Treatment of

Rheumatoid Arthritis
and Associated
Adverse Effects
LUKE AARON
A quick refresher on RA…

 A symmetric, inflammatory, peripheral polyarthritis of unknown

aetiology
 Typically leads to deformity through stretching of tendons and ligaments
and destruction of joints through erosion of cartilage and bone.
 RA should be suspected in the adult patient who presents with
inflammatory polyarthritis (joint pain, swelling, >30m morning stiffness)
 Complete physical exam indicated – synovitis, rheumatoid nodules, signs
of SLE/psoriasis etc.
 Lab tests: RF, anti-CCP antibodies, ESR, CRP, ANA, FBC. Consider
serology, synovial fluid analysis
 Imaging: XR of affected joints.
General Treatment Principles

 Treatment directed towards control of synovitis and prevention

of joint injury
 Principles:
 Early recognition and diagnosis
 Care by an expert, such as a rheumatologist
 Early use of Disease-Modifying Antirheumatic Drugs
 Tight control with a goal of remission or low activity
 Use of anti-inflammatories only as adjuncts to therapy
Early Recognition and Diagnosis

 Best effect from DMARDs

with early intervention
 Recognising before
irreversible injury if
important!
Differential Diagnosis

 Viral poly arthritis (rubella, parvovirus, HBV)

 Systemic rheumatic diseases (SLE, Sjogren’s, dermatomyositis)
 Hypermobility syndrome
 Fibromyalgia
 Reactive arthritis and arthritis of IBD
 Lyme disease
 Psoriatic arthritis
 Polymyalgia rheumatic (can be associated with giant cell arteritis)
 Crystalline arthritis
 Infectious Arthritis
 Osteoarthritis
 Paraneoplastic disease (hypertrophic osteoarthropathy, myelodysplasia)
 Sarcoid arthropathy
 Others… UpToDate article “Diagnosis and Differential Diagnosis of Rheumatoid Arthritis” has a good list!
Care by an Expert

 Early and ongoing care of patients with RA by a

rheumatologist is associated with better disease outcomes
 Reduced joint injury
 Less functional disability
Early use of DMARDs

 Better outcomes are achieved by early intervention

 MTX is generally the first-line DMARD used
 Patients unable or unwilling to take MTX may require an
alternative agent
 Non-biologics: leflunomide, sulfasalazine, hydroxychloroquine (for
limited arthritis without adverse prognostic signs)
 Biologics (particularly TNF-alpha inhibitors): etanercept,
adalimumab
 Patients resistant to initial DMARD therapy → treat with a
combination (eg MTX + SSZ/HCQ/TNFi) + anti-inflammatory
therapy
Pretreatment Evaluation

 Baseline FBC, serum creatinine, LFTs, ESR, CRP

 Screen for hepatitis B and C
 HepB: antiviral therapy before immunosuppressive therapy
 HepC: prefer non-hepatotoxic DMARDs (SSZ/HCQ) preferred
 Ophthalmologic screening for hydroxychloroquine use
 Testing for latent TB (as per 2015 ACR guidelines) prior to all
biologic DMARDs and tofacitinib (these medications may increase
the risk of mycobacterial infection)
 XR before starting MTX: there MAY be ↑ risk of MTX
hypersensitivity pneumonitis in patients with underlying pulmonary
disease → baseline CXR for subsequent comparison
Methotrexate

 A chemotherapy agent and an immune suppressant

 Also commonly used to treat ectopic pregnancies and molar pregnancies
 Multiple mechanisms of action involved in treatment of RA:
 Inhibition of purine metabolism → accumulation of adenosine (anti-inflammatory properties)
 Inhibition of T cell function, selective down-regulation of B cells
 De-activation of a number of enzymes relevant to immune system function
 Inhibition of binding of IL 1-beta to cell surface receptor (inflammatory response mediator)
 Metabolised by liver and intracellularly
 Excreted almost entirely in urine.
 Can be given by mouth or by injection
 PO doses taken weekly to limit toxicity
 Routine FBC, LFTs, creatinine recommended
Initial therapy with methotrexate

 First, MTX is CONTRAINDICATED in:

 Women who are pregnant or contemplating becoming pregnant
(teratogenic!)
 Patients with liver disease or excessive alcohol intake
 Patients with severe renal impairment (eGFR <30)
Methotrexate Dosing

 Single weekly PO dose

 Initiate between 7.5 and 15mg for most patients
 Depends on disease activity, weight, age, comorbidities, renal
function
 Increase dose as tolerated to achieve tight control
 By 2.5-5mg no more frequently than once a month
 Usual maximum dose is 25mg/week
 If maximum dose is ineffective or poorly tolerated, trial subcut
MTX or switch to other DMARD or add TNFi
Folic Acid Supplementation

 Folic acid 1mg daily or folinic acid weekly

 To prevent haematologic and other side effects
Inadequate Treatment Response

 Fail to achieve target in 3-6 months, or require prednisone to

maintain remission
 Change regimen!
Methotrexate side effects

 Nausea, abdo pain, fatigue, fever, dizziness

 Ulcerative stomatitis
 Acute pneumonitis, rarely pulmonary fibrosis
 Hypersensitivity pneumonitis is the MC
 Other lung injuries: pneumonia, noncardiogenic pulmonary oedema, pleural
effusion
 Hepatotoxic
 Rarely kidney failure
 Bone marrow toxicity
 Low WBC count → infection
 Neurotoxicity is possible (“chemo brain”)
Methotrexate Drug Interactions

 Talk to your friendly ward pharmacist!

