Chikungunya O with post-chikungunya disorders Nyong Nyong Mayaro - PDF document

Declaration of interest Management of Chronic Sequelae I declare working as temporary senior consultant for - PAHO and WHO (since 2010) of Arthritogenic Virus Infections: - Sanofi (2017) - Valneva (since 2017) What's New? Coll E. Javelle Prof Fabrice SIMON, MD, PhD Department of Infectious Diseases and Tropical Medicine, LAVERAN Military Teaching Hospital & UMR 190 Unité des virus émergents, Medicine University MARSEILLE – FRANCE UMR Unit é des Virus Coll. E Javelle É mergents UVE IRD 190 ‐ Inserm 1207 1 2 Constellation of the main arthritogenic alphaviruses in 2019 Sindbis What do the adult patients Chikungunya O’ with post-chikungunya disorders Nyong Nyong Mayaro Ross really suffer from ? River >10M cases since 2005 Barmah forest Highest clinical burden Increasing experience 210 references 4821 references 140 references (most in the last 15 years) 117 references 619 references 3057 references 3 4 Chronic arthralgias and stiffness Chronic stage, up to 6 years… Rheumatic symptoms Other symptoms 2012 2008 2012 >once/month 2008 >once/month CHIK+ CHIK- CHIK+ CHIK- CHIK+ CHIK+ Pain 70 35 83 Fatigue 60 32 17 Stiffness 53 18 82 757 military policemen, Headache 42 29 14 Reunion Island, 2006 Swelling 20 2 50 Depression 21 6 6 months after onset 4 672 answerers M: 95%, mean age : 40 yo French gendarmes cohort  126 CHIK+ Reunion exposure, 2006 Simon F, personal data Follow-up 2008-2012 period Marimoutou C et al. BMC Musc Dis 2015 5 6 1

Chronic stage, up to 6 years… Two types of post-CHIK rheumatisms Long impaired quality of life French gendarmes cohort Reunion exposure, 2006 Follow-up 2008-2012 period CHIK+ 2012 2008 CHIK- 2012 2008 Marimoutou C et al. BMC Musc Dis 2015 Simon F et al. French guidelines on chikungunya, Med Mal Infect 2015 7 8 Tenosynovitis, tendonitis, fasciitis, bursitis, enthesitis… Post-CHIK chronic inflammatory rheumatisms F Simon, collection personnelle F Simon, collection personnelle F Simon, collection personnelle F Simon, collection personnelle F Simon, collection personnelle F Simon, collection personnelle 9 10 Multiple clinical and social consequences The post-CHIK vicious circle Chikungunya Pain Stiffness Depression Handicap in daily life Limitation in social Stop of physical life activities Self-depreciation Deconditioning Weight gain Stiffening 11 12 2

The clinical paradox of post-CHIK status On the shelf and beyond For the majority of the patients ʺ Symptomatic ʺ treatments • Pain • 0 10 – Painkillers up to level 3, antineuropathic drugs Physical examination • – NSAIDs, corticosteroids Fatigue • poorly contributive – Physical therapy 0 10 – Psychological support Sadness Biological testings • • frequently normal or 0 10 ʺ Etiopathogenic ʺ treatments • subnormal Handicap in daily life • – Antiviral drugs & anti-CHIKV monoclonal antibodies – Diseases modifying antirheumatic drugs: methotrexate, sulfasalazine, 0 10 Imaging: rare joint • hydroxychloroquine, leflunomide, biological agents… Social consequences • destruction 0 10 Other treatments • Sexual life • – Homeopathy 0 10 – Phytotherapy Quality of life • 0 10 13 14 What are the targets for the treatment? Acute Post-acute Chronic D1-D21 W4-W12 From M4… What should the ideal treatment do? Viremia Viral sanctuary(?) Clinical inflammation Clinical impact 15 16 Anti-CHIK drugs, including MAbs Anti-CHIK drugs, including MAbs Acute Post-acute Chronic Acute Post-acute Chronic D1-D21 W4-W12 From M4… D1-D21 W4-W12 From M4… Viremia Viremia Viral Viral sanctuary(?) sanctuary(?) Expected: Expected: Control of acute symptoms Etiopathogenic treatment of Prevention of chronicity chronicity Clinical Clinical inflammation inflammation Speculative For CIR only? Clinical Clinical impact impact 17 18 3

