Pain Management for Rheumatoid Arthritis

in AdultsPresented by Bradley Roth

Definition and Epidemiology of Rheumatoid Arthritis

• Definition => Chronic autoimmune inflammation & destruction of small synovial joints

• Epidemiology • Arthritis affects 20% of adults worldwide

• RA affects ~387,000 in UK – ~12,000 new cases pa

• Peak incidence 40-60 years old; particularly women

Aetiology of Rheumatoid Arthritis• Origin => unclear with ongoing research

• Trigger => T-cell mediated B-cell & macrophage autoimmune response to unknown infection(s)

• B-cell => increased RF (antibody) production

• Macrophages => cytokines (TNF-a, IL-1) interact with MMP to erode/degrade/destruct synovial fibroblasts of joints & osteoclasts/chondrocytes of bone

Diagnosing Rheumatoid Arthritis

• Classical Early Diagnostic Signs => morning stiffness & joint pain (>3 months)

• Blood Tests => RF (~20% seropositive) + Anti-Cyclin Citrullinated Peptide (CCP/ANA)

• Referral => >3 months synovitis of small joints of undetermined cause

Monitoring and Managing Rheumatoid Arthritis

• Management => relieve pain (fibromyalgia) & modify disease (arthropathy) progress

• Monitoring- Blood Tests and Imaging => RF + CRP + ESR + X-ray (every six months)

• Adequacy of Therapy => determined via disease activity score 28 (DAS28) + HAQ + MDT management

Treatment Pathway for Rheumatoid Arthritis

Pain Management (Newly Diagnosed RA)NSAIDs and Narcotics (Opioids)

Additional Therapies (based on ADL and DAS28 scores)• Physiotherapy

• Occupational therapy• Podiatry

• Therapy (relaxation, stress management, coping)

Second Line Disease Treatment (Moderate RA)Methotrexate + TNF-α Inhibitor Therapy

Second Line Disease Treatment (Severe RA)Methotrexate + Rituximab

Novel Disease Treatments (Unmanageable RA)Surgical Interventions

First Line Disease Treatment (Mild RA)Methotrexate + Second Line DMARD

Case Study: Overview• History • 37 year old man with painful wrists and morning stiffness >3 months

• Examination • Swollen MCP joints in hands. No deformity, nodules or vasculitic lesions

• Blood Tests• Raised CRP, Normal Hb and WCC, RF and ANA negative

• Diagnosis • Early RA; managed with NSAIDs and opiates

WHO Pain Ladder

NSAID Pain Management for Newly Diagnosed RA

• Non-Specific COX-2 => ibuprofen, diclofenac, naproxen• Specific COX-2 => celecoxib, rofecoxib, meloxicam

• MOA => COX-2 inhibition reduces prostaglandin synthesis necessary for nociception axons

• ADRs => Non-specifics COX-1 inhibition causes GI toxicity (PPI), CVS & thrombotic events

• Limitation => omits immunological basis of disease

Opioid Pain Management for Newly Diagnosed RA

• Narcotics => tramadol, morphine, hydrocodone, codeine

• MOA => produces analgesia by opening downstream pain modulation via mu (in CNS) and OP1-3 (in spinal cord) receptors:

• Specifically =>

Mu => inhibits GPCR-mediated adenylate cyclase to block nociceptive NT transmission (substance P, GABA, Dopamine, ACh, NA)

OP1-3 => hyperpolarises postsynaptic membrane to reduce influx of presynaptic Ca2+

Case Study: Review and Management• Six Month Review • Develops TWO painless subcutaneous nodules at 3rd/4th MCPs

• Blood test positive for RF and CRP; but normal C3 and C4 levels

• X-ray evidence reveals MCP joint erosion due to RA

• Management of Arthropathy and Fibromyalgia• Weekly low-dose methotrexate injections (for several years)

First Line Disease Treatment for Mild RA

• Methotrexate + 2nd DMARD => sulfasalazine, hydroxychloroquine, cyclosporine, leflunomide

• Methotrexate MOA => unknown MOA modifies early inflammatory/destructive disease process

• Methotrexate ADR => lowest DMARD ADR profile; includes N&V and skin rashes

Case Study: Review and Management• Two Years Later• Persistent pain, stiffness and swelling of hands• RA unresponsive to methotrexate + 2nd DMARD

• Management of Arthropathy• Prescribed methotrexate + biological DMARDs • IV infusion every 6 months

