Update in rheumatology Dr Patrick Kiely PhD FRCP Consultant Physician and Rheumatologist St George s Hospital London

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1 Update in rheumatology 2014 Dr Patrick Kiely PhD FRCP Consultant Physician and Rheumatologist St George s Hospital London

2 Overview Regional rheumatism Common problems and solutions necks, shoulders, backs, hips and gait Treat to target in rheumatology T2T Gout: urate lowering and new drugs Rheumatoid arthritis Biologic therapies Chronic inflammation and cardiovascular risk PMR and steroid induced osteoporosis Vitamin D, bisphosphonates and when to stop Strontium and denosumab ANA Statins

3 Neck pain and poor sleep Common problem: Pain in region of neck, occiput and shoulder girdle Sleep disturbance Non-restorative sleep Sometimes neuropathic UL symptoms Tingling, burning, numbness Usually unilateral Unusual to describe weakness

4 Cervical spondylosis

50mg 2 hrs before bedtime Surgery: only if persistent

5 Solution: Stabilise the neck in bed Memory foam pillow Soft collar Amitriptyline Neck pain and poor sleep 10mg 50mg 2 hrs before bedtime Surgery: only if persistent neuropathic symptoms, and weakness, and MRI lesion to treat

6 Stiff, restricted and painful shoulder Common problem: Pain in region of shoulder, & upper arm Differentiate frozen shoulder, rotator cuff tendonopathy and AC joint pain

7 Supraspinatus tendonopathy Painful arc through abduction Loss of end of range flexion and internal rotation External rotation PRESERVED

8 Supraspinatus tendonopathy Impingement on the tendon from Osteophytic acromioclavicular joint Osteophytic lateral acromium

9 Supraspinatus tendonopathy Treatment Mobilisation exercises Injection with steroid x 2 Arthroscopic subacromial decompression

10 Frozen shoulder Check external rotation Early and severe restriction All other movements also very restricted

11 Frozen shoulder Glenohumeral injection... in early phase only hydrodilatation Nothing else worthwhile All cases make a full recovery eventually, up to 3 years in some

12 Unexplained leg pain not the hip or knee... Spinal stenosis Trochanteric bursitis Adverse hind foot biomechanics

13 Spinal stenosis Buttock and posterior thigh pain with standing and walking Uni or bilateral May radiate lower Relieved sitting down unlike ischaemic claudication No problem in bed

14 Trochanteric bursitis Patient invariably says my hip Lateral proximal thigh pain Female > Male Worse standing from chair, walking and lying on affected side May radiate to knee or below Hip movements good, sore at extreme external rotation Very tender over the trochanter and with resisted abduction

15 Trochanteric bursitis

16 Trochanteric bursitis management Exercises Weight loss and Pilates Injection Surgery

17 Leg pains, but hips and knees OK think feet and altered biomechanics...

$Back pain management Red flags (fracture, metastasis, lymphoma, IBP) Extremes of the age spectrum be alert!$ and sweats Refer if in doubt Inflammatory back pain (Ank spond) Suspect the diagnosis refer mean 7 years

and sweats Refer if in doubt Inflammatory back pain (Ank spond) Suspect the diagnosis refer mean 7 years

18 Back pain management Red flags (fracture, metastasis, lymphoma, IBP) Extremes of the age spectrum be alert! Severe pain, localised pain, worsening Sleep disturbance and/or morning stiffness Anorexia and weight loss, fever and sweats Refer if in doubt Inflammatory back pain (Ank spond) Suspect the diagnosis refer mean 7 years diagnostic delay MRI SI joints and spine not X-ray Low impact exercises NSAIDs and PPI... ultimately anti-tnf Physio, hydrotherapy

will dissolve sua 300 360 420 480 540 % with attack in 1 yr 10 20 40 55 75 No.