 Penicillins may decrease elimination
 Aminoglycosides may reduce GI absorption
 Retinoids may produce additive hepatotoxicity
 Trimethoprim may produce additive haematotoxicity
 PPIs and valproate have been found to ↑ plasma concentrations
 Caffeine may antagonise effects of methotrexate on RA
Leflunomide

 Orally administered nonbiologic DMARD and

immunosuppressive agent
 Affects many components of the inflammatory response:
inhibits leukocyte adhesion, memory T cells, dendritic cells,
synovial inflammatory cells, interleukins, TGF-beta etc. etc.
 Can be used as monotherapy or in combination
 Monitor for hepatotoxicity
(especially if also on MTX!)
Leflunomide Adverse Effects

 Can potentiate action of warfarin! Talk to your ward pharmacist!!

 Three major AEs:
 Hypertension (esp. if also on NSAID)
 GI: diarrhoea and nausea (15% of patients)
 Liver disease: up to13% get a threefold elevation in aminotransferases
 Cases of fatal liver failure have been reported
 Other AEs:
 Leukopenia, other haematologic toxicity
 Interstitial lung disase, peripheral neuropathy
 Rash and alopecia (up to 15%!)
Sulfasalazine

 SSZ is reduced in colon by bacterial enzyems to sulfapyridine and 5-

ASA. Sulfapyridine active portion in RA, 5-ASA in IBD
 Mechanism of action not identified
 AEs: 20-25% of patients in clinical tirlas withdraw because of
intolerable side effects
 2/3 from GI or CNS toxicity
 HOWEVER< SSZ generally well-tolerated by most RA patients
 Idiosyncratic effects: skin reactions, hepatitis, pneumonitis,
agranulocytosis, haemolytic anaemia
 Dose-related: GI upset, CNS symptoms
 Some men experience infertility
Hydroxychloroquine

 Efficacy when used alone is limited

 Used for mild disease +/- NSAIDs or as part of combination
therapy
 MoA: wide variety of actions, many may be responsible for
HCQ’s immunomodulatory effects!
 AEs – serious side effects extremely rare
 GI problems
 Dermatologic reactions
 Headaches
 Retinopathy – monitor for bull’s eye maculopathy
Biologic Agents

 Agents that:
 Interfere with cytokine function or production
 TNF inhibitors (FIVE available for RA treatment)
 IL-6 inhibitors
 IL-1,-17,-12/23 inhibitors…
 Inhibit the “second signal” required for T-cell activation
 Abatacept – prevents CD28 from binding to CD80/CD86
 Deplete B cells
 Rituximab – lymphoproliferative disorders, rheumatic disorders
 Belimumab – SLE, being studied for Sjogrens
TNF Inhibitors

 TNF-alpha synthesized by activated macrophages and T cells

 Stimulation of release of inflammatory cytokines
 Upregulation of expression of endothelial adhesion molecules
 Coordination of the migration of leukocytes
 Etanercept, infliximab, adalimumab, certolizumab, golimumab
TNF Inhibitor complications:

 Mycobacterial infection, particularly TB

 Cytopenias (neutropenia most common, pancytopenia and aplastic anaemia
are rare)
 ~19% of patients
 Injection site reactions: itching, pain, redness etc.
 Infusion reactions (particularly infliximab): acute (IgE mediated) or
delayed (immune complex-mediated)
 Induction of autoimmunity
 Demyelinating disease
 Heart failure
 Malignancy
Infection risk!

 Cytopenias
 TNF-alpha is an important component of immune system’s
response
 TNF inhibitors associated with increase risk of:
 Bacterial infections (particularly pneumonia)
 Herpes zoster
 TB
 Opportunistic infections
 Screen for latent TB before initiation!
Etanercept and Adalimumab

 Etanercept
 P75 TNF receptor fusion protein → binds TNF molecules
 Used for JIA, RA, psoriatic arthritis, ankylosing spondylitis
 Adalimumab
 Subcut monoclonal antibody
 Approved for use in RA, psoriatic arthritis,
ankylosing spondylitis, Crohn disease
Tocilizumab

 IL-6 receptor antibody

 IV infusion every month, initially 4mg/kg. Can ↑ to 8
 Can also give subcut 162mg every fortnight
 Generally used for RA
patients who have not
responded to MTX or TNFi
 Common AEs
 ↑ cholesterol,
hepatic toxicity,
infusion-related reaction
 Risk of serious infections!
Tofacitinib

 Not a protein, hence not a biologic

 PO JAK inihibitor → decreases signalling by a number of cytokine
receptors
 Effective as monotherapy or combined with MTX
 Can lead to serious infections!
 20-22% get infections, 2-3% get serious infections
 Other significant AEs:
 Hypertension, peripheral oedema
 Nonmelanoma skin carcinoma, anaemia
 Renal failure
DMARDs Compared

 Results from randomized head-to-head trials…

 MTX has faster onset of action, compareable or greater
efficacy, and better long-term tolerance compared with other
nonbiologics.
 HOWEVER, almost all trials performed on patients with well-
established RA
 MTX comparable clinically, but radiologically less beneficial
compared to TNFi alone.
Remember the Principles?

