Slide 1

Iain B McInnes PhD, FRCP, FRSE, FMedSci

Muirhead Professor of Medicine & Director, Institute of Infection, Immunity and Inflammation, University of GlasgowScotland, United Kingdom

Meet the ProfessorRA: Its never that simple, is it?

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Conflict(s) of interest disclosureI live in Glasgow and have Glasgow genes.

Rheumatoid arthritis when the patient is unwell?

If a man will begin with certainties, he shall end in doubts; but if he will be content to begin with doubts he shall end in certainties.

Francis Bacon - circa 1570

This is another way of saying we need to enable data interrogation back in the hands of the people who understand and can interpret the biology.3

Multimorbidity: clinical assessment and management National Institute for Health and Care Excellence, 2016

Multimorbidity per se is associated with:reduced quality of lifehigher mortalityreduced socioeconomic statuspolypharmacy and high treatment burdenhigher rates of adverse drug eventsgreater health services use including emergency hospital admission usually defined as when an individual has two or more long-term conditions

4The understanding of inflammatory rheumatic diseases has over the past decade or so extended from classical disease symptoms to the recognition of various comorbidities.

Thoughts about co-morbidity v multimorbidity...Radner H et a Nature Rev Rheum 10: 252-256 (2014)

5The understanding of inflammatory rheumatic diseases has over the past decade or so extended from classical disease symptoms to the recognition of various comorbidities.

Barnett K et al. (2012). Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study. Lancet; 380(9836):37-43

Multi-morbidity - increasing with age across disciplines

RA median age of onset

Dataset: University of Aberdeen Primary Care Clinical Informatics Unit (PCCIU).1.8 Million Patients, 310 (30%) Scottish Practices.One Years data 01/04/06 to 31/03/07

Final Count: 46 Conditions (agreed by expert panel)Quality and Outcomes Framework (QOF)Information Services Division (ISD) Read Code Groups Bespoke Read Code Groups where necessary

Read Code Only (ever recorded/date restriction) eg CHD/CancerRead Code plus Prescription eg AsthmaPrescription Only eg MigraineEqual Weighting

And next to the RA patients perspective?

The wider context of multimorbidities in RA...Prevalence increased in RAgeneral population - 25%RA ~60%Shared risk factors v independent occurrences?smokingobesitysedentary life stylegenetics / microbiome/diet?Socioeconomic statusAgeGender

Time

8The understanding of inflammatory rheumatic diseases has over the past decade or so extended from classical disease symptoms to the recognition of various comorbidities.

Patient function reduces with morbidity burden per given CDAI

The wider context of multi-morbidities in RA...Radner H Wien Klin Wochenschr (2016) DOI 10.1007/s00508-016-1090-x; Radner H et a Nature Rev Rheum 10: 252-256 (2014)

9The understanding of inflammatory rheumatic diseases has over the past decade or so extended from classical disease symptoms to the recognition of various comorbidities.

Thoughts about multimorbidity...practical steps?Multimorbidity: clinical assessment and management National Institute for Health and Care Excellence, 2016

Follow these steps when delivering an approach to care that takes account of multimorbidity:

Discuss the purpose of an approach to care that takes account of multimorbidity

Establish disease and treatment burden

Establish patient goals, values and priorities

Review medicines and other treatments taking into account evidence of likely benefits and harms for the individual patient and outcomes important to the person

Agree an individualised management plan with the person

10The understanding of inflammatory rheumatic diseases has over the past decade or so extended from classical disease symptoms to the recognition of various comorbidities.

The range of multi(co)morbidities in RA...Devrimci-Ozguven H, et al. JEADV 2000;14:267;Prodanovich S, et al. Arch Dermatol 2009;145:700;Schn MP, Boehncke WH. N Engl J Med 2005;352:18991912;Gelfand JM, et al. Arch Dermatol 2007;143:14931499;Gelfand JM, et al. Infect Dis 2006;126:2194

Cardiovascular diseaseCardiovascular risk factorsLymphoma and other cancersOsteoporosisPsychiatric diseaseInfections / vaccinations

Gastrointestinal diseases

11The understanding of inflammatory rheumatic diseases has over the past decade or so extended from classical disease symptoms to the recognition of various comorbidities.

