Protocol 014
Protocol 014
Protocol 014
Management of
Rheumatoid Arthritis
in Adult Patient
Guideline for management of Rheumatoid Arthritis
in Adult patient
Introduction:
Rheumatoid arthritis (RA) is a chronic inflammatory disease that may result in
significant disability. It is the most common autoimmune inflammatory arthritis in
adults 1. RA has a significant negative impact on the ability to perform daily activities,
including work and household tasks, and health related quality of life, and it
increases mortality 2.3.The management of RA has seen significant advances during
the past 2 decades. Although some patients with RA experience mild illness with
minimal joint destruction, disease progression can lead to significant deformity of the
affected joints.
RA is characterized by inflammation and swelling of the synovium of the joint, with
subsequent destruction of articular structures.4 Patients with active RA also
experience systemic inflammation that is associated with a variety of comorbidities,
most importantly cardiovascular disease, which contribute to the increased morbidity
and mortality noted in this group compared with the general population.5.6
The pain, fatigue, and disability associated with RA result in a significant reduction in
health-related quality of life.7 Additionally, RA imposes a substantial economic
burden upon patients, due to both increased cost of medical care and loss or
reduction of employment, frequently during peak working years.8.9
Reason to develop this guideline:
The reason to develop this guideline due to:
• Some of the RA medications are known or suspected to cause adverse drug reactions or
have black box warning.
• High budget impact of Biologic Disease-modifying anti-rheumatic drugs and Small molecule
DMARDS Janus kinase inhibitors.
• Availability in Saudi Arabia of some RA medications, especially for biologics.
• Presence of bio-similar medications.
Methodology:
It was adopted from international guideline like: ( 2016 European League Against
Rheumatism (EULAR) , 2015 American College of Rheumatology (ACR) and BSR
and BHPR guideline on prescribing drugs in pregnancy and breastfeeding—Part I:
standard and biologic disease modifying anti-rheumatic drugs and corticosteroids),
Studies in the literature review included systematic reviews, randomized controlled
trials (RCTs) and meta-analysis ,review the available drugs in the Ministry Of Health
(MOH), expert opinion of consultant rheumatologist and consultant rheumatologist
clinical pharmacist.
Table 1: Implications of strong and conditional GRADE (Grading of
Recommendations Assessment, Development, and Evaluation) methodology
recommendations.
*=majority means >50% of the people.
Epidemiology:
Incidence:
Rheumatoid arthritis is a relatively common disorder that affects men and women at
the prime of their lives. Only 30% of the causes of rheumatoid arthritis can be
attributed to genetic factors; the rest remain unexplained. Descriptive and analytic
epidemiologic methods may lead to a better understanding of the causative,
precipitating, and modulatory factors in rheumatoid arthritis.10
Prognosis:
Depending on how bad the progression of the disease is, there are some possible
complications patients may experience outside of the regular joint-related symptoms.
These complications and side effects include:
2. Interleukin-6 inhibitors:
Drug Regular Dose17 Adverse drug reaction 18,19
Tocilizumab IV infusion 4 • Endocrine & metabolic: Increased
mg/kg over 1 hour serum cholesterol (>240 mg/dL;
every 4 weeks; >1.5-2 x ULN; combination therapy)
• Hepatic: Increased serum ALT and
increase to 8
increased serum AST
mg/kg every 4 • Miscellaneous: Infusion-related
weeks based on reaction.
clinical response;
doses exceeding
800 mg per
infusion are not
recommended
SubQ dosing
(Weight less than
100 kg): 162 mg
subQ every other
week; increase to
162 mg SUBQ
every week based
on clinical
response
(Weight 100 kg or
greater) 162 mg
subQ every week
Switching from IV
to subQ, give the
first subQ dose
instead of the next
scheduled IV
dose
3. Selective T-Cell Costimulation Blocker
Drug Regular Dose 17 Adverse drug reaction 18,19
Abatacept IV infusion: Weight • Central nervous system:
based dose every Headache
2 wk for two doses • Gastrointestinal: Nausea
and then monthly • Respiratory: Nasopharyngitis,
(i.e., 750 mg for upper respiratory tract infection
those weighing 60– • Miscellaneous: Infection,
100 kg) antibody development.
SubQ dosing with
IV loading dose:
Give weight-based
IV loading dose,
then 125 mg subQ
within 1 day of
loading dose,
followed by 125 mg
subQ once weekly
SubQ dosing
without IV loading
dose: 125 mg subQ
weekly
Transitioning from
IV to subQ therapy:
125 mg subQ in
place of next
scheduled IV dose,
followed by 125 mg
subQ once weekly
• Glucocorticoids:
Steroids have been widely used for suppressing pain and inflammation in arthritis
since many years. Corticosteroids acts by inhibiting induction of COX enzyme.
