Dr.Kaushik S. Bhojani, DNB, MNAMS Consultant Rheumatologist Kennisha Rheumatology Care & Diagnostics, Bhandup, Mumbai

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1 Dr.Kaushik S. Bhojani, DNB, MNAMS Consultant Rheumatologist Kennisha Rheumatology Care & Diagnostics, Bhandup, Mumbai Important achievements 16 Publications (15 National and 1 International) 8 Poster presentations at national conference Photo Chapter on Septic Arthritis in Manual of Rheumatology (3 rd Edition) Areas of special interest Systemic Sclerosis and SSc Overlap Syndrome Bad obstetric History

2 Low dose steroids in RA treatment in the Era of Biologicals: Friend or Foe Debate at the IRACON 2016, Kochi Dr Kaushik S. Bhojani Kennisha Rheumatology Care & Diagnostics Mumbai

3 FRIEND OR FOE

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5 Historical Aspects of Steroids 1950: Nobel Prize for discovery of steroids and their use in RA Euphoria on discovery of MAGIC BULLET against RA Rampant use

6 LARGE DOSES and MISUSE Quackery Self Use or rather Self Abuse Serious Side effects including Infections Dream debut became Horror story

7 RECENT RESURGENCE: REDEFINING ROLE OF STEROIDS IN RA

8 Definition of steroid doses Low Dose Prednisolone less than 7.5mg per day or equivalent Moderate Dose Prednisolone 7.5mg to 30 mg/day High Dose Prednisolone 30 mg to 100mg/day Buttgereit F et al, Ann Rheum Dis 2002, 61:

9 Disease modifying effect in early RA 1983: Harris et al: First study (small sample size) Prednisolone 5mg/day vs. Placebo showed reduction in radiographic erosions. 1995: Kirwan et al: 128 patients, steroids vs Placebo on background DMARD therapy. significant clinical improvement plus reduction in radiographic progression in steroid group. García-Magallón, et al Reumatol Clin. 2013;9(5):

10 COBRA Study RA <2 years Combo of SSz+ Mtx vs SSz monotherapy Steroid 60mg per day tapered over 28 weeks Increased Sharp score in SSz group at 28, 56 and 80 weeks. The lower radiological damage in steroid group was evident even 5 yrs later. Drawback : Assumption that SSz and combination of Mtx and SSz have same effect.

11 Rau et al (2000) 196 patients RA <2yrs Significant difference in radiographic damage at 6, 12 and 24 months in steroid group vs. placebo on back ground of Mtx or Parenteral gold Radiographic progression in placebo group was 4 times that of the steroid group in the first 6 months. Differences were significant even at 24months however most significant in first 6 months:

12 Cochrane library Meta-analysis 2007 Effectiveness of corticosteroids for inhibiting radiographic progression 15 randomised clinical controlled trials 1414 patients mostly early RA In most cases GC were added to conventional DMARDs Difference in radiographic progression was evident in all studies except one.

13 Meta-analysis 2010 DMARD monotherapy, combination therapy of Two DMARD plus GC, GC monotherapy & Biologicals Data from 70 trials All groups showed reduced rate of progression in 1 st year by 48 to 84%. Rate of radiographic progression in the DMARD Combo + GC was 0.62% Vs. 0.61% in Biological plus Mtx groups

14 Touche

15 BeSt Study 508 patients: 4 groups 5 year follow up data Sequential monotherapy vs Stepwise addition therapy vs Combination therapy with steroids tapered by week 6 to 7.5mg per day vs Mtx and Biological combination. Combination therapy and Biological group did better at one year with less radiographic progression. Addition of high dose steroid therapy to combination therapy mitigates advantage of Initial biologic therapy

16 TEAR study (Treatment of early aggressive RA) Investigator initiated randomised placebo controlled trial 4 strategies Mtx Monotherapy, Mtx to step up therapy, Triple combination therapy, Mtx Plus Etanercept No advantages of Biological combination in clinical and radiographic outcomes vs. step up combination DMARD therapy at 6 months

17 Other important uses of Steroids in RA Addition to triple DMARD combination therapy in uncontrolled RA in patients who cannot afford or are unwilling for Biologicals. Bridge therapy in Treatment of RA To control intermittent flares of the disease with short bursts of steroids Intra-articular injection in the odd recalcitrant Joint

18 Pregnancy and lactation Safe drugs in Pregnancy: HCQ, SSz and steroids Steroids get metabolised by 11 β hydroxysteroid dehydrogenase to Inactive forms Maternal to Fetal ratio of concentration is10 :1 Hence low to Moderate doses safe in pregnancy.

