RA + Spondyloarthropathy Flashcards
Dactylitis is a marker of disease severity in which condition?
Psoriatic arthritis
What joints dose RA affect?
Usually the small joints of the hands (MCP, PIP), sparing the DIPS. Can also affect larger joints like knee/ankle but they occur later. Can also affect atlantoaxial joint
What are the classic hand signs of RA?
- Radial deviation of wrist
- Ulnar deviation of fingers at MCPs
- Swan neck deformity: flexion at DIP, hyperextension at PIP
- Boutonniere deformity: flexion at PIP, hyperextension at DIP
- Z deformity of thumb: Z deformity of thumb (Hitchhiker thumb): IP hyperextension and MCP flexion
Extraarticular manifestations of RA
- Skin: rheumatoid nodules, vasculitis, raynaud phenomenon
- Lung: pulmonary nodules (related to subcutaneous rheumatoid nodules), pleural effusion, interstitial lung disease
- Ophthal: episcleritis, scleritis
- Neuro: carpal tunnel, cervical cord compression
- Cardio: premature atheroscleroris, CAD, PVD
- Felty Syndrome: triad of RA, neutropenia, splenomegaly
- Lymphoma (3x risk)
What patterns of ILD are associated with RA?
UIP: usual interstitial pneumonia - subpleural reticulation, apical basal gradient, traction bronchiectasis, honeycombing
NSIP: non specific interstitial pneumonia
- subpleural sparing, traction bronchiectasis, apical basal traction, ground glass changes
Characteristics of felty syndrome
- Felty syndrome-in longstanding, sero+, nodular, deforming RA
- Splenomegaly, leukopenia, lower limb ulceration, hyperpigmentation, bone marrow hyperplastic suppressed by ongoing inflammation
- Triad: chronic arthritis + neutropenia + splenomegaly
- Associations
Extra-articular features including nodules, lymphadenopathy, leg ulcers
HLA-DR4 - BM: normal myelopoiesis, maturation arrest
- ↑ susceptibility to infection
- ↑ risk of lymphoproliferative disease
- Treatment
Aggressive RA treatment
G-CSF or GM-CSF
What conditions is HLADR4 associated with?
RA
Addison disease
Type 1 Diabetes
(RAD/ADR)
What increases the genetic predisposition for RA
HLADR1
HLADR4 (main one)
HLA-DRB1-04
Environmental factors of RA
- Smoking - increases the risk in seropositive RA
- Hormones: OCP decrease risk of RA especially ACPA positive disease
- Periodontal disease: Prophyromonaas gingivalis 4x increased risk of RA
RF and anti-CCP in RA
Anti-CCP
- Highly specific 95%
- Precede onset of RA and an important predictor for the development of RA
- Associated with more severe and destructive disease and associated with RA related ILD, CVD
- Better predictor of erosive disease
- Presence means increased change of responding to rituximab following failure of anti-TNFa therapy
RF
- An antibody (usually IgM) directed against Fc portion of humanIgG
- Seropositive patients = more severe clinical disease, more complications, increased cardiac risk
- Can decrease/seroneg with effective treatment
- Better predictor of extra-articular manifestations
Neither RF or anti-CCP are helpful to assess currrent RA activity
What non-RA situations is RF associated with?