19 Treat to target in rheumatology T2T Gout If serum uric acid lowered to 300 mmol/l the risk of recurring acute attacks of gout will be virtually abolished, and tophi will dissolve sua % with attack in 1 yr No. attacks/yr 1 6 Rate of dissolution of tophi correlates with absolute sua concentration

Indications for urate-lowering therapy: Dont forget the vast majority of patients with hyperuricaemia never get gout; this is not a diagnostic test Asymptomatic hyperuricaemia is not an indication

20 Indications for urate-lowering therapy: Dont forget the vast majority of patients with hyperuricaemia never get gout; this is not a diagnostic test Asymptomatic hyperuricaemia is not an indication for urate-lowering agents It is a trigger to think about the metabolic syndrome Commence urate lowering measures if: 1. Recurrent troublesome acute attacks (eg 3 or more per year) 2. Tophaceous deposits 3. Gout with evidence of erosive change 4. Gout associated with interstitial nephropathy 5. Uric acid stone formation 6. Acute uric acid nephropathy 7. Prophylaxis against tumour lysis syndrome in patients receiving chemotherapy (rasburicase may also be considered in this situation)

21 Urate lowering options Dietary modification only a modest effect on sua, eg 10-15% reduction with a low-purine diet Consult the UK gout society diet sheet Stop beer and fructose rich drinks, wine is neutral Stop/switch therapies which elevate sua

22 Effects of different types of alcohol on serum uric acid Results similar in men and women, and at lower and higher levels of BMI.

23 Fructose Only CHO known to SUA Men who drink two or more sugary soft drinks a day have an 85% higher risk of gout than those who drink less than one a month. US sales: soft drinks % Single largest food source of calories Diet drinks OK

24 Cheers

25 Urate lowering drug therapies required for most patients slow titration to target sua in all cases T2T 300mmol/L Co-prescribe colchicine to prevent flare Allopurinol Vitamin C Febuxostat Fenofibrate Benzbromarone Losartan

involved (MCP, PIP,MTP) Symmetrical involvement Early

26 Rheumatoid Arthritis GPs see newly presenting patients THINK Inflammatory Arthritis if Peripheral small joints involved (MCP, PIP,MTP) Symmetrical involvement Early morning stiffness Soft tissue swelling or effusion NSAIDs help

27 Not an emergency... but an URGENCY to refer erosions occur early in RA, commonly >50% at a year Poor prognostic markers at diagnosis: Large number of involved joints RF strong positive ACPA (CCP), strong positive Smoking Early erosions High disability scores

28 % of those respondents who gave up work early because of their RA What does this mean? Loss or change in employment NRAS 2007 survey How many years after RA was diagnosed did you have to stop working? Within a year Within 3 years Within 6 years 6-10 years Over 10 years Not stated Personal cost.. financial, self esteem, physical & mental Societal cost.. tax contributor to tax receiver

29 So what can treatment do.. We have moved from therapeutic nihilism token drug treatment too little too late nurturing the patient towards inevitable disability and demise To the possibility that newly diagnosed patients can be cured in existing patients, progression of damage can be halted and quality of life recovered But to achieve this we need to intervene aggressively

30 Starting treatment early Lard LR et al (Leiden) Am J Med 2001; 111:446 Rheumatoid arthritis patients Cohort 1 ( ) delayed treatment strategy, n = 109 Delay between 1 st clinic visit and first DMARD mean 123 (50 273) days Cohort 2 ( ) early treatment strategy, n = 97 Delay between 1 st clinic visit and first DMARD mean 15 (14 21) days Majority treated with HCQ or SSZ, monotherapy

31 Lard et al: early (15 days) versus delayed (4 months) therapy in early RA

32 Lard et al: early (15 days) versus delayed (4 months) therapy in early RA

33 RA guideline Key priorities for implementation Referral for specialist treatment Refer for specialist opinion any person with suspected persistent synovitis of undetermined cause Refer urgently if any of the following apply: The small joints of the hands and feet are affected More than one joint is affected There has been a delay of 3 months or longer between onset of symptoms and seeking medical advice

34 UK practice? Early Rheumatoid Arthritis Network (ERAN) 638 newly diagnosed patients Mean time from symptom onset to start of therapy 8 months Conclusion 1 Treating early makes a big difference Waterford

