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Therapeutics > Session 7: Rheumatology > Flashcards

Session 7: Rheumatology Flashcards

1
Q

Name conditions where alterations in the immune system contributes to the pathogenesis?

A

Rheumatologic immune-mediated diseases
Multiple sclerosis
Coeliac disease
Type 1 DM

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2
Q

What are the symtoms of RA?

A

Morning stiffness
Joint tenderness
swelling
pain on motion
difficulty in performing daily activities

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3
Q

What are the patient outcomes in RA?

A

Joint damage and physical disability - reduction in QOL and premature mortality
- disease activity is a good indicator of damage and physical activity. Shown in swollen joint counts, levels of acute phase reactants and composite indices of disease activity

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4
Q

Extra-articular features of RA occur in 18-41% of patients. What are they?

A

-Cardiac disease: vasculitis, pericarditis
-Pulmonary disease = rheumatoid nodules, pulmonary fibrosis, pleural effusion
-Nervous system: peripheral neuropathies
-Gastroenterology: splenomegaly
-Skin disease: rheumatic nodules, ulcers
-Eye disease: scleritis/episcleritis, Sjogren’s syndrome
-Haematological disease: anaemia, cytopenias
-Renal disease: glomerular nephritis
-Systemic: fever, weight loss, fatigue

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5
Q

How do cardiac features of RA present?

A

Myocardial: CHF, Left ventricular hypertrophy, amyloidosis
Valvular: vegetations, valvular nodles
Pericardial: pericardial effusion
Electrical: arrhythmias
Vascular: atherosclerosis, vasculitis, thrombosis

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6
Q

Describe the pathogenesis of RA?

A
  1. Pre-arthritis: susceptibility genes + environmental factors (e.g. smoking, bacteria, viruses) + epigenetic modifications + post-translational modifications (e.g. acetylation, methylation, phosphorylation)
  2. Loss of tolerance, development of autoantibodies (RF, ACPA)
  3. Asymptomatic synovitis (cellular infiltrate)
  4. Symptomatic arthritis
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7
Q

What are the principles of management of RA?

A
  • Early diagnosis and management
  • Achievement of disease control (remission state or low disease activity)
  • Maintenance of tight control = disease-modifying therapy
  • Control of symptoms (NSAIDS, steroids)
  • Long-term care (management of morbidities, complications, effects on therapy
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8
Q

What are PROs?

A

Patient recorded outcomes
- Used to assess the treatment response

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9
Q

What is the Treat to Target (T2T) approach?

A
  • Frequent periodic reassessment of disease activity
  • Adjustment of DMARD regimen at least every 3-6 months
    Adjunctive/ bridge therapy (NSAIDs/ steroids)
  • T2T is generally more important than the specific agent used
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10
Q

What tools are used for the assessment of disease activity in RA?

A
  • DAS28 (disease acitivity score of 28 joints)
  • SDAI (simple disease acitivty index)
  • CDAI (clinical disease acitivity index)
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11
Q

What does the DAS28 measure?

A
  1. Physician assessment of Joint (number of swollen and tender joints
  2. Patient’s and physician’s assessment of disease activity
  3. Laboratory marker of inflammation
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12
Q

What does the SDAI measure?

A

Numerical sum of outcome of parameters:

Physician’s assessment of the joints
patient’s and physician’s assessment of disease activity
acute phase reactant measurement

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13
Q

What does the CDAI measure?

A

Incorporates the same elements of SDAI + DAS28 except that it does not require measuring acute-phase reactants and allows for immediate scoring.

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14
Q

What is the scoring system for DAS28 monitoring of RA disease activity?

A

<2.6 Remission
2.6-3.2 low disease activity
3.2-5.1 moderate disease activity
>5.1 high disease acitivity

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15
Q

What are the pros of DAS28 and what can it be used for?

A

Fast, easy and valid.
Used to monitor change in disease activity which can be used to estimate response to treatment.

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16
Q

What is the T2T pathway?

