Rheumatoid arthritis

 Normally the body can differentiate between self and non-self, however several autoimmune conditions
are identified where the body produce an inappropriate immune response against its own healthy
tissue.

 Rheumatoid arthritis (RA) is a common, chronic, progressive autoimmune condition that

primarily affects the joint and synovium but can also have detrimental effects on organ systems
throughout the body such as cardiovascular and it can reduce a patient’s average life expectancy
 It can cause joints destruction leading to substantial and devastating effects on one’s ability to function
and complete basic activities of daily living.

 Etiology:-The disease results from a mixture of genetic susceptibility and nongenetic factors combined
with a triggering event.

❖ Nongenetic or environmental factors possibly associated with RA include cigarette use and obesity.

❖ An infectious process is hypothesized to be the primary trigger. The Epstein–Barr virus and retroviruses
are most commonly associated with the disease. Infections of Mycoplasma spp. also have been
suspected as bacterial triggers,
 Rheumatoid arthritis
Pathogenesis:-
 Rheumatoid arthritis is a complex systemic inflammatory condition,
 The disease manifest initially as symmetric swollen and tender joints of the hands and feet
 The inflammation leads to joint destruction with resultant functional disability
 The inflammatory cytokines, IL-1 and TNF-α, have a major role in the disease.

Antigen-presenting cells present antigens to T cells, which

stimulate B cells to differentiate into plasma cells that produce
Autoantigen autoantibodies. Ag-Ab-complex activates macrophages which
release cytokines such as TNFα and IL6 that stimulate
fibroblasts to produce matrix metalloproteinases which degrade
the bone matrix. Activated macrophages also release IL1 and
TNFα that stimulate release of lysosomal enzymes promoting
bone matrix destruction. IL17 produced by T-cells and
macrophages stimulate the activity of osteoclasts leading to
bone destruction.
(APC; antigen-presenting cell) Autoantigen e.g
(MMP; matrix metalloproteinase) Fc fragment of IgG or CCP
 Rheumatoid arthritis
Signs and symptoms
o joint swelling (Hands, wrists, ankles, and feet
most affected, often bilaterally)
o prolonged morning stiffness, often for more
than 30 minutes.
o joint may appear erythematous, and warmer
than surrounding tissue.
o Decreased functionality
o Deformities with advanced disease
o Symptoms present for 6 weeks or more
 Rheumatoid arthritis
 Laboratory Findings
Rheumatoid factor (Ab against IgG) detected in 70% of patients .
Negative RF does not exclude the possibility. About 5 % of normal individuals
( not suffering from the disease) may be positive for this test
 Anti-cyclic citrullinated peptide antibodies (ACCP) or(ACPA) are more specific
for disease ( detected in 90% of patients or more).
patients with rheumatoid arthritis may show positivity to this test prior to
the onset of symptoms
 Erythrocyte sedimentation rate and C-reactive proteins may indicate the
presence of a nonspecific inflammatory process
 Synovial fluid analysis through joint aspiration typically demonstrates a high
white blood cell count in the absence of crystals or infection
Diagnosis
 Rheumatoid arthritis
Nonpharmacologic Treatment

➢ Physical therapy is beneficial for reducing pain and inflammation while

preserving joint function.

➢ The benefits of exercise and physical activity, including aerobic activity and
muscle-strengthening exercises, have been demonstrated to improve RA-related
disease outcomes.

➢ Weight loss can help decrease the stress on joints.

➢ Emotional and psychological support.

➢ Surgical options, including joint replacements, are reserved for patients with
more severe disease where there may have significant cartilage loss.
 Rheumatoid arthritis
Pharmacotherapy

 Available pharmacologic therapies do not reverse joint damage that has already
occurred. Therefore, early appropriate treatment of RA is essential.

 Pharmacotherapy for RA includes

❑ I- Anti-inflammatory drugs for symptomatic relief

and

❑ II- Immunosuppressive agents that reduce the inflammatory process, with the goals
of reducing inflammation and pain, and halting or slowing disease progression.
(DMARD= disease modifying anti-rheumatoid drugs)
 I- Anti-Inflammatory Drugs
❖ Nonsteroidal Anti-Inflammatory Drugs
 NSAIDs inhibit prostaglandin synthesis and can provide anti-inflammatory as
well as analgesic effects.
 However, they do not slow disease progression and should not be used as
monotherapy.
 NSAIDs can provide symptomatic relief of pain and stiffness and can be effective
as adjuncts to DMARD therapy in patients with RA.
 They have a more rapid onset of action than DMARDs and may be beneficial to
“bridge” patients while DMARDs take effect..
 ❖ Glucocorticoids
➢ Glucocorticoids have been used in the treatment of RA for their anti-inflammatory and immune-
modulating effects.
➢ Although these agents can slow the progression of RA, however, they should not be used as
monotherapy in the treatment of RA, particularly due to the potential for serious, long-term adverse
effects.
 Similar to NSAIDs, glucocorticoids can be used to “bridge” patients while DMARDs take effect.
 They can be used as adjuncts to DMARDs at the lowest dose possible and for short term in patients
with refractory disease.
➢ Short-term glucocorticoid is defined as less than 3 months of therapy and low-dose
glucocorticoid is defined as prednisone <10 mg/day or its equivalent.
➢ Intra-articular injections is associated with fewer systemic adverse effects but it should not be
repeated more often than every 3 months because of the potential for accelerated loss of cartilage
in the joint. .
 Patients with RA are at a higher risk of developing osteoporosis, and the use of long-term
glucocorticoids doubles this risk.
 Pharmacotherapy
II- DISEASE-MODIFYING ANTIRHEUMATIC DRUGS (DMARDS)

