Rheumatoid Arthritis Medical Treatment ( Prof. Fathy EL-Belasy) Strategy & Drugs

Guidelines
for

Medical Treatment
of

Rheumatoid Arthritis
Prof. Fathy Mohamed EL-Belasy (MD)
Prof. of Internal Medicine & Rheumatology
Faculty of Medicine
Alexandria University

Medical Treatment of RA
Prof. Fathy El-Belasy

An autoimmune disease characterized by
symmetric erosive synovitis & sometimes multisystem
involvement. It affects approximately 1% of the world’s
population who are genetically predisposed.
Most patients exhibit a chronic fluctuating
course; if left untreated results in progressive joint
destruction, deformity, disability & premature death.


Smoking has recently been recognized as a
critical factor for the development of RF-positive

RA, for the production of ACPA & is associated with
more severe disease & reduced response to therapy.
As such smoking cessation should be an essential part
of treatment of Rheumatoid patients.


Some clinicians considered RA
as a cancer of the synovial tissue
which
proliferates
in
an
uncontrolled fashion (pannus)
 erosions of the surrounding
bone, cartilage and damage of
tendons & ligaments leading to
irreversible joint destruction and
deformity.


I-General Principles

1-The ultimate aim of the treatment for any disease is to
achieve a cure.

In RA there is no cure; so the treatment target is
either remission in early cases or low disease activity in
long standing RA patients.



Low

disease

activity

means:

relief

of

symptoms, preservation of function and prevention
of structural damage & deformity.

Treatment must continue as in cases of DM
or HTN. Discontinuation of treatment even in
cases of remission  Rebound flare.



Early diagnosis, Early referral to a
specialist, Early aggressive therapy

2- The concept of early initiation of more
aggressive

therapy

is

important

because

irreversible joint damage develops within the first 3

month after disease onset.



So early diagnosis, early referral to a
specialist and early aggressive therapy (tight
control) (window of opportunity, i.e. within the
first 3 month of diagnosis), will delay or prevent

the

risk

of

bone

erosions,

joint

destruction, deformity; which may improve
patient’s survival and increase the number of
years that patients enjoy a better quality of life.



3-Majority of patients are seen by
non-specialists who may not be aware
about the emergency situation; so

patients are seen 1-2 years after onset of
the disease.

Early referral to a specialist is of utmost
importance.



4- NSAIDs:

Are Symptom Modifying Anti Rheumatic
Drugs (SMARDs) i.e. do not stop the progress of
the disease, so used during the bridge stage
because DMARDs has no analgesic effect. So
NSAIDs are used till the onset of the effect of

DMARDs.

Leflunomide & MTX (one month) till the onset of its effect

while SSZ & HCQ (3-6 month),GCs (hours).


5-Patient’s assessment




(A) Disease Activity

Disease activity is assessed during each clinical visit
by:
• Duration of morning stiffness.

• Number of tender or swollen joints.
• CRP.
• Fatigue
Drug failure is considered after 3-6 month drug trial.



(B) High resolution musculoskeletal ultrasonography

Along with disease activity

assessment to evaluate the
success of DMARDs or
Biologic therapy because it
shows synovitis or early
erosions.

(C) Laboratory investigations

• CBC

• HCV Ab

• Liver

• HB sAg

profile
• Renal
profile
• FBS

• CRP
• ACPA
• RF


II

Recommendations for
management of RA

II-Recommendations for management of RA


The patient has to be appropriately informed about

• The disease itself.

• Treatment options (DMARDs or Biologics) must
be

a

shared

rheumatologists.

decision

between

patient

and



(1) Methotrexate monotherapy

In cases of DMARDs naïve patients Methotrexate
should be initiated as first line mono-therapy
{with/without Glucocorticoids} at the maximally
tolerated dose (7.5-25mg & rarely 30mg/week). (7.5-

20 PO & switch to SC or IM if the dose >20mg/week).



(1) Methotrexate monotherapy
MTX

is

the

most

effective,

safe

(ease

of

administration, low cost and of long term therapy (515ys).
It is first line agent & the anchor drug for combination
therapy with other DMARDs & Biologic agents.

Do not forget to add 1mg folic acid/day to guard against
GIT, hematologic or pulmonary side effects.



(2) Methotrexate + Synthetic DMARDs

2-Patients
present

who

with

inspite

continue
active

to

disease

of

MTX

monotherapy, addition of another
conventional

DMARD

is

combined with MTX in a step up

combination therapy.



Tailor treatment according to disease activity
(i)

MTX + HCQ.