Moreover, corticosteroids also inhibits release of collagenase and lysosomal enzyme
by reducing macrophage phagocytosis and IL-1 secretion. 20
Glucocorticoids are generally better avoided on the long-run because of adverse
effects which include :
- CNS: Headache and steroid psychosis.
- Cardiovascular: hypertension.
- Skin: easy bruising, poor wound healing, skin atrophy and acne.
- Endocrine: Cushing’s syndrome, osteoporosis, diabetes, hirsutism, hypokalemia
and weight gain.
- Musculoskeletal: steroid myopathy and avascular necrosis.
- Eye: cataract and glaucoma.21
Initial Therapy
1-In patients with newly diagnosed early Rheumatoid Arthritis (Figure 1), start
treatment with a single csDMARD, preferably methotrexate (start with oral 7.5–15
mg/week and increase the dose to 20 mg/week for maximum response if needed.
Use subcutaneous Methotrexate, if patient had gastric intolerance to oral MTX. (LOE
low)
2-In patients with contraindication or intolerance to methotrexate, we consider
alternatives such as sulphasalazine. (LOE low)
3-As we expect DMARDs to take a few weeks to produce a therapeutic effect, we
might bridge the patients with a tapering course of corticosteroids and NSAIDs to
control the pain and inflammation.
4-In patients with moderate to high disease activity, we might consider initiating
treatment with combination DMARDs from the beginning.
5-A minimal period of 3 months is given before a major change to therapy is made.
6-Treatment target should be achieved within 6 months.
Inadequate or no response:
1-If there’s no improvement by 3 months after the initial therapy or the treatment
target wasn’t reached by 6 months we alter the therapy (Figure1)
2-In the absence of poor prognostic factors, we add a second csDMARD if we
initially started with a single agent.
3-In the presence of poor prognostic factors or in those who started initially with a
combination csDMARDs, we add a biologic DMARD or JAK inhibitor. (LOE
moderate to very low). As we have no preference to any of the biologics, the choice
will largely depend on the patient’s condition, cost ,preference and comorbidities.
4-If a patient fails multiple biologic DMARDs, switch to JAK inhibitor, like tofacitinib,
is considered. (LOE low to very low).
Recommendations:
1.Patients presenting arthritis should be referred to, and seen by, rheumatologist,
within 6 weeks after the onset of symptoms.
2.Among the DMARDS, methotrexate is considered to be the (anchor drug) and,
unless contraindicated, should be part of the first treatment strategy.
3.Arthritis activity should be assessed at 1-month to 3-months intervals until the
treatment target has been reached.
Achieve improvement
Yes
No at 3 months and target
at 6 months
Poor
prognostic
factors Continue
Change biological
DMARDs or use a
Jak-I Continue
Figure 1:
➔ Conventional synthetic DMARDs (cs DMARDs) e.g. methotrexate, 24
leflunomida, SSZ, HCQ
Monitoring of rheumatoid arthritis:Monitoring:
➔ Targeted synthetic DMARDs (ts DMARDs) e.g. Tofacitinib
*Based on logistic issues (MOH)
* We have no preference to any of the biologics; the choice will be largely dependent on the patient's
condition, preference and comorbidities.
The following table shows the recommendations for monitoring CBC, LFT and renal
function for patients on csDMARDs therapy.
Agent < 3 months 3 – 6 months > 6 months
Leflunomide 2 – 4 weeks 8 – 12 weeks 12 weeks
Methotrexate 2 – 4 weeks 8 – 12 weeks 12 weeks
Sulfasalazine 2 – 4 weeks 8 – 12 weeks 12 weeks
PPD or IGRA
test
Negative Positive
No Latent TB Chest X ray
Sputum
AFB culture and smear
Positive Negative
Treat active TB Treat Latent TB
Use of biologics and DMARDs in high-risk populations:23.24.25,26
Risk factor Recommendations
Congestive Heart Failure -Use combination DMARDs or NON-
TNFi biologics (Abatacept, Rituximab,
Tocilizumab, Tofacitinib) are preferred
over TNFi in heart failure. ( LOE
moderate to very low).
-Use of TNFi should be avoided
because of the risk of worsening heart
failure.
-Choice of therapy according to patients'
co-morbidities, contraindications, cost &
convenience
Hepatitis B -Patients infected with Hepatitis B Virus
can receive immunosuppression after
receiving prophylactic antiviral therapy
for Hepatitis B.
-Same recommendations as in patients
without this condition (LOE very low)
-Choice of therapy according to
patients' co-morbidities,
contraindications, cost & convenience
Hepatitis C -Patients receiving treatment for
Hepatitis C virus infection can receive
the same treatment as in patients
without this condition. (LOE very low)
-In patients with Hepatitis C infection
that are not receiving antiviral therapy,
use of csDMARDs is preferred over
TNFi (LOE very low)
-Choice of therapy according to
patients' co-morbidities,
contraindications, cost & convenience
Previously treated or untreated Skin -csDMARDs are preferred over
Cancer biologics and tofacitinib. (LOE very
low)
-Choice of therapy according to
patients' co-morbidities,
contraindications, cost & convenience
References:
Guideline for management of Rheumatoid Arthritis in Adult patients at Prince Sultan
Military Medical City (PSMMC).
1- Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, et al.
Estimates of the prevalence of arthritis and other rheumatic conditions in the United
States: part I. Arthritis Rheum 2008;58:15–25.
2- Pincus T, Callahan LF, SaleWG, Brooks AL, Payne LE, Vaughn WK. Severe
functional declines, work disability, and increased mortality in seventy-five
rheumatoid arthritis patients studied over nine years. Arthritis Rheum 1984;27:864–
72.
3- Salaffi F, Sarzi-Puttini P, Girolimetti R, Atzeni F, Gasparini S, Grassi W. Health-
related quality of life in fibromyalgia patients: a comparison with rheumatoid arthritis
patients and the general population using the SF-36 health survey. Clin Exp
Rheumatol 2009;27(5 Suppl 56):S67–74.
4- Firestein GS. Evolving concepts of rheumatoid arthritis. Nature. 2003;423(6937):356-
361.
5- Dougados M, Soubrier M, Antunez A, et al. Prevalence of comorbidities in
rheumatoid arthritis and evaluation of their monitoring: results of an international,
cross-sectional study (COMORA). Ann Rheum Dis. 2014;73(1):62-68.
6- Goodson N, Marks J, Lunt M, Symmons D. Cardiovascular admissions and mortality
in an inception cohort of patients with rheumatoid arthritis with onset in the 1980s and
1990s. Ann Rheum Dis. 2005;64(11):1595-1601.
7- Dominick KL, Ahern FM, Gold CH, Heller DA. Health-related quality of life among
older adults with arthritis. Health Qual Life Outcomes. 2004;2:5.
8- Hulsemann JL, Mittendorf T, Merkesdal S, et al. Direct costs related to rheumatoid
arthritis: the patient perspective. Ann Rheum Dis. 2005;64(10):1456-1461.
9- Sokka T, Kautiainen H, Pincus T, et al. Work disability remains a major problem in
rheumatoid arthritis in the 2000s: data from 32 countries in the QUEST-RA study.
Arthritis Res Ther. 2010; 12(2):R42.
10- Gibofsky A. Overview of epidemiology, pathophysiology, and diagnosis of rheumatoid
arthritis. Am J Manag Care. 2012 Dec;18(13 Suppl):S295-302.
11- https://www.rheumatoidarthritis.org/ra/prognosis/
12- https://www.rheumatoidarthritis.org/ra/prognosis/life-expectancy/
13- https://rheumatoidarthritis.net/medical-conditions-occurring-along-with-ra/
14- Schiff M. Emerging treatments for rheumatoid arthritis. Am J Med.1997;102
Supplement (1S):11S-15S.
15- Wahl C, Liptay S, Adler G, Schmid RM. Sulfasalazine: a potent and specific inhibitor
of nuclear factor kappa B. J Clin Invest.1998;101(5):1163-1174.
16- Ruckemann K, Fairbanks LD, Carrey EA, Hawrylowicz CM, Richards DF,
Kirschbaum B, Simmonds HA. Leflunomide inhibits pyrimidine de novo synthesis in
mitogen-stimulated T-lymphocytes from healthy humans. J Biol Chem.1998;
273(34):21682-21691.
17- Micromedex.com 2019 ,All Rights Reserved.
18- Chisholm-burns Marie et al. PHARMACOTHERAPY PRINCIPLES & PRACTICE.
The McGraw-Hill Companies, 2008.
19- Burke Rachel et al. Biologic Disease-Modifying Antirheumatic Drugs. Chronic
Illnesses II. PSAP, 2014 .
20- Boyce E. Pharmacology of antiarthritic drugs. Clin Podiatr Med Surg.1992;9(2):327-
348.
21- Lexicomp accessed 17/December/2017.
22- Seibert K, Zhang Y, Leahy K, Hauser S, Masferrer J, Perkins W, Lee L, Isakson P.
Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in
inflammation and pain. Proc Natl Acad Sci.1994;91(25):12013-12017.
23- Singh et al. 2015 American College of Rheumatology Guideline for the Treatment of
Rheumatoid Arthritis. ACR RA Treatment Recommendations.2015.
24- BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding—
Part I: standard and biologic disease modifying anti-rheumatic drugs and
corticosteroids, Rheumatology 2016;55:16931697.
25- Mariette X, et al. Lack of placental transfer of certolizumab pegol during pregnancy:
results from CRIB, a prospective, postmarketing, pharmacokinetic study. Ann Rheum
Dis 2017;0:1–6.
26- Clowse MEB, et al. Minimal to no transfer of certolizumab pegol into breast milk:
results from CRADLE, a prospective, postmarketing, multicentre, pharmacokinetic
study. Ann Rheum Dis 2017;0:1–7.