Methotrexate is considered the first-line treatment for rheumatoid arthritis and has been used to treat the disease since the 1980s. It works by reducing inflammation and immune system activity. While its exact mechanism is unknown, it likely involves effects on T cells, B cells, and cytokines like TNF-α, IL-6, and IL-1. Common side effects include liver and kidney toxicity. Future research seeks to develop targeted drug delivery methods to increase effectiveness and reduce side effects. Methotrexate remains a cornerstone therapy for rheumatoid arthritis treatment.

1. Methotrexate:A Cornerstone in
Rheumatoid Arthritis Treatment

2. Methotrexate:A Cornerstone in
Rheumatoid Arthritis Treatment
Prepared by
Nusrat Fatemee
Department of Pharmacy
East West University

3. What is Rheumatoid Arthritis?
 Rheumatoid Arthritis (RA) is a chronic, progressive,
inflammatory autoimmune disease associated with
articular, extra-articular and systemic effect.
It has been reported that RA affects ~0.5-1% of
adult population of the developed region.
Mortality rates are more than twice as high in RA
patients compared to general population.
The prevalence of rheumatoid arthritis in most
Caucasian populations approaches 1% among
adults 18 and over and increases with age,
approaching 2% and 5% in men and women,
respectively, by age 65.

4. Pathophysiology
 Its exact cause is unknown, but genetic and environmental
factors are contributory.
 Recent findings suggest a genetic basis for disease
development. More than 80% of patients carry the epitope
of the HLA-DRB1*04 cluster and patients expressing two
HLA-DRB1*04 alleles are at elevated risk for nodular
disease, major organ involvement and surgery related to
joint destruction.
 Single-nucleotide polymorphism genotyping across the
MHC has identified additional alleles related to RA risk,
including those found on the conserved A1-B8-DR3 (8.1)
haplotype and those near the HLA-DPB1 gene . Other RA-
associated loci are PTPN22, PADI4, STAT4, TRAF1-C5
and TNFAIP3, although non-MHC risk alleles may represent
only 35% of the genetic burden of RA.
 Environmental factors, such as smoking and infection, may
also influence the development, rate of progression and
severity of RA.

5. Pathophysiology
 T cells, B cells and the orchestrated interaction of pro-
inflammatory cytokines play key roles in the pathophysiology
of RA.
 Differentiation of T cells into Th 17 (TH17) cells results in the
production of IL-17, a potent cytokine that promotes synovitis.
 B cells further the pathogenic process through antigen
presentation and autoantibody and cytokine production.
 Antigen-activated CD4+ T cells amplify the immune response
by stimulating other mononuclear cells, synovial fibroblasts,
chondrocytes and osteoclasts.
 The release of cytokines, especially TNF-a, IL-6 and IL-1,
causes synovial inflammation.
 In addition to their articular effects, pro-inflammatory
cytokines promote the development of systemic effects,
including production of acute-phase proteins (such as CRP),
anaemia of chronic disease, cardiovascular disease and
osteoporosis and affect the hypothalamic-pituitary -adrenal
axis, resulting in fatigue and depression.

6. Pathophysiology
FIG. 1 Schematic view of a normal joint (a) and a joint affected by RA
(b) The joint affected by RA (b) shows increased inflammation and
cellular activity.

7. Goal of Therapy
According to a study which was conducted in 2012 the
goal of present-day therapy for rheumatoid arthritis is to
control the underlying inflammatory disease. Attainment of
this goal will alleviate pain, restore patients’ quality of life,
and ultimately, preserve their independence and ability to
perform activities of daily living and vocational and
avocational pursuits.
Major long-term goals of treatment are to prevent joint
destruction and prevent comorbidities of disease and
treatment, including heart disease and osteoporosis.