(ii) MTX + SSZ.
(iii) MTX + Leflunomide.
Most experts no longer use loading dose if combined with
MTX because of increased liver toxicity while HCQ minimize
hepatic toxicity of MTX & lower LDL & T.G
(iv) MTX + one or two or 3 DMARDs ± short term GCs.
combination of these drugs with different modes of action
allows the use of lower (individual) drug doses thus minimizing
toxicity without reducing efficacy.



Glucocorticoids (GCs)

GCs is added at low to moderately high doses to Synthetic or
Biologic DMARDs whether monotherapy or in combination.
Morning 8-10am low dose <10mg/d gives a rapid relief of
symptoms because it behaves as:
• Anti cytokines (Anti IL-1,IL-2, Anti TNF )
• Anti COX
NSAID effect
• Anti LOX
So they have actions equivalent to Anticytokines
DMARDs, NSAIDs
As well as inhibit lymphocyte proliferation & antigen presentation.



Glucocorticoids (GCs) (cont.)

GCs has a disease modifying effect without harmful side
effects especially if used with Ca & Vit D in a dose <10mg
(7.5mg/d)
But more rapid improvement may be achieved by addition
of GCs at a higher dose in cases of visceral
involvement,
e.g.
pericarditis, pleurisy, fever, vasculitis)for a short term
Ask for bone mineral density (BMD) DEXA scan during
follow up.



Glucocorticoids (GCs) (cont.)

GCs minipulse therapy:
During exacerbation of the disease GCs are used in
a dose of 200-250mg IM or IV for 3 successive days, then
go back to maintenance low dose

This minipulse is equivalent to 1000mg/d pulse therapy
in SLE
No prolonged suppression of hypothalamic pituitary
adrenal axis (HPA); so it has no adverse effect like that of
long term use of GCs.



According to disease activity
(iv) MTX + one or two or 3 DMARDs ± short term GCs.

combination of these drugs with different modes
of action allows the use of lower (individual) drug doses
thus minimizing toxicity without reducing efficacy.



(3) Methotrexate + Biologics

I.

If the treatment target is not achieved (remission/low
disease activity) with MTX +

two or more synthetic

DMARDs ± short term GCs after 3-6 month.

II. Or in cases of High Disease Activity (HDA) and poor
prognostic factors; addition of biologic therapy should be
considered from the start.



Poor prognostic factors:

(i) Female patient
(ii) Smoker
(iii) Old age
(iv) Positive family history
(v) High ESR or CRP
(vi)High titer of ACPA (Anti CCP) or RF
(vii)Early joint erosion at disease onset.
(viii)Extra-articular manifestations (SC
ulcers, PN)
(ix)Worse physical function.
(x) Poly-articular initial presentation.

nodules

or



Despite of the ongoing discussion, at the

moment there is not enough evidence to support
generalized use of biologic in association with MTX
as first line therapy by doing so, we would be over
treating at least 15-40% of patients who would
respond

to

DMARDs.

MTX

mono-therapy

or

MTX

+



If biological DMARDs + MTX is considered start
with 1st generation anti TNFα

When Anti TNF α and Methotrexate is combined

remission rate doubles.



If biological DMARDs + MTX is considered start with 1st
generation anti TNFα

(i)Etanercept (ENBREL) (Totally humanized) 50mg SC/week.



(ii)Adalimumab (HUMIRA)

(Totally humanized) 40 mg SC/2 weeks.




(iii)Infliximab (REMICADE): Chimeric monoclonal Ab (mouse
25% & human 75%) 3mg/kg slow IV infusion (2hrs) 0,2 W, 6 W 2
month.




(iv)Golimumab (SIMPONI): Totally humanized 50mg SC/month.




(v)Certolizumab Pegol (CIMZIA) (S.C) totally humanized
400mg at 0,2,4 weeks & then 200mg/2 weeks.



MTX is included in all combination therapy:

-Combination between MTX + biologic therapy provides great
benefit in improving signs & symptoms of RA; preventing
radiographic destruction & improving physical functions in

comparison to MTX or biologic monotherapy.

-No combination of two biologic therapy because of high rate of

adverse effects & lack of any additive effect



N.B: TNF is responsible for systemic
manifestations:
1. Fever.
2. Anemia.

3. Cachexia.
4. Depression.
5. Endocrine effect of cytokines.
6. Joint inflammation.



(4) If the treatment target is not achieved
(remission/low disease activity) with MTX + 1st generation
anti TNF , go to 2nd generation Biological drugs.
(i)Abatacept (selective co-stimulation modulator).

Dose according to body weight (10mg/kg):



(i)Abatacept
(ORENCIA)
(selective
co-stimulation
modulator) FDA approved in August 2011 subcutaneous
formulation of Abatacept.
A fixed 125-mg dose administered subcutaneously once a week
after a single intravenous loading dose of approximately 10 mg/kg.