 Unlike the NSAIDs, which only reduce the symptoms of rheumatoid arthritis , DMARDs have been
shown to slow the course of the disease, induce remission, and prevent further destruction of the
joints and involved tissues.

 Historically classified as such because, unlike NSAIDs, they lowered the erythrocyte
sedimentation rate (ESR) the marker of acute inflammation.

 These therapies include conventional synthetic (cs) , biologic (b) and targeted synthetic (ts) disease-
modifying antirheumatic drugs (recently designated csDMARDs and bDMARDs, respectively).
csDMARD bDMARD tsDMARD
❖methotrexate, are large proteins, molecules which are often small synthetic molecules that inhibit
❖hydroxychloroquine, produced by recombinant DNA technology. : kinase enzymes functioning as signalling

❖ leflunomide, ❖TNF-α inhibitors e.g. adalimumab, infliximab mechanisms in immune cels

IL ab eg. anakinra ❖ JAK inhibitors e.g. Tofacitinib
❖ sulfasalazine
 Traditional = Classical DISEASE-MODIFYING ANTIRHEUMATIC DRUGS
( Cs DMARDS)

 Monotherapy may be initiated with any of the traditional DMARDs, although

methotrexate is generally preferred.

 For patients with inadequate response to monotherapy, a combination of traditional

DMARDs, or use of a TNF inhibitor or non-TNF biologic (bDMARD) agent may be
needed.

 The clinical effects of traditional DMARD are usually slow (months) in onset, and it
is usual to provide NSAID ‘cover’ or glucocorticoids during this induction phase
 csDMARD
Methotrexate
➢ Methotrexate is considered the DMARD of choice for most patients with RA.
➢ It is superior to other DMARDs in terms of efficacy and patient tolerance

➢ Methotrexate inhibits dihydrofolate reductase thus reduces the availability of

active folate required for purine nucleotide and DNA synthesis, leading to
immunosuppressive and anti-inflammatory effects.

➢ In addition, it interferes with polymorphonuclear leukocyte chemotaxis

➢ It also inhibit the production of cytokines and free radicals that damage the
synovial membrane

➢ The drug can be given orally or subcutaneously or intramuscularly and has a

fairly rapid onset of action, with benefits observed as early as 2 to 3 weeks
after therapy is started.
Methotrexate.
➢ It is recommended to start treatment with 7.5 mg weekly. According to patient response,
methotrexate is increased to the most common dosing regimen for the treatment of RA,
which is 15–25 mg weekly
➢ Methotrexate is also used as antineoplastic drug. Doses of methotrexate required for RA
treatment are much lower than those needed in cancer chemotherapy and generally
administered once weekly, thereby minimizing adverse effects.
➢ adverse effects
➢ Mucosal ulceration
➢ Cytopenias (particularly leukopenia),
➢ Cirrhosis of the liver,
➢ Acute pneumonia-like syndrome may occur with chronic administration.
➢ The incidence of GI and liver function test abnormalities can be reduced by the use of
leucovorin = folinic acid 24 hours after each weekly dose , although this may decrease the
efficacy of the methotrexate by about 10%
➢ Periodic liver function tests, complete blood counts, and monitoring for signs of infection are
recommended.
➢ The use of methotrexate is contraindicated in pregnancy
 Leflunomide
➢ Leflunomide is a prodrug metabolized 100% in the intestines to the active form, teriflunomide
➢ Teriflunomide is a reversible inhibitor of dihydroorotate dehydrogenase (DHODH), an
enzyme necessary for pyrimidine synthesis.
➢ Consequently, leflunomide inhibits T-cell proliferation and reduces production of
autoantibodies by B cells.
➢ Dose 100 mg for 3 days followed by 20 mg
➢ Leflunomide is completely absorbed from the gut and has a plasma half-life of 19 days.
➢ Leflunomide may be used as monotherapy in patients who have intolerance or
contraindications to use of methotrexate in RA, or it may be used in combination with
methotrexate for patients with suboptimal response to methotrexate alone.(with caution??)
➢ It is subject to enterohepatic recirculation. Cholestyramine can enhance leflunomide
excretion and increases total clearance by approximately 50%. Cholestyramine wash out
regimen is 8 g three times daily for 11 days is indicated for women planning to get pregnant

➢ Adverse effects weight loss, allergic reactions, including a flu-like syndrome, skin rash,
The drug is not recommended in patients with liver disease as it can be hepatotoxic.
 Sulphasalazine
➢ Orally administered sulfasalazine is approximately 30% absorbed in the small intestines.
The remaining 70% is converted by bacterial action into sulfapyridine &
5-aminosalisylate (mesalazine) in the large intestines.