8. Historical Perspective
Methotrexate (MTX), formerly known as amethopterin is a folic acid
analogue was first reported in 1948 to produce temporary remission of
acute leukemia of children, was also reported in 1951 to produce an
important and rapid improvement in patients with rheumatoid arthritis
(RA) and psoriasis. By 1972, low dose pulse methotrexate was
observed to be useful in RA, but it was not until 1980 that additional
beneficial effects of methotrexate in the treatment of patients with
refractory RA appeared in the literature. Subsequently, both
uncontrolled experience and double blind prospective trials have
demonstrated efficacy and acceptable tolerability and safety of
methotrexate in the treatment of patients with RA.
Formula
C20H22N8O5
Molar mass
454.44 g/mol

9. How Does MTX Work in RA
Remission?

10. Relative Studies & Current Status
Presently, MTX is considered as the anchor drug among the
DMARDs and it is globally regarded as the first medical
treatment option for RA.
The use of MTX in early RA started in 1980 and its use has
significantly increased in the last few years. Indeed, recent
studies have shown an increased use of MTX from 5 to 90%
in Finland and from 25 to 90% in the USA.
The combination of MTX with biologic agents is probably the
most effective therapy we currently have to treat RA.

11. Pharmacogenetics
 Recent advances in genetics, particularly
pharmacogenetics, may permit the prediction of an
individual patient’s response to MTX. Currently available
data demonstrate the potential, but also the limitations of
genetic polymorphism analyses . At present, there are no
reliable means to predict an individual patient’s response to
MTX, although pharmacogenetics seems to have a
promising role.
 Genetic variations (single nucleotide polymorphisms) in
enzymes associated with MTX metabolism and
regeneration of reduced folates have been studied.
However although genetic polymorphisms in the folate
metabolic pathway and MTX transporters modify MTX
toxicity, they do not seem to influence MTX efficacy

12. Dosage & Administration
 Indicated for management of
severe, active rheumatoid
arthritis (RA) in adults who have
had an insufficient response or
intolerance to an adequate trial
of first-line therapy including full
dose NSAIDs.
 Initial: 7.5 mg oral as a single
weekly dose, OR 2.5 mg oral
dose q12hr for 3 sequential
doses per week.
 Increase oral dose to optimum
response; single dose not to
exceed 20 mg/week oral.

13. Side Effects
Hypersensitivity
Pregnancy/Lactation
Alcohol
Hepatic & renal
impairment.
Caution should be taken
when concomitantly
administered with NSAIDS.

14. Future Perspective
 Manipulation of the MTX molecule may provide a better
therapeutic profile for RA patients. Thus, polyglutamation of
the drug, a metabolic step that appears to play a role both
in its therapeutic properties and hepatic side effects, might
be a potential starting point.
methods of targeted drug delivery, in order to increase
drug accumulation at the site of inflammation, may increase
effectiveness and reduce toxicity.
Albumincoupled and liposomally conjugated MTX, both of
which are more potent than MTX in inhibiting inflammation
in animal models, are under preclinical evaluation.
Future investigation is needed to target therapy more
accurately, in order to determine which patients respond
best not only to MTX, but all available synthetic and
biologic drugs and their combinations.

15. References
Choy, E. (2012). Understanding the dynamics: pathways involved in the
pathogenesis of rheumatoid arthritis. Rheumatology, 51(suppl 5), pp.v3-v11.
Davis, J. and Matteson, E. (2012). My Treatment Approach to Rheumatoid
Arthritis. Mayo Clinic Proceedings, 87(7), pp.659-673.
Kinder, A. (2005). The treatment of inflammatory arthritis with methotrexate in
clinical practice: treatment duration and incidence of adverse drug reactions.
Rheumatology, 44(1), pp.61-66.
Rau, R. and Herborn, G. (2004). Benefit and risk of methotrexate treatment in
rheumatoid arthritis. CLINICAL AND EXPERIMENTAL RHEUMATOLOGY,
22(Suppl. 35), pp.S83-S94.
Kaltsonoudis, E., Papagoras, C. and Drosos, A. (2012). Current and future role
of methotrexate in the therapeutic armamentarium for rheumatoid arthritis.
International Journal of Clinical Rheumatology, 7(2), pp.179-189.