Principles of Pharmacology Sabine Montaut

Axel Gmez-Ortigoza Aguirre 0317218

Disease-modifying antirheumatic drugs

Rheumatoid arthritis (RA) is one of the most common forms of arthritis,
accounting for 22% of all deaths from arthritis and other rheumatic conditions (2). This
aggressive chronic disease, characterized by synovial inflammation of the joints results
in joint deformity, and functional disability, which in turn lead to an increase in
mortality probability (5). This disease affects approximately 1.3 million Americans, and
is more prevalent in women (2.5 times more common) than in men (1). The onset of the
illness usually occurs in the middle-aged of the patient (mean = 66.8 years), but it can
also occur during the 20s and 30s. A particular hallmark of the disease is joint damage,
occurs early in the development of RA, often within the first two years of the disease
(3). Broadly, RA and all of its resulting symptoms and effects cause significant
systemic damage, which shortens the lifespan of the patient.

A distinctive pattern of joint erosion can be seen radiographically but such a pattern is
rarely present in early disease and is, therefore, of little help diagnostically in the first
period of RA. Nevertheless, the clinical appearance of RA does become more
distinctive as the disease evolves. The clinical manifestations of early RA can be
extremely subtle and no single clinical finding or test abnormality by itself is diagnostic.
A firm diagnosis becomes possible only when a sufficient number of clinical findings
have been presented and the established diagnostic criteria are satisfied. The process of
determining what kind of therapy to go by is appropriate after the establishment of an
accurate diagnosis and assessment of the most likely prognosis. Even when the actual
prognosis of RA remains a partially unknown, some markers are identified as
predisposition factors. Therefore, initiation of treatment with a particular agent or group
of compounds should ordinarily be delayed until the diagnosis is no longer in doubt (4).

Determining the most likely clinical course for patients with early RA is difficult and
requires careful longitudinal observation in combination with thoughtful integration of
clinical, laboratory and radiographic data. Three broad patterns of clinical disease
activity can present, often referred to as: long clinical remissions, intermittent disease,
and progressive disease. Generally the course of development emerge as individual-
dependent events on a population of patients with RA (5). It is patients who develop the
pattern of progressive disease as well as those with more severe intermittent disease
who require an alternative therapy. And the associated toxicities can best be justified in
these patients, since there is no other effective option.

Until now, there is no effective curative therapy to cease RA, there are a variety of
options when regarding the assessment of the disease. There are 2 main categories of
agents for treating RA. The first being those agents which afford only symptomatic
relief (i.e. acetylsalicylic acid, nonsteroidal anti-inflammatory drugs (NSAIDs) and
corticosteroids). The second group is composed of those agents that can effectively
modify the disease. Which involve slowing the development of the disease as well as
redirecting it. A common name for this group is second-line agents, they are also widely
known as disease-modifying antirheumatic drugs (DMARD). These DMARDs exist in
either natural or synthetic form. Along with glucocorticoids, DMARDs constitute the
different therapy options for treating RA. This disease modifying compounds act on the
inflammation itself, preventing the development of the disease, but not eradicating it.

Because erosive changes in bone and joints are irreversible in almost all of the cases,
they represent the very damage that DMARDs are intended to prevent. Consequently,
delaying the initiation of DMARD therapy until characteristic x-ray changes appear; is
conceptually a self-defeating approach. Because the very symptom needed to approve
the use of these compound is the very problem that DMARDs attack. Thus they always
administered too late, and some damage will be inevitable. Still, they can prevent
further damage very efficiently. Newer approaches involving selective, specific and
directional inhibition of lymphocyte and cytokine activity offer hope for more efficient
and less toxic alternatives in the near future (i.e. Abatacept).

These DMARD are broadly classified into three main groups in terms of their relative
toxicity: high, medium and low toxicity. The effects of disease-modifying therapies take
from 7 weeks to 7 months to be noticed evidently in the patient. The main constraint of
DMARD is the toxicity, which limits the effectiveness of the therapy (in terms of dose
and therapy duration), thus monitoring the drug concentration on patients is mandatory.
Some examples of high toxicity DMARD are chlorambucil and cyclophosphamide,
which are often used to treat patients with very advanced stages of the disease. Milder
but still toxic DMARD are for example azathioprine, penicillamine (D-penicillamine),
methotrexate and parenteral gold. For the early stages of the disease, soft DMAD such
as auranofin, hydroxychloroquine, minocycline, and sulfasalazine are preferred because
of their relative low toxicity (4). Gold salts, which were once extensively used, are no
longer recommended because of their significant toxicities and questionable efficacy.