Anti-inflammatory drugs Anti-inflammatory drugs Acute Post-acute Chronic Acute Post-acute Chronic D1-D21 W4-W12 From M4… D1-D21 W4-W12 From M4… Viremia Viremia Viral Viral sanctuary(?) sanctuary(?) Expected: Expected: Control of acute articular symptoms Symptomatic treatment Prevention of chronicity of chronic pain and handicap Clinical Clinical inflammation inflammation Clinical Clinical impact impact 19 20 Disease-modifying antirheumatic drugs (DMARDs) What are the good endpoints? Acute Post-acute Chronic Viral load… • D1-D21 W4-W12 From M4… Number of tender joints • Number of swollen joints • Morning stiffness • Viremia Clinically-assessed stiffness • Viral Pain • sanctuary(?) Expected: Functional testings The most important • Etiopathogenic treatment Quality of life for the patients • of chronic joint inflammation Drug tolerance Clinical • inflammation Social life • CRP • Should target Rheumatoid factors • the CIR only Clinical … • impact 21 22 An exponential number of papers on the treatment Many scientific papers (in vitro, animal studies) Many cases reports Is there any magic bullet for the treatment? Few series Experts’ opinions Some clinical trials Reviews PubMed, « chikungunya » & « treatment », 2019/06/06 Meta-analyses National & international guidelines 23 24 4

Numerous reviews of the literature Very few relevant data for EBM in CHIK disease Only few CT, very few RCT Poor quality of the studies: numerous bias & low level of proof Different methodologies  impossible comparison Main criticisms : no randomization, pooling MSD&CIR, endpoints Sales G et al. Rev Assoc Med Bras 2018 Da Cuhna RV et al. Mem Inst Osw Cruz 2017 Sales G et al. Rev Assoc Med Bras 2018 Marti-Carvajal A et al. PLoS One. 2017 Zaid et al. Arthr Rheum 2018 Marti-Carvajal A et al. PLoS One. 2017 25 26 Antiviral drugs and anti-CHIKV MAb Painkillers Analgesics • Antiviral drugs active anti-CHIKV • – Paracetamol: hepatotoxicity when used on chronic liver disease or – Chloroquine : one RCT in Reunion 2006  not efficient overdose – Ribavirin +/- doxycycline: no RCT – Dipyrone: initially recommended in Brazil, risk for medullar toxicity – Sofosbuvir: no RCT – Some other candidates being studied in vitro Opioids • – For refractory pain only. Short use. Anti-CHIKV Mab • – One being developed: no RCT Antineuropathic painkillers • Efficacy at late stage speculative for both – To be added for patients with DN4 score >4 • Not recommended at any stage Recommended after D10. Cautious use in patients with underlying conditions. De Lamballerie X et al. Vector Borne Zoonotic Dis. 2008 Da Silveira Oliveira AF et al. Molecules 2017 Brito C et al. Rev Soc Bras Med Trop 2016 27 28 NSAIDs & corticosteroids Methotrexate Systemic NSAIDs • In vitro study suggests non benefit in acute stage • – No class has been shown to be superior Recommended as first-line treatment for RA (ARA, EULAR) • – Full dose x few weeks when possible – For patients fulfiling definition criteria – Avoid if patient with coronary diseases, renal failure, hypertension, risk – After 4-6 weeks for digestive bleeding… Empirically used in post-CHIK RA by rheumatologists in • Reunion island since 2005 Corticosteroids • No well-designed RCT • – Cautious use : low dose, short time, no long-action (DXM) Some case series with positive results • – Followed by NSAID to avoid clinical rebound – Possible adverse effects – Long-term adverse effects in patients older than 40: osteoporosis, – Some failure when started too late cataract Recommended, with caution in older adults Recommended as first-line treatment for CIR only Consider the diagnosis of CIR if refractory Requires biological follow-up Search for an alternative for long-term treatment Taylor A et al. PLoS One 2013 Simon F et al. French guidelines on chikungunya, Med Mal Infect 2015 29 30 5

Experience of methotrexate in Reunion island, 2005-2010 Experience of methotrexate in Reunion island, 2005-2010 77% of de novo CIR received MTX • 100% of RA , 80% of SA, <1/3 of UP • 75% efficacy (54/72) vs 25% failure (18/72) • Well tolerated • 15% second line treatment with biotherapy (12/72) (TNF blockers, abatercept, rituximab or tocilizumab) Javelle E et al. ISHEID 2013, Marseille Javelle E et al. ISHEID 2013, Marseille 31 32 Biological agents Hydroxychloroquine Only few cases reports Recommended in some CIR • • – Anti-TNF, rituximab, tocilizumab Contradictory data in the litterature • Not recommended as first-line treatment in RA • Proposed in the Brazilian guidelines • Expensive and not always available vs MTX or HCQ • Requires monitoring of ocular and cutaneous adverse effects • For confirmed CIR as second-line treatment only To be prescribed by a rheumatologist/internist Caution after a tropical stay (TB, strongyloidiasis) Simon F et al. French guidelines on chikungunya, Med Mal Infect 2015 Simon F et al. French guidelines on chikungunya, Med Mal Infect 2015 33 34 Homeopathy, phytotherapy Physical medicine Low level of proof for these tools that are use daily… No proof of efficacy • • – Poorly studied Only one RCT in Brazil: benefit of adjunctive Pilates • – Reduction in pain, fatigue, and increase of QoL Safe and benefitial fore many patients with post-CHIK • disorders Recommended at post-acute and chronic stage Not recommended at any stage Marques C et al. Clin Rehab 2019 35 36 6