19 Steroids: Side effects Should I Say?

20 Side effects of Steroids Osteoporosis Myopathy Weight Gain Hyperglycemia Hypertension Cardiovascular Morbidity Ocular Side effects: Cataract / Glaucoma GI adverse effects Pancreatitis Osteonecrosis Infection Dermatological

21 Side effects of Steroids Fear of toxicity is based on experience from use of high dose of steroids. Review of adverse effects from trials using low dose GC in RA Arthritis & Rheumatism council low dose GC (ACR )study 1995, Low dose prednisolone therapy (LDPT ) study 2000, Utrecht study 2002 WOSERACT 2004 Silva J.A.et al. Ann. Rheum. Dis.65, : 2006

22 Side effects of steroids Osteoporosis 1997 Review of 18 prospective trials with 329 patients At a mean dose of almost 9 mg prednisone equivalent per day, the best estimate of bone loss overall in spine and hip (without bisphosphonate treatment) is only 1.5% a year. GC amplify the risk of OP due to the RA itself by a factor of 2.

23 RA itself is an independent risk factor for osteoporosis. reduced physical activity, increased levels of inflammatory cytokines, which stimulate differentiation of osteoclasts and thus lead to bone loss. Possibly, GC in RA, help in reducing disease activity and help prevent bone loss than otherwise. Data from the four extensively reviewed trials showed that BMD loss over 2 years is not significantly different from that with placebo Strategies for the prevention and treatment of GCinduced osteoporosis are well established

24 Diabetes Mellitus Slightly increased fasting glucose and increased PP values. Patients with risk factors are at increased risk. In 4 studies no cases of new onset diabetes The Utrecht trial - a significant increase in mean (SD) fasting glucose was seen in the prednisone group at 2 years. However, even in this study, hyperglycaemia, developed in only 2/40 pts

25 Weight gain Data from 4 trials: Increase of mean body weight by 4 8% over 2 years. In 2 trials: Weight gain was significantly higher than in the placebo group. These observations were confirmed in the COBRA trial, but the differences were nullified after prednisone was stopped

26 Cataract: Posterior Subcapsular cataract 15% patients developed cataract on 5-15mg/day NO INCIDENCE in 4 trials in 2 years Glaucoma: Mildly increased risk However on dose <7.5mg/day incidence is only 3%. Possible genetic basis

27 Dyslipidaemia, atherosclerosis, cardiac disease: Increased risk of CAD Animal studies showed increased Atherosclerosis but reduced plaque formation In fact the risk could be lower due to reduction in inflammatory load GI- risk: increased risk mainly when used with NSAIDs Data from 4 trials show no increased risk

28 Infection: Risk increases with dose and duration Low risk at low doses Meta analysis of 71 trials with >2000 patients. Of these 5 trials were with rheumatic diseases, 2 with RA. Risk similar to Placebo Data from 4 trials showed no increased risk on doses less than 10mg per day for 2 years.

29 Dermatological Cosmetic issue Available data suggest cutaneous effects are relatively uncommon and minor with low dose GC treatment, although data on incidence are scarce. In the four extensively reviewed trials on low dose GC treatment in RA and the COBRA study, serious cutaneous adverse effects were not reported, (trial duration relatively short for development of these complications).

30 Osteonecrosis Suspected dose related, Sometimes disease related Data scarce on low dose. No incidence in 4 trials Myopathy: Rare on low doses of GC Hypertension: data from 4 trials did not show any effect of low dose GC on BP

31 Era of Biologics: Initial Euphoria Similar Story Touted as a potential cure Again Nobel Prize for Anti TNF discovery But VERY Expensive (Possibly saving grace) Large adverse event Profile

32 Era of Biologics: Ground Reality

33 Which ever the biologic, average response of ACR 50 is only about 60% (56 to 67 %) ACR 50 of Mtx monotherapy itself is 41% Triple Therapy approximately 61% with lesser withdrawals due to Adv Effects. Mtx combined with Anti TNF s superior to Mtx for inhibiting Radiographic progression BUT mean change over 1yr was less than the clinically important difference of 5 units on the Sharp- van der Heijde scale Glen S Hazlewood et al BMJ 2016;353:i1777

34 Comparison of efficacy No Data of Comparative efficacy of one molecule versus the other Though claimed to be targeted therapy by virtue of actions on specific cytokines the use is still random and first choice differs between clinicians. The only exception being potentially better response with Rituximab in seropositive RA

35 Side effects of Biologicals Costs Infections : TB & Other SERIOUS INFECTIONS Allergic reactions which are now on the wane given Humanized Anti TNF

36 Data on Infection on Biologicals Meta analysis of 66 randomized controlled trials and 22 long-term extension studies met the selection criteria. Estimated incidence rates (95 % confidence intervals [CIs]) for abatacept, rituximab, tocilizumab, and tumor necrosis factor inhibitors were 3.04 (2.49, 3.72), 3.72 (2.99, 4.62), 5.45 (4.26, 6.96), and 4.90 (4.41, 5.44), respectively. Incidence rates (95 % CIs) for tofacitinib 5 and 10 mg twice daily (BID) in phase 3 trials were 3.02 (2.25, 4.05) and 3.00 (2.24, 4.02), respectively. Corresponding incidence rates in long-term extension studies were 2.50 (2.05, 3.04) and 3.19 (2.74, 3.72). The risk ratios (95 % CIs) vs placebo for tofacitinib 5 and 10 mg BID were 2.21 (0.60, 8.14) and 2.02 (0.56, 7.28), respectively. Strand et al:arthritis Res Ther. 2015; 17: 362.