RA & cardiovascular diseasePrasad M et al Nat Reviews Cardiol (2015) 12 168

Cardiovascular / metabolic

1. Choy E and Sattar N. Ann Rheum Dis 2009;68:460469.2. Genovese MC, et al. Arthritis Rheum 2008;58:29682980.Lipids and inflammation the lipid paradoxInflammation in humans - lipids (LDL-C, HDL-C, triglycerides)1Post-MI, post-surgerySepsis, trauma, ITU1Cancer RA inflammation leads to a proportional lipids

Inflammation resolution/suppression lipids (HDL-C and LDL-C, plus triglycerides)

Cardiovascular / metabolic

BaselinePre-RAUntreated RARA treated with biologicsLipid levelsCRP (or inflammation)

Treated RA with biologicsCholesterolTriglyceridesHDL-CCRP

Active untreated RA (in general)CholesterolTriglyceridesHDL-CCRP

Be cautious in use of CV risk factor scores

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Choy & Sattar P460 A & p467 B

Choy & Sattar p465 B & p467 CGenovese 2008 p2978 AChoy & Sattar p467 A

RA clinical assessment & managementMeasure BP (clinic) Non-fasting lipids to get TC and HDL-cTC and HDL-c same fasting vs non-fastingAsk re: smoking statusAssess BMINext, plug data into risk score of choiceNational preferred tools recommendedEU SCORE plus multiplication factor?x1.5

Cardiovascular / metabolic

EULAR 2015 recommendation update for cardiovascular risk management in patients with rheumatoid arthritisRecommendations 2015Level ofevidenceVoting(0-10) 6CV risk score models should be adapted for patients with RA by a 1.5 multiplication factor, if this is not already included in the score.3-4, C-D7CV risk management should be carried out according to national guidelines in RA, AS or PsA. Antihypertensives and statins may be used as in the general population.3-4, C-D8Prescription of NSAIDs in RA and PsA should be with caution, especially for patients with a documented CV disease or in the presence of CV risk factors. NSAIDs are recommended as first-line drug treatment for AS patients with pain and stiffness (unless contra-indicated).2A-3C-D9Corticosteroids: for prolonged treatment, the glucocorticoid dosage should be kept to a minimum, and a glucocorticoid taper should be attempted in case of remission or low disease activity; the reasons to continue glucocorticoid therapy should be regularly checked.3C10Life style recommendations should emphasise the benefits of a healthy diet, regular exercise and smoking cessation. 4D, 3C, 1B

Nurmohamed M, et al. EULAR 2015 SP0033June 10, 2015, 17:0018:30 Hot Topics Session 2: EULAR recommendation update on cardiovascular disease in RA

Cardiovascular / metabolic

What we currently have in terms of recommendations for the treatment of comorbidities and risk factors. To discuss that most likely and update and extension to the other comorbidities would be needed.

Reference #4

Please see also slide #28:Current evidence suggests CV risk multiplier maybe also necessary in severe psoriasis, perhaps not in PsAAlthough how this finding is factored into clinical management is currently unclear

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RA CVD Pharmacotherapy? Lipid lowering Statin use when risk > threshold for intervention Thresholds per national guidelinesIf RA therapy moves TC/LDL-C into risk group - treatDose adjustment not needed in active RABlood pressure 50% not measured When measured 80% not treated Most guidelines suggest SBP 140/90

Cardiovascular / metabolic

Rollefstad S et al. Ann Rheum Dis 2014;0:1-7. doi:10.1136/annrheumdis-2013-204636.

RA: lifestyle changes matter!Obesity causal for CVD3As: Ask, Assess, Advice New NICE guidance: 3% weight loss realisticThen keep off (diet first then add activity) Alcohol Remind sensible limits and manage expectation of protective effects!Smoking cessation remind, direct towards helpEmpathise / behavioural / pharmacotherapyLowers non-CVD morbidity

NHS Scotland Fife Dr Helen HarrisCardiovascular / metabolic

RA & heart failure?Heart FailureRCT derived cause for concernDefine degree of heart failureWork with cardiologistTNFi reduced N-proBNP in RA observational cohortRA therapeutic decisions?Optimise cDMARDsCaution with TNFi class III & IV), corticosteroids & NSAIDsRituximab contraindicated in class IV heart failure (EMA)

Cardiovascular / metabolic

American College of Rheumatology RA Management Guidelines 2015

Interactions:

EducationEnvironmentEconomy

Thinking of the past to inform the future - infection?

