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

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

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

Cervical spondylosis

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

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

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

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

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

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

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

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

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

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

Trochanteric bursitis

Trochanteric bursitis management Exercises Weight loss and Pilates Injection Surgery

Leg pains, but hips and knees OK – think feet and altered biomechanics... Who does a good biomechanical assessment in your area ?

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 Back pain management

Treat – to – target in rheumatology T2T Gout If serum uric acid lowered to 300  mol/L the risk of recurring acute attacks of gout will be virtually abolished, and tophi will dissolve Rate of dissolution of tophi correlates with absolute sUA concentration sUA % with attack in 1 yr No. attacks/yr16

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)

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

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

Fructose Only CHO known to ↑ SUA US sales: soft drinks 1977 – 1997 ↑ 61% Single largest food source of calories Diet drinks – OK 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.

Cheers…

Urate lowering drug therapies required for most patients –slow titration to target sUA in all cases –T2T 300  mol/L –Co-prescribe colchicine to prevent flare –AllopurinolVitamin C –FebuxostatFenofibrate –BenzbromaroneLosartan

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

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

Personal cost.. financial, self esteem, physical & mental Societal cost.. tax contributor to tax receiver What does this mean ? Loss or change in employment NRAS 2007 survey

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 So what can treatment do..

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

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

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

Conclusion 1 Treating early makes a big difference UK practice ? Early Rheumatoid Arthritis Network (ERAN) 638 newly diagnosed patients 2002 – 2007 Mean time from symptom onset to start of therapy 8 months Waterford

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%

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

Fundamental concept Minimizing cumulative inflammation (inflammation-time AUC) improves all outcomes 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

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

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

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

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

DAS changes in TICORA Trial Tight vs. conventional p< (after month 3) Conventional monotherapy Tight control 0 Months treatment Grigor et al. Lancet 2004 DAS score

TICORA: Number of patients responding at 18 months assessment (intention to treat analysis) Intensive group (n = 55) Routine group (n = 55) Odds ratio (95% CI) p value EULAR good response 45 (82%)24 (44%)5.8 (2.4 – 13.9)< EULAR remission 36 (65%) 9 (16%)9.7 ( )< ACR 20 response50 (91%)35 (64%)5.7 ( )< ACR 50 response46 (84%)22 (40%)6.1 ( )< ACR 70 response 39 (71%) 10 (18%) 11 ( ) <

Change of DAS-28 between usual care and tight control, according to a fixed-effects model 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 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 Schipper LG et al. Rheumatol. 2010; 49: 2154–2164

Biologics Nomenclature -iximabChimeric antibody Infliximab -zumabHumanized antibody Tocilizumab -umabHuman antibody Adalimumab, Golimumab -ceptFusion protein Etanercept, Abatacept

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

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

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

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

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

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

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 When to stop bisphosphonates

What about Strontium ranelate ? Venous thromboembolic risk Cardiovascular safety risk –serious cardiac disorders, including MI: RR 1.6 (1.07–2.38) cf placebo –Contraindicated in patients with: ischaemic heart disease, peripheral arterial disease, cerebrovascular disease; a history of these conditions, or in patients with uncontrolled hypertension... for every 1,000 patient-years of treatment there are 4 additional serious heart problems and 4 more cases of thromboses, whereas the drug has only a ‘modest’ benefit in terms of fracture prevention, preventing around 5 non-spinal fractures, 15 new spinal fractures and 0.4 hip fractures for every 1,000 patient-years. The PRAC therefore recommended the drug ‘be suspended until there are new data showing a favourable balance in a defined group’. The CHMP considered that the cardiovascular risk in patients taking Strontium can be managed by restricting its use to patients with no history of heart and circulatory problems and limiting its use to those who cannot take other medicines approved for the treatment of osteoporosis. In addition, patients treated with Strontium should be screened and monitored regularly, every 6 to 12 months.

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 What about Denosumab ? Number ofindependentrisk factors Age (years) Not recommended or older

ANA ? Measure this in the correct clinical context –You are wondering about a connective tissue disease CTD SLE Alopecia Malar rash Oral ulcers Raynaud’s Arthralgia Myositis Muscle weakness Rash Raynauds Dyspnoea Weak swallow, aspiration Scleroderma Raynaud’s, Reflux Thick skin Arthralgia Sjogren’s Dry eyes and mouth Fatigue Arthralgia Raynaud’s 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

Statins and myopathies Myalgia 2 – 11% Myositis with raised CK 0.5% Rhabdomyolysis 0.1% (new antibody HMGCoA) Increased risk : –Dose effect –Statins metabolised by cytochrome P450 (CYP) 3A4 Inhibitors will increase serum levels: Simva & Atorva –Elderly (reduced metabolism) –CKD, hepatic disease, xs alcohol

Statins and CYP3A4 inhibitors Simvastatin and Atorvastatin (not Pravastatin) Avoid CYP3A4 inhibitors –Grapefruit juice, diltiazem, verapamil, clarithromycin, erythromycin, fluconazole, itraconazole and ketoconazole

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 –Strontium and denosumab ANA Statins