• Therapeutic Goal of Biological DMARDs• Manage chronic inflammation• Limit structural damage to preserve joint function

Second Line Disease Treatment for Moderate RA

• Biological DMARDs => etanercept, infliximab, rituximab

• Therapeutic Goal => Allow healing by neutralising pro-inflammatory factors involved in synovitis and joint erosion

• General ADRs => immunosuppression, opportunistic infection, N&V; infusion reactions (hives, itching, chest tightness, SOB, angioedema, dizziness, weakness, cough)

• General Contraindications => drug/latex allergies, leukaemia, anaemia, CVS, thrombocytopenia, MS, hepatitis, HIV, TB

Second Line Disease Treatment for Moderate RA

• Etanercept and Infliximab

• General MOA => blocks inflammatory pathway mediated by TNF-α and other pro-inflammatory factors

• Infliximab MOA => anti-TNF-α antibody binds to and neutralizes TNF-α expressed by WBCs

• Etanercept MOA => IgG TNF-α antagonist p75 domain binds to TNFR to block activity of cellular p75

Second Line Disease Treatment for Moderate RA

• Rituximab

• Structure => anti CD20 antibody; derived from Chinese hamster ovary (containing gentamicin)

• MOA =>• Unclear mechanism(s)

• Maybe involve in depleting B-cell production of autoantibodies and cytokines

• Via interference of B-cell/T-cell interactions

• Suspected that Fab binds to CD20 on B-cells whilst Fc mediates B-cell lysis via CDC, ADCC and apoptosis

NICE: Assessment Group Analysis into Rituximab

• Assessment group (2015) systematic review• Treatment efficacies => for RA after failure of

ONE TNF inhibitor therapy

• 35 studies => 2 RCTs (3 excluded for irrelevance), 1 Non-RCT and 29 uncontrolled studies

• Clinical effectiveness => ACR20, 50 & 70 and improvement on DAS28/HAQ scores

• ACR20, 50, 70 => percentage of TJC/SJC improvement

ACR Improvement => 3/5 parameters for tender/swollen joint counts (TJC/SJC)

NICE: Clinical Effectiveness of Rituximab in REFLEX

• REFLEX Aim => valid phase III RCT evaluating efficacy and safety of rituximab at 24 weeks

• REFLEX Design => 1x course of rituximab against placebo (+ ongoing methotrexate) in 517 patients with previously inadequate response to ONE TNF inhibitor therapy

• REFLEX Results => greater response rates improvements (ACR) and mean improvements (DAS28/HAQ) in 1x rituximab group than placebo

Figure: REFLEX Trial (2006) - Result SIX Months After Treatment

NICE: Clinical Effectiveness of Rituximab in SUNRISE

• SUNRISE Aim => phase III RCT evaluating efficacy and safety of rituximab at 24 & 48 weeks; discounted due to delay in submission for review

• SUNRISE Design => 1x course rituximab (with placebo) against 2x course of rituximab at 24 & 48 weeks respectively (with ongoing methotrexate) in 559 patients with inadequate response to TNF inhibitors

• SUNRISE Results => greater response rates improvements (ACR) and mean improvements (DAS28/HAQ) in 2x rituximab group than placebo

Figure: SUNRISE Trial (2010) - Result 48 Weeks After Treatment

NICE: Appraisal Committee Conclusion into Rituximab

• Appraisal Committee Review• Clinically Effective => compared to placebo; but equal to abatercept (ATTAIN trial)• Cost Effective => compared to abatercept (via cost-utility analysis - base-care analysis)

• Recommended Treatment Option • Treatment => 2/3x course rituximab (per 6 months) + ongoing methotrexate • Candidate => severe RA with inadequate response to DMARD & ONE TNF inhibitor• Rituximab Contraindication => use adalimumab, etanercept, infliximab, abatacept

• Limitation/Future Research => • RCTs => to directly compare effectiveness of rituximab (w/wo methotrexate) against

other TNF inhibitors (adalimumab, etanercept, infliximab)

Surgical Options for RA• Surgical Outcomes• Relieve pain and improve function of deformed joints • For patients unresponsive to therapy• Surgery NOT always successful due to multiple small joints affected

• Surgery choices• Arthroplasty

• Arthroscopy

• Carpal tunnel release

• Other => cervical spinal fusion (to treat severe neck pain and nerve problems), finger and hand surgeries, synovectomy (remove inflamed joint tissue)

Any Questions?Thank You