Infection

Infections and Treating RA

Chronic infectionUTICOPDSeptic arthritisBronchiectasis (r/o ILD!)ProsthesesArticular structuresValves / stents / implants

ConsiderAgeDiabetes mellitusChronic renal impairmentGlucocorticoids

Infection

Infection and RA therapeutics hepatitis viruses?InfectionVigilance think!Screening per protocolIn partnership with patient and primary care physician

Treatable conditions

Hepatitis viruses ACR guidelinesHIV - Consider TNF- inhibitors in patients with HIV infection and CD4 counts >200106/L

Richards et al BMJ 2015;351:h3658American College of Rheumatology RA Management Guidelines 2015

Infection and RA therapeutics general infections?InfectionRA imposes increased infectious risk, also associate with high disease activityOften face a patient with intercurrent and frequent infectionsUTICOPDCutaneous

Consider:Primary use of cDMARD plus combinations as toleratedBiologics marginal preference for abatacept (Conditional)Minimize corticosteroidsOptimize diabetic controlDiscuss anti-infectious prophylaxis with ID physicians

See: American College of Rheumatology RA Management Guidelines 2015Plus opinion of speaker

RA biologic therapy and risks of sepsis and death once infection has occured?Richter A, et al. Ann Rheum Dis 2016;75:16671673

Infection

DMARDs and Vaccine ImmunogenicityMTXTNFiABARTXTOCTOFAInfluenza+/-OK+/-OKOKPPSV-23(Pneumovax)+/-+/- OKZoster??????TetanusOKOKOK

Winthrop et al. ACR 78th Annual Conference 2012Assen et al. Ann Rheum 2011Coulson et al. Ann Rheum Dis 2011 Kapetanovic et al. Clin Rheumatol 2011Kapetanovic et al. Arthritis Res Ther 2013Bingham et al. Arthritis Rheum 2010Tay et al. Arthritis Res Ther 2007Oren Ann et al. Rheum Dis 2008Ribeiro et al. Arthritis Care Res 2013Mori et al. Ann Rheum Dis 2012Table complied by Dr Kevin Winthrop, Oregon and gifted to the speaker.

Recall: vaccine efficacy is commonly measured by elevation (change from baseline or booster) in antibody titre, rarely by impact on infectious event rateNeed for vaccination?

Caveats----HAI tends to be preserved, but pandemic alone is decreased with TNF and aba. The B component typically with weaker responses. Also, TNF shows decrease in specific B cell responses to all antigens.Elkayam with decreased response to pneumovax with TNFiFrano salinas in SpA also with decreased with TNFi

Toci study---one with MTX versus Toc/MTX in which the TOC/MTX group showed decreased responses as compared to MTX alone. The Mori study showed TOC did not impair responses as compared to RA control (non MTX DMARD)/.pl

Synergy present between MTX and Tofa and likely other biologics with regard to decreased PCV-23

PCV-13 we have no data. But pcv-7 with---

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Vaccination within the ACR Guidelines?Need for vaccination?

American College of Rheumatology RA Management Guidelines 2015

Inflammation and cancer

Rudolph Virchow

provided a rationale for the use of cytokine and chemokine blockade, and further investigation of NSAIDs, in the chemoprevention and treatment of malignant disease

Malignancy

Malignancy and Treating RA

Inflammation, cancer & RA?The clinical challengesRA per se, carries increased risk of lymphoma and some solid tumours.so look carefully at outset;Risks imposed by biologic therapeutics is negligible for most tumours, outcomes if onset during therapy equivalent.Caution however with melanomaMore data requiredRisks imposed by prior malignancy?Malignancy

Clinical conundrum so what should we do after malignancy?Ensure oncologist is informed and in partnershipOptimise tumour therapeuticsCapture RA disease suppression!Increase patient confidence that the totality of their health is considered

Optimise use of cDMARDSConsider combination (resetting the immune paradigm?)GlucocorticoidsModerate T-2-T strategy the dysutility argument

Choose biologic if necessaryRituximab if 5yrsExcept melanoma (no TNFi)

Malignancy

RA and depression: frequency?29Dougados M, et al. Ann Rheum Dis 2014;73:6268.

RA patients report significant psychiatric symptoms in 6 - 41% of casesDepressionSuicidal ideation

Depression

Think about the problem

Explain intrinsic versus reactive impact on mood state mediated by RAPatients understand this!

Screen if indicated, resourcedBDI-II

Treat in partnership with psychiatric or primary care services & family

RA and depression?

Engelbrecht M et al Arthritis Care Res (2016

Depression

Clinical conundra set by multimorbidity and RA therapeutics take home?

This remains the art of medicineRheumatologists treat peoplewell

We make individual decisionsFocus on the person and their goalsTreat conditions in concert