A
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17
Q

What does DMARD stand for?

A

Disease-modifying antirheumatic drugs

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17
Q

What factors might influence treatment for RA?

A

Disability and function
Comorbidities
Joint damage

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18
Q

How is RA treated initially?

A

DMARD monotherapy
Comorbidity therapy
Symptomatic measurement
Regular monitoring: disease activity, drug toxicity, identification and management of morbidity

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19
Q

Give named examples of conventional synthetic DMARDS (csDMARDS)

A

Methotrexate
Leflunomide
Sulphasalazine
Hydroxychloroquine

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20
Q

What is the drug profile for Methotrexate?

A

Analog of folic acid
targets: folate-dependent processes, adensine signalling, methyl-donor production, ROS, adhesion-molecule expression, alteration of cytokine profiles, eicosanoids and MMPs
Side effects: Increased liver enzymes, pulmonary damage

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21
Q

Drug profile for leflunomide

A

Pyrimidine synthesis inhibitor
Targets: DHODH-dependent pathway leukocyte adhesion: rapidly dividing cells, ILs, kinases
Side effects: HTN, diarrhoea, and nausea

22
Q

What is the drug profile for sulphasalazine?

A

Pyrimidine synthesis inhibitor
Targets: COX and PGE2; leukotriene production and chemotaxis; inflammatory cytokines (ILs and TNFa) adenosine signalling
SE: GI, CNS, haematological adverse effects.

23
Q

Drug profile for Hydroxychloroquine

A

Targets: Toll-like receptor; lysosomotropic action; monocyte-derived pro-inflammatory cytokines; anti-inflammatory effects; cellular immune reaction; T cell responses; neutrophils; cartilage metabolism and degradation
SE: GI, skin, CNS adverse effects and retinal toxicity

24
Q

Name some common reasons for failure of initial DMARD therapy

A

Resistance: failure to meet target e.g. remission/ disease low disease activity, need for long term steroids/ repeated steroid use, progession of erosive disease or structural disease.
- Toxicity or intolerance

25
Q

What are the options for escalation of DMARD therapy?

A
  • Multiple DMARDS
  • csDMARD and cytokine targeted therapy
  • biological DMARD therapy
  • JAK inhibitor as combination or monotherapy
26
Q

What is TNF and what is its role in inflammation?

A

TNF-alpha and IL-1 are major macrophage derived cytokines in rheumatic joints.
They induce the synthesis and secretion of matrix-degrading proteases prostanoids IL6, 8 and GM-CSF
TNF is secreted mainly by macrophages + T cells
TNF receptors are expressed by almost all mammalian cells

27
Q

Which cells does TNF impact and how?

A

-T and B lymphocytes: stimulates RANKL expression
-Macrophages: promote differentiation (e.g. increased osteoclast activity)
-Synoviocytes, macrophages, chondrocytes (MMPs, collagenase, stromelysin)
-Synthesis of protein and lipid inflammatory molecules
-Activation of gene transcription

28
Q

Nomenclature of anti-cytokine therapies (mAb)

A

cept = fusion of receptor to Fc part of human IgG
mab = monoclonal antibody
ximab = chimeric mAb
xumab/zumab = humanized mAb
umab = fully human mAb

29
Q

What type of mAb is Adalimumab and what is its regime?

A

Recombinant fully human mAb
Regime: 40mg subcut every 2 weeks

30
Q

What type of mAb is certrolizumab?

A

Humanised anti-TNF alpha fab fragment

31
Q

What type of mAb is Infliximab

A

Chimeric mAb directed against TNF

31
Q

What type of mAb is Golimumab?

A

Human IgG kappa mAb specific for human TNF alpha

32
Q

What type of mAb is Etanercept

A

Soluble p75 TNF receptor fusion protein

33
Q

What is the efficacy of anti-TNF agents?

A
  • effectve with combination with methotrexate
  • 20-60% response rates acording to ACR measure of disease activity
  • ACR parameters = inflammation (ESR, CRP), TJC, SJC, patient assessment, physician assessment, disability questionnaire
34
Q

Which factors influence which anti-TNF agent is given?