- Sjogrens (75-95%), cryoglobulinemia (40-100%), SLE (15-35%), other autoimmune diagnosis
- Non-rheumatic: indolent/chronic infection (Hep B/Hep C, TB), malignancy
- Very high titre consider:
Cryoglobulinaemia
Primary sjogren’s syndrome
Xray findings of RA
- Symmetric involvement
- Periarticular Soft Tissue Swelling (joint effusion, tenosynovitis)
- Joint Space Narrowing ← Pannus + MMPs
- Bony Erosions/Marginal erosions ← Pannus + Osteoclasts
- Periarticular Osteopenia/Juxtaarticular osteoporosis ← RANKL + Osteoclasts (periarticular osteopenia often early xray sign)
- Deformities + Subluxation in advanced disease
Early x-ray findings
loss of joint space
juxta-articular osteoporosis
soft-tissue swelling
Late x-ray findings
periarticular erosions
subluxation
Benefits of US and MRI in RA
US
- Greater sensitivity to detect synovitis
- Power doppler to detect inflammatory activity
- Early detection of cartilage and bone structural damage
- Multiple joints affected
MRI
- Detailed info regarding synovitis, marrow oedema (precursor to erosions) and erosions
- Limited one joint per exam
Joint aspirate of RA
- Opaque/Translucent
- High Protein ← Inflammatory Exudate
- Moderately High Neutrophil Count ← Due to Complement Activation (c5a)
- Mildly Low Glucose ← Consumption by Inflammatory Cells
- Low Viscosity ← Neutrophilic Enzymes/MMPs break down hyaluronic acid
- Negative Culture & Polarising Microscopy
↑ Proteins & Neutrophils but ↓ Glucose & Viscosity
Histopathological features of synovial biopsy in RA
Pathophysiology
- Synovial lining hyperplasia with underlying granulation tissue
- Lymphohistiocytic Infiltrate → B & T Cells, Plasma Cells, Macrophages
- Hypervascularity → Vasodilation + Angiogenesis
- Sparse Fibrinopurulent Exudate ← Fibrin + Dead Neutrophils
- Increased Osteoclastic Activity in Underlying Bone
- Neutrophils NOT found in synovium but in synovial fluid
- Osteoclastic activity in the underlying bone → allows pannus to penetrate into the bone and cause juxta-articular erosions, subchondral cysts and osteoporosis
- Involves a genetic predisposition to RA in addition to environmental factors
- Genetic Predisposition + Hormonal Factors (Estrogen)
- Environmental Exposure → Infection + Smoking
- Loss of Self-Tolerance
- Autoreactive CD4+ T Cell
- Stimulate Autoreactive B Cell → Plasma Cell
- Plasma Cells produce Auto-antibodies → RF + Anti-CCP
- Immune Complex Formation
- Deposition into the Synovial Cavity
- Trigger Inflammatory Response by activating Complement + Macrophages
- Macrophages release IL-1, IL-6 & TNF-a
- Inflammatory Cytokines activate Fibroblastic Release of MMPs & RANK-L
▪ Matrix metalloproteinases (MMPs) are a group of enzymes that in concert are responsible for the degradation of most extracellular matrix proteins during organogenesis, growth and normal tissue turnover.
▪ RANKL induces the differentiation of monocyte/macrophage–lineage cells into the bone–resorbing cells called osteoclasts - RANK-L stimulates Osteoclast Production & Activity → Bone Erosions
- Complement (c5a) draws in Neutrophils
- Inflammatory Cells + Granulation Tissue + Synovial Hyperplasia = Pannus
▪ Pannus = Mass of synovium and synovial stroma consisting of:
▫ Inflammatory cells → Neutrophils + Macrophages + Lymphocytes
▫ Granulation Tissue
▫ Synovial fibroblasts
▪ This grows over the cartilage and causes cartilage and bone erosion - Pannus ultimately chews away the cartilage and eventually into the bone
Treatment of RA
- 1st Line: NSAIDS + steroids + DMARDs (MTX)
MTX is the mainstay treatment
Patients unable to take MTX may require an alternative agent, such as HCQ, SSZ, or LEF. - 2nd Line: In patients resistant to initial DMARD therapy (eg, MTX), treat with a combination of DMARDs (eg, MTX plus SSZ and HCQ, or MTX plus a TNF inhibitor)
- 3rd Line: If failing above treatment then biological DMARD or tsDMARD (eg: JAK inhibitors)
Examples of biological dmards
- TNF-alpha inhibitors: Etanercept, Infliximab, Adalimumab
- T cell costimulation inhibitor (CD80/86): abatacept - soluble fusion protein consisting of CTLA-4 linked to IgG, blocks CD80/86
- IL-6 receptor antagonist: Tocilizumab
- IL-1 receptor antagonist: Anakinra
- JAK Inhibitors: Baricitinib (Jak 1,2), Tofacitinib (Jak 1,3), Upadacitinib (Jak 1)
- Anti-CD20 (B cells): Rituximab
Will need to screen for TB risk factors and perform quantiferon, may require prophylactic isoniazid
All BDMARDs are more efficacious when combined with conventional DMARDs
What medications do you avoid giving with methotrexate?