➢ Sulfasalazine is primarily eliminated unchanged via the kidney, while sulfapyridine is

primarily metabolized in the liver by N-acetylation and excreted in the urine.
➢ Some individuals are slow acetylation, which could result in sulfasalazine intolerance

➢ Sulfasalazine and its metabolites prevent the maturation of antigen presenting cells (APCs)
to inhibit the activation and proliferation of both T cells and B cells.
➢ Inhibit the release of inflammatory cytokines
➢ Adverse effects of sulfasalazine involve the GI system, including nausea and vomiting.
➢ Contraindicated for those with sulpha or salicylate allergy
➢ Dose:- start with 250-500 twice daily then increased to 1.5 g twice daily
➢ Sulfasalazine is perhaps the safest for pregnant women
➢ Sulfasalazine is also considered safe for women wishing to breastfeed
Hydroxychloroquine
➢ Is an antimalarial drug related to chloroquine, is extensively used as a DMARD.
➢ It is a less toxic metabolite of chloroquine
➢ They are administered orally and are accumulated in tissues with a half-life of 40–50 days.
➢ They are metabolized in the liver by CYP2C8 and CYP3A4
➢ It reduces chemotaxis and phagocytosis
➢ It causes stabilization of lysosomal enzymes and trapping of free radicals
➢ It inhibits DNA and RNA synthesis
➢ It does not produce the myelosuppressive, hepatic, and renal toxicities that many
other DMARDs produce.
Adverse ocular effects, QTc prolongation and risk of ventricular arrhythmia ,hypoglycemia,
ototoxicity, retinopathy ,blurred vision and night blindness. ophthalmologic monitoring every 12
months is advised
➢ Ocular adverse effects are minimal when the guidelines doses are not exceeded
( 400 mg/day for hydroxychloroquine and 250 mg/day for chloroquine)-
daily dose divided in 2 or 4 doses
➢ They appear to be relatively safe in pregnancy. (category C)
 bDMARD
 IL-1 and TNF-α are proinflammatory cytokines involved in the pathogenesis of RA. When secreted by
synovial macrophages, IL-1 and TNF-α stimulate synovial cells to proliferate and synthesize
collagenase, thereby degrading cartilage and stimulating bone resorption.

 bDMARD are more powerful as immunosuppressants than CsDMARD but their use are
associated with a high risk of infection.

 The TNF-α inhibitors e.g.(adalimumab, infliximab) are usually employed in RA after a patient has an
inadequate
. response to traditional DMARDs.

 These agents may be used alone or in combination with traditional DMARDs. If a patient has failed
monotherapy with one TNF-α inhibitor, a traditional DMARD may be added, or therapy with a different
bDMARD may be tried.

➢ Combination with cDMARD increase the anti-rheumatoid activity and decrease the chance
that bDMARD being identified by the body as foreign proteins
bDMARD
 Examples of bDMARD
 Adalimumab
is a fully human anti-tumor necrosis factor alpha
monoclonal antibody,.
 Infliximab Fragment
antigen
is a chimeric monoclonal antibody composed of binding

human and murine regions. The antibody binds

specifically to human TNF-α and inhibits binding with
its receptors..
 Anakinra
is a recombinant IL-1receptor antagonist .
It Blocks IL-1 from binding to its receptors.
 tsDMARD
 Janus-associated Kinase (JAK) Inhibitors

synthetic small molecules that inhibit kinase enzymes responsible for mediating the effect of
cytokines on immune cells e.g. Tofacitinib

 if a patient does not have an adequate response to or is otherwise unable to receive

csDMARDS or bDMARDs.

 Tofacitinib is indicated for treatment of moderate to severe RA as monotherapy or in

combination with csDMARDs.

 A distinct advantage of JAK inhibitors over biologic DMARDs is that they are given orally

 Potential adverse reactions:- Increased risk of infection, malignancy, thrombosis risk.

Precautions for the use of bDMARDS or tsDMAARD
 TNF-α inhibitors should be used cautiously in those with heart failure, as they can cause
and/or worsen pre-existing heart failure

 An increased risk of lymphoma and other cancers has been observed with the use of
TNF-α inhibitors and tsDMARD

 Patients receiving bDMARDs or tsDMARDs are at increased risk for infections,

reactivation of dormant infections such as tuberculosis, hepatitis B , fungal opportunistic
infections, and sepsis. prompting the necessity for testing of all patients for tuberculosis prior
to the initiation of treatment.

 A combination of two bDMARD or (bDMARD +tsDMARD) should not be used as it is

associated with a great risk of infection

 Guidelines do recommend that patients be immunized against other relevant infections,

such as pneumonia or influenza prior to beginning treatment.

➢ Live vaccinations should not be administered to patients taking any of the

biologic DMARDs.or tsDMARDs