35 Starting treatment not so early mono or combination therapy? FinRA Co study (Mottonen, Arthritis Rheum 2002; 46: 894) Early Rheumatoid arthritis patients (< 2 years) DMARD sequential monotherapy versus Combination MTX/SSZ/HCQ therapy, including prednisolone Delay in institution of DMARD Monotherapy: median 7 months symptoms < 4 months in 23/86, 27% Combination: median 6 months symptoms < 4 months in 26/79, 33%

36 FinRA Co: early versus delayed therapy in early RA: 2 year remission rates

37 CRP (mg/l) Fundamental concept Minimizing cumulative inflammation (inflammation-time AUC) improves all outcomes Placebo + MTX Infliximab + MTX Weeks This means Detect & refer early Treat early, with a fast acting agent to suppress inflammation quickly Refer on the basis of history and examination Don t wait for blood results to decide whether to refer; ESR/CRP may be normal, RF may be negative No point doing X-rays we use US if in doubt about synovitis Bolus steroid (Depomedrone 120mg) if cant get early appointment

38 Intervening aggressively Using therapies to maximum advantage Starting as soon as possible after RA onset Combination therapies Biologic therapies Principles of TIGHT control T2T

39 RA guideline Key priorities for implementation Disease modifying and biological drugs In newly diagnosed offer a combination of DMARDs (including MTX and at least one other DMARD, plus short term steroids) as 1 st line treatment asap, ideally within 3 months of onset of persistent symptoms If combination DMARD therapy is not appropriate, start DMARD monotherapy placing greater emphasis on fast escalation to a clinically effective dose rather than on the choice of DMARD Once sustained & satisfactory levels of disease control are achieved then cautiously try to reduce drug doses to levels that still maintain disease control

40 Tight control/treat-2-target T2T Aim to suppress inflammation to a low level / remission use a valid objective measure of current RA activity decide on a target outcome A protocol dictates whether to increase or decrease treatment; not doctor-patient conspiracy Assess frequently (monthly 6 weekly) Use adequate treatment fast acting induction regime Steroids currently available (evidence for anti-tnf agents) more than one drug at a time

41 Tight control Ticora study (Grigor, Lancet 2004; 364:263) Rheumatoid arthritis patients Disease duration <5 years, mean months Routine care: n=55 visits every 3 months sequential monotherapy or combination therapy allowed Tight control: n=55 Target defined DAS44 score 2.4 (moderate activity) monthly visits standardized assessments protocol driven escalating DMARD therapy intra-articular and intra-muscular steroids

42 DAS score DAS changes in TICORA Trial Tight vs. conventional p< (after month 3) Conventional monotherapy Tight control Months treatment Grigor et al. Lancet 2004

43 TICORA: Number of patients responding at 18 months assessment (intention to treat analysis) EULAR good response Intensive group (n = 55) Routine group (n = 55) Odds ratio (95% CI) p value 45 (82%) 24 (44%) 5.8 ( ) < EULAR remission 36 (65%) 9 (16%) 9.7 ( ) < ACR 20 response 50 (91%) 35 (64%) 5.7 ( ) < ACR 50 response 46 (84%) 22 (40%) 6.1 ( ) < ACR 70 response 39 (71%) 10 (18%) 11 (4.5-27) <

44 Change of DAS-28 between usual care and tight control, according to a fixed-effects model Grigor et al. (3) Goekoop-Ruiterman et al. (29) Verstappen et al. (18) Protocolized tight control Van Hulst et al. (28) Fransen et al. (27) Fransen et al. (8) Non-protocolized tight control Monitoring with protocolized treatment adjustments Monitoring without protocolized treatment adjustments Data are presented as MD in change of DAS-28 between usual care and tight control Overall effect is presented as a WMD in change of DAS-28 between usual care and tight control Schipper LG et al. Rheumatol. 2010; 49:

45 Biologics Nomenclature -iximab Chimeric antibody Infliximab -zumab Tocilizumab -umab Adalimumab, Golimumab -cept Etanercept, Abatacept Humanized antibody Human antibody Fusion protein

46 Evolution of monoclonal antibodies Murine Antibody Chimaeric Antibody 70% Human Humanised Antibody 95% Human Fully Human Antibody 100% Human Human Mouse

47 Anti-TNF agents Adalimumab Etanercept Certolizumab Golimumab Infliximab Anti-B cell Rituximab Anti-IL6 Tocilizumab T cell co stimulation inhibitor Abatacept NICE RA commissioning algorithm. 1WithGolimumab.pdf

48 Chronic inflammation and cardiovascular risk Independent risk factor for atheromatous disease SLE 50 x increased risk MI/CVA RA 4 x increased risk this means careful control of traditional risk factors to diabetic targets Bp <130/80, LDL < 2.6 greater emphasis on robustly suppressing inflammation we must try harder

49 PMR Age: 50 +, usually 70 + Raised ESR and normal CRP? Anaemia, paraprotein Initial dose of prednisolone: 15mg, sometimes 20mg Taper and duration One month initial dose Aim for 10mg at 2-3 months, 1mg less per month down to 5mg by 8 months Hold at 5mg for 18 months, then 1mg less per month down to zero by 2 years Co-prescriptions Vitamin D and bisphosphonates Vitamin C Enquire about varicella immunity Mimics: hypothyroid menopause chronic sepsis malignancy osteomalacia

50 Steroid induced osteoporosis Bone prophylaxis Vitamin D3 T2T >80 nmol/l: 1000U/day nmol/l: 5000U/day <50 nmol/l: 20,000U 3x weekly Bisphosphonates

$femoral fractures (often$

51 When to stop bisphosphonates Risk benefit becomes adverse > 5 years ONJ and atypical femoral fractures (often bilateral)

52 When to stop bisphosphonates 5-10 years Consider what has happened since the patient was started on a bisphosphonate NO fracture and Osteopenia STOP NO fracture and Osteoporosis HOLIDAY (use FRAX if patient anxious) FRACTURE switch to an alternative bone sparing drug Denosumab, Strontium or Teriparatide depending on T score, co-morbidity and NICE guidance

53 What about Denosumab? NICE TA 204 recommended in patients: unable to comply with the special instructions for administering alendronate and either risedronate or etidronate, or have an intolerance of, or a contraindication to, those treatments and who have a combination of T-score, age and independent clinical risk factors for fracture (parental history of hip fracture, alcohol intake of 4 units per day, and RA) Threshold T scores for Denosumab treatment Number of independent risk factors Age (years) Not recommended or older

ANA? Measure this in the correct clinical context You are wondering about a connective tissue disease Sjogren s Dry eyes and mouth Fatigue Arthralgia Raynaud s SLE Alopecia Malar rash Oral ulcers

54 ANA? Measure this in the correct clinical context You are wondering about a connective tissue disease Sjogren s Dry eyes and mouth Fatigue Arthralgia Raynaud s SLE Alopecia Malar rash Oral ulcers Raynaud s Arthralgia CTD Myositis Muscle weakness Rash Raynauds Dyspnoea Weak swallow, aspiration Titer interpretation: 1 in 80 likely normal up to 15% of healthy population have a positive ANA if titer > 1 in 80 ENA, ds DNA, C3/4 Scleroderma Raynaud s, Reflux Thick skin Arthralgia

55 Thank you Regional rheumatism Common problems and solutions necks, shoulders, backs, hips and gait Treat to target in rheumatology T2T Gout: urate lowering and new drugs Rheumatoid arthritis Biologic therapies Chronic inflammation and cardiovascular risk PMR and steroid induced osteoporosis Vitamin D, bisphosphonates and when to stop Denosumab ANA

Early synovitis clinics

Early synovitis clinics Jeremy Jones MD FRACP FAFRM Consultant Rheumatologist, Llandudno General Hospital Honorary Research Fellow School of Sport, Health and Exercise Sciences Bangor University RA medication