 Principles:
 Early recognition and diagnosis
 Care by an expert, such as a rheumatologist
 Early use of Disease-Modifying Antirheumatic Drugs
 Tight control with a goal of remission or low activity
 Use of anti-inflammatories only as adjuncts to therapy
Tight Control

 Therapeutic target is remission or a state of minimal disease

activity
 Involves optimising therapy as discussed
 Exacerbations despite preceding control (“flare”): temporary
increase in anti-inflammatories. Glucocorticoids may be required.
 Strategies for tight control:
 Periodic reassessment of disease activity (usu. 3monthly)
 Adjustment of DMARD regimens every 3-6m as needed
 Administration of Anti-inflammatory adjuncts to maintain control
until DMARD therapies sufficiently effective
Assessment and Monitoring

 Monitoring involves…
 Patient and clinician assessment of symptoms and functional status
 Evaluation of joint involvement and extraarticular manifestations
(Physical exam!)
 Laboratory markers
 Imaging
Symptoms and Functional Status

 Degree of joint pain, duration of morning stiffness, severity of

fatigue
 Evidence for and changes in extraarticular manifestations of
RA including fever, anorexia, malaise, weight loss, symptoms
of cardiovascular disease
 Note: exclude infection before blaming fever on RA!
 What is the patient’s functional capacity? ADLs? Hobbies?
Sports?
 There are standard questionnaires you can search for!
 Also remember to assess for drug AEs!!!
Physical Examination

 Assess changes in previously affected joints

 Look for appearance of inflammation in previously uninvolved
joints
 28-joint examination
 Wrists, elbows, shoulders, knees, MCPs, PIPJs of hands
 Appropriate if feet are not involved.
 If feet involved, MTPs and PIPJs of feet should be assessed too!
 Swelling, tenderness, loss of motion, deformity
 Periodic general physical exam too; esp. skin (rheumatoid
nodules), lungs (pleural or interstitial disease)
Laboratory Markers

 Acute phase reactants: CRP, ESRR

 Other relevant lab results:
 Anaemia of chronic disease
 ↓ albumin may be assoc. w/ ↑ disease activity
 Ongoing inflammation can mildly elevate platelet counts
 FBC, creatinine, LFTs to monitor for drug effects
 Glucose, lipids, bone mineral density testing if on
glucocorticoids
Imaging

 Plain XRs of affected

joints appropriate early
in course
 Serve as baseline for
evaluating changes
 In general, repeat every
2 years in patients with
remission
Composite Measures

 Calculators found online can give a score to describe disease activity

 Use inputs such as:
 Number of tender joints
 Number of Swollen Joints
 ESR
 Patient’s global assessment
 Evaluator’s global assessments of activity
 If you’re interested:
 DAS28
 SDAI
 CDAI
Anti-inflammatory Adjuncts

 Used primarily as adjuncts for temporary control of disease

activity in…
 Patients newly started on DMARDs
 Patients who require a DMARD regimen change
 Patients experiencing disease flairs
 Glucocorticoids are rapidly tapered as tolerated once control
achieved
NSAIDs

 Should be used for initial therapy, unless contraindicated by

GI/renal disease or heart failure.
 Dose required by patients may vary: titrate to optimum
tolerated level
 Ibuprofen, naproxen, piroxicam
Glucocorticoids

 PO glucocorticoids used in initial treatment in:

 Severely active RA
 Less severe disease when NSAIDs inadequate
 Prednisone 5-20mg/day
 Taper rapidly as tolerated when disease control achieved
Drug Therapy for Flares

 Single affected joint: consider intraarticular glucocorticoid

injection (avoid need for prolonged systemic steroids!)
 Widespread flares: short term prednisolone, usually <15mg per
day
 Severe flares: pulse IV methylprednisolone
Don’t forget Nonpharmacologic
therapies!

 Important in the comprehensive management of RA

 Patient education
 Psychosocial interventions
 Rest, exercise, physical/occupational therapy
 Nutritional and dietary counselling (active RA assoc. w/ anorexia, poor
dietary intake)
 Interventions to reduce risks of cardiovascular disease (increased risk of
coronary atherosclerosis in RA)
 Screening for and treatment of osteoporosis )RA causes gradual loss of bone
mineral density)
 Immunizations to decrease risk of infectious complications of
immunosuppressive therapies