37 Incidence rates for serious infections with biologic DMARDs and tofacitinib across RCTs* and LTE studies. Strand et al:arthritis Res Ther. 2015; 17: 362.

38 Systematic review of 106 trials of RA patients on biologic and reported on serious infections. Compared to traditional DMARDs, standard-dose biologic (odds ratio [OR],1.31; 95% credible interval [CrI], 1.09 to 1.58) and highdose biologic (OR, 1.90; 95% Crl, 1.50 to 2.39) were associated with an increased risk of serious infections, while low-dose biologics (OR, 0.93; 95% CrI, 0.65 to 1.33) were not. The risk was lower in Mtx naive patients compared with traditional DMARD- or anti-tnf-biologic-experienced. The absolute increase in the number of serious infections per 1000 patients treated each year compared to traditional DMARDs ranged from 6 for standard-dose biologic to 55 for combination biologic therapy. Interpretation: Standard-dose and high-dose biologics (with/without traditional DMARDs) are associated with an increase in serious infections compared to traditional DMARDs in RA, while low-dose biologics are not. Clinicians should discuss the balance between benefit and harm with the individual RA patient before initiating biologic therapy. J.A. Singh et al Lancet July 18; 386(9990): doi: /s (14)

39 Risk of serious infection with biologics in treating patients with RA: Systematic Review and Metaanalysis J.A. Singh et al Lancet July 18; 386(9990): doi: /s (14)

40 Costs of Biologicals /similars Originator Biosimilar To patient Infliximab 41000/100mg 34000/100mg Adalimumab NA 25000/40mg Golimumab 1.2l ac/50mg NA 47000/mg Certolizumab NA NA NA Etanercept 7500/25mg 6000/25mg 3900/25mg Anakinra NA NA NA Tocilizumab 42000/400mg NA 15000/400mg Abatacept 52000/500mg 52000/500mg Rituximab 1.5 lacs/2gms 1.5lacs/2gms 80000/2gms

41 Country / Specific Issues Cost constraints. Reluctance: The lack of awareness and hence lack of perception about the morbidity of uncontrolled RA. Irrational fears / social pressures TB endemic in our country.

42 Biosimilars: Another story By the very character of the Biologicals and their processes, No two batches can be the same So Batch two is a Biosimilar of Batch one anyway Now add to that Biosimilars Except for trial data we do not comparative studies

43 To Summarise Low dose steroids definitely a better bet even in the biological era Side effects profile of low dose steroids not common, not serious and manageable Biologics still expensive even after advent of Biosimilars. For long term the entire world finds them a difficult proposition. Adverse Event profile of biologicals is possibly much worse than low dose steroids

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45 REBUTTAL

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47 Try telling a patient You have RA and I want to give you a drug which costs Rs fifteen to twenty thousand per month that also is a discounted rate. I will first check whether you have dormant TB bacteria in your body so you will need baseline tests for TB etc. AND there is a risk of TB infection while on these drugs. You are also at risk of other serious and sometimes life threatening infections.

48 You have to avoid crowded places because of Risk of infection. So avoid going to Marriages, Functions, Social gatherings. You have to preferably avoid public transport. I cannot guarantee a cure. I cannot assure you whether the drug will completely treat your disease.

49 We may need to change the Biological drug to another equally expensive one if this one does not work. We will have to try 4 to 5 doses to determine whether the first drug is working and then plan on switching to another. Even if the first drug works, You may need more than 4 to 5 doses also. This drug is not re-imbursed through medicare in India so you have to fund yourself.

50 On the other Hand: If You Speak the truth Steroids are considered taboo however at low doses the side effects are not severe. Most side effects can be managed by us. Risk of Infection on low doses is not high. They cost as less as Rs 5 per strip of 10 tablets. Your cost of therapy will be approximately Rs Two thousand per month including 3 DMARDs steroids, Calcium etc

51 Effect of the Combo When you combine low dose steroids to the combination of three anti-rheumatic drugs, chances are that the effect will be almost as good as the Biologicals. If you do not improve despite our best efforts on this combination we could always then consider Biologicals

52 You know What. It s a no brainer The patient has already chosen the latter option. Now Its your turn

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