Trimethorpim +/- sulfamethoxazole due to risk of myelosuppression
MOA and SE of methotrexate
ANCHOR DRUG FOR RA
MOA:
Methotrexate inhibits dihydrofolate reductase, preventing the reduction of dihydrobiopterin (BH2) to tetrahydrobiopterin (BH4), leading to nitric oxide synthase uncoupling and increased sensitivity of T cells to apoptosis, thereby diminishing immune responses. reduce PURINE SYNTHESIS
nausea, oral ulcers, hair loss, abnormal LFTs, cytopenias, risk of pneumonitis (increases with prior ILD), teratogenicity (needs to be held for 3 months prior to attempting conception) - preventable by prophylactic folates
Main SE
- hepatitis
- pneumonitis - can occur at any stage in treatment
- myelosuppression
Contraindication
- pregnancy
- alcoholism, liver disease
Note: subcut methotrexate more effective than oral
For cytopenias - folinic acid
Can be used prior to surgery, don’t need to stop
Sulfasalazine in RA and SE
- Useful when methotrexate contraindicated, eg: regular alcohol intake
- Reduces radiographic
- AEs:
Hypersensitivity reactions (mainly cutaneous), nausea, diarrhea, agranulocytosis, drug-induced lupus, azoospermia, hepatitis, pneumonitis, aplastic anaemia, haemolytic anaemia
SE: skin reactions (can cause DRESS), hepatitis, pneumonitis, agranulocytosis, aplastic anamiea
- Fever, rash, deranged LFTS - stop drug and do not rechallenge.
- The most common DMARDs to lead to AE within triple tx(mtx, ssz, hcq) regimens
Can be used in pregnancy
SE
- Oligospermia
- Steven Johnson Syndrome
- Pneumonitis
- Myelosuppression
- May colour tears - stained contact lenses
- Hepatitis
Cautions
- G6PD deficiency
- Allergic to aspirin or sulphonamides (cross reactivity)
Hydroxychlorquine in RA and SE
- Best tolerated DMARD but modest clinical defect
- No effect on radiographic progression
- First line treatment for palindromic rheumatism
- AEs
Hyperpigmentation
Retinopathy/Maculopathy
Bulls eye retinopathy - may result in severe and permanent eye loss - Limit dose to 5mg/kg
- Baseline ophthalmology exam within first year, annual screening after 5y
- Risk factors: high dose/duration of treatment; renal disease; pre-existing retinal disease; concomitant use of tamoxifen
Rarely: myopathy, cardiomyopathy
Lefluonmide in RA and SE
- Inhibits pyrimidine synthesis
- Slow radiographic progression
- AE: diarrhoea, hypertension, pneumonitis, teratogenic, peripheral neuropathy
- CI: pregnant + breast feeding, liver disease, haem abnormalities
Conjugated and excreted renally and in the gut
Extensive enterohepatic circulation = long half life
Require cholestyramine for washout
- Long half life 2 weeks
leflunomide has a very long wash-out period of up to a year which requires co-administration of cholestyramine
When is TNFi used in RA?
Effective in MTX incomplete responders
More effective when combined with methotrexate
Which TNFi is safe in pregnancy?
Certolizumab: lacks an Fc fragment, very little crosses the placenta
Can also use other TNFi
SE of TNFi
- Infections
- Opportunistic infections, eg: TB
Usually present as extrapulmonary manifestations, eg: weight loss - Malignancies - non melanoma skin cancer, lymphoma
- Demyelination especially etanercept
- Autoantibodies - ANA/ds DNA
Highest in infliximab, lowest in etanercept + certolizumab, methotrexate prevents antibody formation - Hepatotxocity
- Dermatologic reactions
- Lupus like syndromes
- Uncommon: psoraisis, vasculitis, sarcoidosis, drug induced lupus
Common to reactivate latent TB or hep B .
Abatacept in RA
- T cell costimulation inhibitor (CD80/86) - CTLA bound to Ig binds to B7
- Effective in MTx incomplete responders - approved in combination with Mtx
- Similar efficacy to TNFi
- More effective if anti-CCP positive
- Slows radiographic progress
- Lower risk of infections compared with TNFi and IL6 so may be safer in patients with infections such as bronchectasis
CTLA-4 Ig: inhibits binding of CD28 to CD80/86
Prevents T cell receiving co-stimulatory signal
SE: headaches, nausea, increased infections (but better than other bDMARDs), increased risk of haematological malignancies, exacerbates COPD
Tocliziumab in RA and SE
- IL6 inhibtior
SE:
- LFT changes,
- neutropenia,
- hyperlipidaemia (CV risk not increased),
- intestinal perforation (avoid in diverticulosis)
Rituximab in RA and SE
B cell inhibitor
Greatest benefit in seropositive patients
SE: infections, PJP, progressive multifocal leukoencephalopathy (PML), reactivation of hep b, diminished response to vaccinations
Avoid in Hep B
Effective in rheumatoid lung disease
JAK inhibitors in RA and SE (targeted synthetic DMARD)
Work in the cell nucleus
JAK: cytoplasmic tyrosine kinases, crucial for signal transduction to the nucleus from membrane receptors for cytokines
- Initiating players of JAK/STAT pathway
- Binding of effector molecules to JAK –> signal transduction to nucleus
Tofacitinib (Jak 1,3)
Baricitinib (Jak 1,2)
Upadacitinib (Jak 1)
More effective than adalimumab (TNFi) in methotrexate resistant RA
SE:
- Risk of thrombosis, appears higher for baricitinib
- High risk of shingles
- Similar to IL6 inhibitor: LFT changes, neutropenia, hyperlipidaemia, lower intestinal perforation
- Cytopenia including anaemia
- Malignancies
- Sudden CV risk
Jak1 : most important in RA
Jak 2: thrombosis
Jak3: cytopenias
In which situations should the following biologics be avoided: TNFi Tocilizumab Rituximab JAK inhibitors
- TNFi: MS or family history of MS
- Tocilizumab: diverticulitis
- Rituximab: Hep B infection
- JAK inhibitors: thrombosis/vte, zoster
In which situations would the following biologics be favoured?
