutional symptoms
Cutaneous involvement
GPA specific clinical features
ENT manifestations - crusting, sinusitis, hearing loss, saddle nose
Subglottic/airway stenosis, nodules/cavities
Peripheral nerve involvement in 15% of patients
Retro-orbital pseudotumour, other granulomatous masses
cANCA-PR3 predominant
MPA specific features
Rhinosinusitis, sensori-neural hearing loss
ILD
Peripheral involvement in 70% of pts - MMN, peripheral neuropathy
pANCA-MPO predominant
Management of GPA/MPA
High dose GC + rituximab
High dose GC + cyclosphosphamide
Clinical features of EGPA
Prodromal phase
- Severe allergic asthma attacks (chief concern)
- Allergic rhinitis/sinusitis
Eosinophilic phase
- Lung disease
- Pericarditis
- Gastrointestinal involvement: bleeding, ischemia, perforation
Vasculitic phase
- Skin nodules, palpable purpura
- Mononeuritis multiplex (loss of motor and sensory function with wrist or foot drop), symmetric or asymmetric polyneuropathy
- Pauci-immune glomerulonephritis
Treatment of EGPA
Nonsevere disease
Oral glucocorticoids: e.g., prednisone
PLUS a glucocorticoid-sparing agent: e.g., mepolizumab (preferred), methotrexate, OR mycophenolate mofetil
Severe disease
High-dose glucocorticoids: e.g., methylprednisolone pulses OR prednisone
PLUS a glucocorticoid-sparing agent: e.g., rituximab (preferred) OR cyclophosphamide
Clinical features of takayasu arteritis
Constitutional Sx
Carotidynia
Arterial stenosis/occlusion –> claudication, absent pulses
Discordant BP, bruits
Aortic dissection, aortic root dilatation with aortic valve regurgitation
Clinical features of polyarteritis nodosa
Constitutional symptoms
Skin changes - purpura, panniculitis, livedo, necrotising vasculitis in dermis
Renal - infarctions/ischaemia leading to impairment, HTN
Neurological - MMN, neuropathy
GI - mesenteric angina, wt loss, bowel perforation
Myalgias
Diagnosis of PAN
ANCA negative
Aneurysms on angiography/CTA/MRA
Biopsy of involved tissue
Clinical features of IgA vasculitis
Preceded by infection especially URTI
Purpura
Arthralgia/arthritis
GI Sx - abdo pain, nausea, GI haemorrhage
Renal - haematuria +/- proteinuria, progression to ESKD
Diagnosis of IgA vasculitis
Usually made on biopsy
Leukocyclastic vasculitis with IgA deposition present
Causes of cryoglobulinaemic vasculitis
Hepatitis C (most common)
Hepatitis B
CTD e.g. SLE
Primary Sjogren’s
Clinical features of cryoglobulinaemic vasculitis
Classic triad - purpura, weakness, arthralgia
Constitutional Sx
Peripheral neuropathy
Renal disease - GN
Diagnosis and management of cryoglobulinaemic vasculitis
Presence of cryoglobulinaemia
RF positive
Low complement
Screen for underlying causes - HCV/HBV/HIV, ANA/ENA/dsDNA, SPEP
Assess disease extent - CK, MSU, FBC, LFTs etc.
Treatment of underlying disease
Severe disease with GC + RTx
Characteristics of hypocomplementaemic urticarial vasculitis
Clinical urticaria with cutaneous leucocytoclastic vasculitis on biopsy
Low complement levels
Urticaria
Arthralgia
Major organ involvement
Triggers of RA
Smoking
Silica
Gingivitis
Gut microbiota
Risk factors for RA
HLA DRB gene (-01, -04)
STAT4
PADI
PTPN22
Smoking
Periodontitis
Gut dysbiosis
Anti-CCP
Cells involved in pathogenesis of RA
TNF
IL-1
IL-6
JAK signalling
Citrullination
T reg (protective factor)
OPG (protective factor)
What cell is most predominant in RA synovial fluid
Neutrophils
What is involved in joint lining inflammation in RA?