A

Pt factors: morbidities, pt convenience
- Regulatory issues: NICE guidance, local arrangements
- Safety issues
- Economic/ financial issues
- Biosimilar

35
Q

What are the risks of anti-TNF therapy?

A

Increased risk of reactivation of TB, Hep B
Risk of infections such as Chickenpox
drug-induced lupus
demyelinating disorders
hepatotoxicity

36
Q

What possible pathways occur in the MOA of Rituximab?

A
  • Fc gamma receptor-mediated antibody-dependent cytotoxicity and phagocytosis
  • Complement-dependent cytotoxicity
  • Promotion of apoptosis
  • Growth arrest
37
Q

What are the adverse effects of rituximab?

A

infusion reactions, hypogammaglobulinaemia, infection, reactivation of hep B, neutropenia

38
Q

What type of drug can be used for T cell targeted therapy and what is its MoA?

A

Abatacept = fully human soluble fusion protein
MoA: T-cell co-stimulator modulator, inhibits T cell activation by binding to CD50 and CD86 blocking interaction with CD28.

39
Q

What is the adverse side effects of abatacept?

A

infusion reaction, risk of infection

40
Q

What is the role of IL-6?

A

-Inflammatory pathways activated by IL-6

-IL-6 induces pannus formation, and osteoclast activation and mediates inflammation

41
Q

What is the role of IL-6 antagonism?

A
  • Multiple effects on the innate and adaptive immune system
  • Contributes to host defence against stress
  • Dysregulated production of IL-6 is pathological in rheumatological and other disorders
42
Q

What are the systemic effects of IL-6?

A

Inflammation = increased cardiovascular risk
Acts on liver = acute phase proteins
CRP - acute phase response, hepcidin production = anaemia
HPA-axis - fatigue and mood

43
Q

Name and give the type of anti- Il-6 agents, their MoA

A

Tocilizumab = humanized anti-human IL-6 receptor antibody. Binds to both membrane-bound and soluble forms of human IL-6 receptor.

Sarilumab = human mAb against both membrane-bound and soluble form of Il-6.

44
Q

What are the SE of anti IL-6 therapies?

A

-Neutropenia/other cytopenias
-LFT abnormalities
-Dyslipidaemia
-Infection
-Intestinal perforation

45
Q

Which inflammatory mediators are involved in RA pathophysiology?

A

-Type I/II cytokine receptor
-TNF receptor
-TGF-B receptor
-Tol/IL-1 receptor
-Chemokine receptor
-Receptor tyrosine kinase

46
Q

What is the JAK STAT pathway?

A

4 members: JAK1, 2, 3 TYK2
They are cytoplasmic tyrosine kinases that phosphorylate tyrosine residues on themselves (autophosphorylation) or on adjacent molecules (transphosphorylation)
Mediate downstream effects of different molecules including IL, IFN, colony stimulating factors (granulocyte macrophage), growth factors, EPO.

46
Q

Which signalling cascades are involved in RA pathophysiology?

A

MAPK, SYK, P13K, NF,kB, JAK

46
Q

When are JAK inhibtors used?

A

Patients with inadequate response to methotrexate or intolerance
Failure of bDMARDS
Convenience - pills are easy to travel with.
Needle phobia
Can be used as a monotherapy

47
Q

Name current JAK inhibitors and their targets

A

Baricitinib JAK 1/3
Tofacitinib JAK 2
Upadacitinib JAK 1
Filgotinib JAK 1
Peficitinib JAK 1, 2, 3, TYK 2

47
Q

What safety concerns are there about JAK inhibitors?

A

JAK inhibitors alter serum lipid levels, which may influence a number of CV events, infection, malignancy, haem = anaemia, neutropenia, lymphocytes, increased LFTs, increased creatinine, risk of GI perforation

47
Q
A

Therapeutics (7 decks)

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