TNFi
Rituximab
Abatacept
- TNFI: pregnancy, history of treated malignancy
- Rituximab: past or current lymphoma, past serious infections, MS
- Abatacept: past serious infections
What medications should be trialled in TNFi insufficient responders?
- Abatacept: T cell costimulation inhibitor CD80/86
- Rituximab CD20
- Tofacitinib JAK 1/2/3 inhibitor
Vaccinations before commencing biological DMARD
- Pneumovax and annual flu vaccine
- For JAK inhibitor
Zoster: as live vaccine need to wait 4 weeks before commencing, safe to administer with pred < 20mg/daily and conventional dmard - Rituximab: associated with impaired vaccination response, need to administer 6 months after last infusion
If live vaccine needs to be administered while on bDMARD - WH for 4 weeks, administer vaccine, resume after 4 weeks
- Vaccinate for Hep B, pneumococcus, fluvax
- No live vaccines (yellow fever, MMR, BCF, VZV) on biologicas or MTX or Arava or Pred >10mg)
DMARDs and pre-operative management
- Stress dose corticosteroids
- Methotrexate: WH 1 week before surgery (risk of toxicity if patient develops post op AKI
- BDMARD: WH one treatment cycle, resume 2 weeks post op
What is the effect of RA on fertility?
- Longer time to pregnancy for RA women trying to conceive
- Associations: increased age, nulliparity, disease activity, preconception use of NSAIDs and pred >7.5
- NSAIDs used near time of conception/early pregnancy may interfere with implantation
Effects of pregnancy on RA
- Reduced RA activity during pregnancy
- 90% will flare during post-partum period usually within the first 3 months
What DMARDs can be used during pregnancy?
- TNFI are safe, but consider stopping at 30-32 to decrease passage across placenta - certolizumab is still safe to continue
- Infants exposed to TNFi in utero should not receive live vaccines for first 6months of life (eg: rotavirus)
Low risk during pregnancy: hydroxychoroquine, sulfasazline, pred <10mg/daily, azathioprine, cyclosporin, tnfi
High risk: methotrexate, lefluonmide
Cardiovascular disease in RA
RA is an independent risk factor for cardiovascular disease
What are poor prognostic factors for RA
- Sustained high levels of synovial and systemic inflammation
- RhF and/or ACPA titre
- Early erosions on imaging studies
- Other
Extra-articular features: ILD, nodules
Smoking
Poor education, decreased socioeconomic status
HLA-DRB1*04 homozygosity (shared epitope)
Poor prognostic features rheumatoid factor positive anti-CCP antibodies poor functional status at presentation X-ray: early erosions (e.g. after < 2 years) extra articular features e.g. nodules HLA DR4 insidious onset
What is palindromic rheumatism
- Palindromic rheumatism (PR) is a rare type of inflammatory arthritis. Between attacks of joint pain and swelling, the symptoms disappear, and the affected joints go back to normal with no lasting damage.
- Sudden onset, peaks within hours and lasts 24-48 hours.
- Can involve single or multiple joints, does not cause joint destruction and similar predisposing genetic risk factors to RA
- Treat with hydroxychloroquine to reduce risk of progression to RA
What is remitting seronegative symmetric synovitis with pitting oedema (RS3PE)
Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome is an acute-onset disorder in the elderly, characterized by symmetrical synovitis with pitting edema of the dorsum of the hands and feet (“boxing glove appearance”, and is a known paraneoplastic syndrome
Tenosynovitis +++
Good response to steroids
RF + Anti CCP negative