(ii)Rituximab

(MABTHERA)

(selective B cell depletion)




(iii)Tocilizumab (ACTEMRA)

(IL-6 inhibitor) 8mg/kg/month
It has been proven to work with or
without methotrexate.



In cases of refractory severe RA with contraindications to all
biologic & synthetic DMARDs

Try Azathioprine
Cyclosporine A ( keep an eye on BP & renal profile)
Or Cyclophosphamide (which is used in exceptional
situations).

A number of DMARDs has been excluded such as:
D-Penicillamine, Minocycline, Auranofen because of
its insufficient effect.
Gold being effective drug, but limited availability &
newer therapies resulted in less wide spread of the drug.



If a patient with long standing (sustained) remission
for 12 month
ACR/EULAR 2011 Definition
of Remission
• At any time point, a patient must satisfy all of the
following:

• – Tender Joint Count ≤1
• – Swollen Joint Count ≤1
• – CRP ≤1 mg/dL
• – Patient Global Assessment ≤1 (on a 0-10 scale)



If a patient with long standing (sustained) remission
for 12 month
• Tapper GCs at 1st.
• Start to tapper biologic DMARDs (expand interval
between the doses or reduce the dose).
• But continue synthetic DMARDs in low dose
because stoppage of synthetic DMARDs may lead to
flare.



Biological DMARDs characteristics

• Provides rapid relief of signs & symptoms of RA
• Onset of action within days or weeks.
• Slowing or halting the progression of joint erosion.
• Leads to remission in 2/3 of cases of RA; the
remaining 1/3 shift to another biologic after 3-6

month.




• Anti TNF are contraindicated during pregnancy and

lactation.




• Biologic DMARDs should be continued indefinitely
or until side effects or therapeutic failure.
• Ideally biologic DMARDs should be available to all
patients who might benefit from them (the cost is the
problem).



Biologic DMARDs: Precautions & Contraindications:
• Increase
risk
of
bacterial
infection:
(septic
arthritis, osteomyelitis, pyelonephritis, pneumonia, cellulitis)
• Screening for active or latent TB with +ve purified protein
derivative (PPD) test.
• Indurated area <5mm is +ve in patients who are immunocompromised
• Also ask for X-Ray chest, history of TB treatment.
• CHF: in spite of increased TNF in heart failure.
• Optic neuritis, demyelinating diseases.
• Significant coronary artery disease.



Biologic DMARDs: Precautions & Contraindications:
• Not contraindicated in solid tumors if there is no recurrence in
the past 5 years, however it should be avoided in lymphomas.
• COPD
• Viral infection HCV, HBV, HIV (reactivation of viral infection)
• Temporarily suspended in patients undergoing surgery (one
week before & one week after surgery).
• Avoid vaccination with live attenuated vaccine (German
measles, oral Polio, Rabies and Herpes Zoster)
• Influenza vaccine & pneumococcal vaccine if required should
be given 2-4 weeks prior to administration of biologic therapy.



Comorbidities
• Osteoporosis due to disease itself or GCs so add Ca & Vit D &
ask for DEXA as follow up.
• Cardiovascular disease: RA is a CV risk factor it is 60% higher
just a year after diagnosis of RA.
• It is the FIRST cause of death in RA.
• Intensive treatment by MTX & anti TNF Biologic therapy
reduce CV events by 70% (low dose aspirin, check for
cholesterol level, HTN, DM, obesity, smoking or other risk
factors).
• Infection: is the SECOND most common cause of death.
• COPD: RA patients are two times more likely to have COPD.



Tofacitinib (Xelijanz)

The U.S. Food and Drug Administration

approved Xeljanz (tofacitinib) to treat adults with
moderately to severely active rheumatoid arthritis (RA)
who have had an inadequate response to, or who are
intolerant of, methotrexate. Nov. 6, 2012



It may be used as monotherapy or in combination
with methotrexate or other non-biologic diseasemodifying antirheumatic drugs (DMARDs) (5 mg
BID)
 XELJANZ should not be used in combination with

biologic DMARDs or potent immuno-suppressants
such as azathioprine and cyclosporine.




In April 2013 the Committee for Medical
Products was of the opinion that the benefits of

Tofacitinib (Xeljanz) did not outweigh its risks and
recommended
authorization.

that

it

be

refused

marketing




These safety concerns include:
• Serious infections.

• certain cancers.
• gastro-intestinal perforations.
• liver damage.
•

and problems with increased lipid levels in the blood.

Conclusion
There is a great need for a new more effective
and less toxic drug which completely cure the

disease.

However, until a true cure is found, treatment
of RA must be given on a long term basis to
maintain clinical effectiveness.

Rheumatoid Arthritis Medical Treatment ( Prof. Fathy EL-Belasy) Strategy & Drugs

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