Demographic features, which indicate a worse prognosis in early RA, include: a
younger age at the time of onset, and the patients sex. Women generally show a poorer
prognosis than men of comparable age. The actual implications of the individuals
genetic makeup remains unclear but certain HLA alleles, most notably DR-4, have been
associated with more aggressive manifestations of the disease. The presence of
rheumatoid factor and the appearance of rheumatoid nodules are also associated with a
poorer outcome in terms of recovery. The presence of thrombocytosis (high platelet
counts) and an elevated acute phase reactant such as the erythrocyte sedimentation rate
or the C-reactive protein tests, account for a reference point to determine the degree of
inflammation. No finding is more alerting, than the persistence and worsening of
synovial proliferation (increase in synovial tissue mass product of chronic
inflammation), which highlights the need for careful longitudinal joint evaluation (4).

Despite the unknown cause of RA, its been suggested that: genetic background
(specifically HLA alleles, most notably DR-4 for developed cases) and
host/environment interactions (through auto-immune response) play a key role on the
appearance and development of the disease (5). In this sense, the progression velocity of
the disease in each patient is prominently variable; it ranges from spontaneous
remission to relentless progression. Other factors associated to RA can be used as
markers for diagnostics such as erythrocyte sedimentation rate or the C-reactive protein.

The timing of the application for therapeutic agents in general, determines in great
measure the effectiveness of the drug. So is the case for rheumatoid diseases, for
example after a clinical profile of aggressive inflammation presents itself, thats the
optimal time to apply disease-modifying therapy. This way no irreversible damage
presents in the patient. For example, a patient who has suffered a severe case of AR is
treated with a disease-modifying agent, but the damage was already too severe and the
functionality of the joints is compromised. Accordingly, this time window of
application in which treatments effectivity is maximized is very narrow. And thus the
early detection of the disease plays a key role in the effectivity of the treatment.

Selecting among these different options in terms of the therapy to use for each patient to
treat RA mainly depends on the stage of the disease, as well as to the particular profile
of both the patient and that of each drug/treatment. Thus it represents a very heavy and
key aspect in determining weather or not the patient will successfully recover or not.

Since DMARDs came to market and physicians started to apply them as a therapy, they
have been used in co-administration with other compounds. Depending on the specific
characteristics of both the patients profile and the diseases stage of development.
Different sets of combinations between DMARDs and other drugs can be designed
rationally to favor: complementary mechanisms of action, non-interfering
pharmacokinetics, and non-overlapping toxicities. It has been successfully co-
administered with: methotrexate, cyclosporine, chloroquine, hydroxychloroquine,
leflunomide, infliximab, adalimumab, rituximab, and etanercept. On the other hand co-
administration with; azathioprine, auranofin, or sulfasalazine and methotrexate give no
additional therapeutic benefit. Other combinations include: intramuscular gold with
hydroxychloroquine. While it might seem intuitive to think that combination therapy
would result in an increased toxicity, regularly this does not occur. Combination therapy
is becoming the rule for treating RA patients who are not responding positively to the
first monotherapy.

Smolen et al. proposed an algorithm for recommendations to doctors and patients in the
choosing of the correct therapy for each case, depicted in this flow diagram (Figure 1).
It mainly depends on the stage of the disease but other factors are presented and taken
into consideration. All the analysis presented turns in relation to the cost effectiveness
of the drug. The therapies that were considered as part of the dataset for propositions of
therapies were the following: disease-modifying antirheumatic drugs (DMARD),
methotrexate (MTX), rheumatoid factor/anti-citrullinated peptide antibodies
(F/ACPA), and tumour necrosis factor (TNF).

The authors included the following areas of the disease as part of the analysis: (a)
synthetic DMARDs as monotherapy or in combination without glucocorticoids (GCs);
(b) GCs alone and in combination with synthetic DMARD(s); (c) biological DMARDs;
(d) treatment strategies; (e) economic issues (6). But not only the cost effectiveness is
considerable and some factors where not considered by these authors. Like for example
the toxicity of the agent, as well as the effectiveness of the agent. As mentioned before,
the therapeutical index of the compounds is a very important constrain in this kind of
therapies, since they involve a relatively long period of time. In conclusion, neither the
pathogenicity of the disease nor the actual mechanism of action of many of the
therapeutical agents is completely comprehended.