Synovitis
Bone erosion
Pannus
Cartilage degradation
Pathogenesis of RA
TNF, IL-1, IL-6 –> PG, COX –> Swelling/pain
IL-2, IGN –> RANKL –> bone damage
IL-12, IL-15, IL-18, IL-17 –> MMP, aggrecanase –> cartilage loss
Main T cells involved in RA
Th1
Th17
T reg cells
Role of Treg cells in RA
Produced by thymus
Suppress activation and expansion of naive T cells and its differentiation to effector T cells i.e. T helper cells
X-ray findings in RA
Destruction of peri-articular bone (osteopenia)
Erosions
Pathogenesis of bone erosion in RA
Mediated by osteoclasts
Inflammation promotes osteoclast activity (driven by cytokines TNF, IL-1, IL-6) causing erosions
Protective factors of bone erosions in RA
Osteoprotegrin (OPG) protects bone by blocking osteoclast development
Clinical features of RA
Small joint involvement
Symmetrical
AM stiffness lasting one hour
Can be either monoarthritis or polyarthritis
Heberden’s nodes
Osteophytes
Juxta-articular sclerosis
DIP joints spared
Investigation findings in RA
RhF or anti-CCP –> one third of RA pts are seronegative
Imaging findings - nodules, erosions
Pathologies with DIP sparing
RA
SLE
Pathologies with DIP involvement
Psoriasis
Gout
OA
Rheumatoid factor characteristics
Autoantibody (usually IgM) directed against Fc portion of IgG
Rheumatoid factor has high titre in which conditions
RA (70-90%)
Sjogren’s (75-95%)
Cryoglobulinemia (40-100%)
Anti-CCP in RA
Highly specific for RA (90% specificity)
Highly predictive of RA in asymptomatic and early undifferentiated arthritis
Reasonable sensitivity
Marker of erosive disease but not useful in assessing current RA activity
Predictors of severity in RA
Presence of erosions
Anti-CCP
RF
Indicators of RA activity
CRP
ESR
Swollen joint count
What should MTX not be combined with in RA?
Leflunomide - increases risk of ILD, pancytopenia etc.
Biologic therapy in RA
TNF blockade
IL-1 blockade
IL-6 blockade
Costim blockade
B cell depletion
JAK kinase blockade
Agents available for TNF blockade
Infliximab - Chimeric IgG1 monoclonal Ab
Etanercept - Rh TNF recombinant
Adalimumab - human monoclonal Ab
Precautions for TNF blockade
TB
Congestive heart failure
Demyelinating disease
Lymphoma
Lupus-like syndrome or serology ANA/dsDNA
Cancer in last 5 years
Infections - do not initiate whilst active infection present
MOA of B cell therapies
Anti CD20 - B cell depleting
Anti CD22 - B cell modulating
Anti CD 40/CTLA1Ig - blocking co-stimulation
BlySL/BAFFL - Blocks B cell activation/differentiation
MOA of rituximab
Chimeric monoclonal Ab to CD20
MOA of tofacitinib
JAK1/3 inhibitor –> blocks multiple cytokines
MOA of baracitinib
JAK 1/2 inhibitor
Increased risk of infection and VTE
Current therapy in RA
Non-biologic DMARDs
- MTX
- Leflunomide
- SSP
- HCQ
Biologic DMARDs
- Anti TNF - Etanercept, infliximab, adalimumab, golimumab, certilizumab
- Rituximab - anti CD20
- Abatacept - CTLA4-Ig
- Tocilizumab - IL-6 inhibitor
- Tofacitinib - JAK1/3 inhibitor
- Baricitinib - JAK1/2
- Upatacitinib - JAK inhibitor
Relationship between RA and CVD
RA is an independent risk factor for CAD
Atherogenesis/RA inflammatory pathology overlap
CRP directly associated with risk
CVS risk management and inflammation crucial