Even when the molecular mechanisms underlying this disease are very well
characterized and understood. The structural bases for the causes or the factors that
control the appearance of this disease are still widely unknown. The only relatively
associated factors are genetic predisposal in addition to a previous host-defense immune
response.

In order to asses the effectiveness of a certain compound or agent into the treatment of
RA, the American College of Rheumatology (ACR) has created a scoring system to
classify the improvement of the RA symptoms, such as inflammation degree. And they
have called it ACR-n, where n represents the percentage of improvement. For example,
a ACR20 score means that a patients RA has improved by 20%, an ACR70 score
means it has improved by 70%, and so forth. An ACR20 score, a person with RA must
have at least 20% fewer tender joints and at least 20% fewer swollen joints. The factors
that this score takes into consideration are: the persons overall assessment of his or her
RA, the physicians global assessment of the persons RA, the persons assessment of
his or her own pain, the persons assessment of his or her own physical functioning, and
the results of an erythrocyte sedimentation rate or C-reactive protein blood test, which
give insight in the degree of inflammation (9). This kind of score is used both by
clinicians, doctors, researchers and patients. This enables them to quantify and contrast
the degree of severity of the patients RA, as well as to recognize weather or not there
has been a considerable improvement of the symptoms and an arrest in the development
of the disease in general.

The following are some of the most widely used DMARDs to treat RA:
Methotrexate
Methotrexate is the most commonly used DMARD; the first choice to treat RA and its
used in 5070% of patients. It is at lower doses than those needed for cancer
chemotherapy. But can also be used to treat diseases such as psoriasis.

The mechanism of action at low doses such as the ones used in the RA relates to
inhibition of aminoimidazolecarboxamide ribonucleotide (AICAR) transformylase and
thymidylate synthetase, with secondary effects on polymorphonuclear chemotaxis, this
effects inhibits the growth of rapidly dividing cells. This compound has direct inhibitory
effects on proliferation and stimulates apoptosis in immune-inflammatory cells. There is
also some effect on dihydrofolate reductase and this affects lymphocyte and
macrophage function, but this is not its principal mechanism of action. Additionally,
inhibition of proinflammatory cytokines linked to rheumatoid synovitis has been shown,
leading to decreased inflammation seen with rheumatoid arthritis.

The drug is given through oral administration, 70% absorbed after administration. It is
metabolized to a less active hydroxylated metabolite. Both the parent compound and the
metabolite are polyglutamated within cells, where they stay for prolonged periods.
Methotrexates serum half-life is usually only 69 hours, although it may be as long as
24 hours in some individuals. The concentration is increased in the presence of
hydroxychloroquine, which can reduce the clearance or increase the tubular
reabsorption of methotrexate. This drug is excreted in the urine, but up to 30% may be
excreted in the bile.

The most common dosing regimen for the treatment of RA is 1525 mg weekly, but this
can be increased to enhance the effect over the disease up to 3035 mg weekly. The
drug not only attacks the present symptoms of RA, but also decreases the rate of
appearance of new erosions. There is evidence to support its use in juvenile chronic
arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, polymyositis,
dermatomyositis, Wegeners granulomatosis, giant cell arteritis, systemic lupus
erythematosus, and vasculitis.

Some of the common side effects are nausea and mucosal ulcers. Frequently,
progressive dose-related hepatotoxicity can present in the form of hapetic enzyme
concentration increase, but cirrhosis is rare (< 1%). Liver toxicity is not related to serum
methotrexate concentrations, and liver biopsy checks are only recommended every 5
years. A rare hypersensitivity lung reaction with acute shortness of breath is well
documented; as well as pseudolymphomatous reactions are reported. Co-administration
with leucovorin 24 hours after each weakly dose can reduce gastrointestinal and liver
function test abnormalities. The daily co-administration of folic acid can be used, giving
the same effect as leucovorin, although this may decrease the efficacy of the
methotrexate. This drug is contraindicated in pregnancy (7).

Abatacept
This compound acts as a co-stimulation modulator, meaning that it inhibits the
activation of T-cells. Its mechanism depends on the mechanism by which T-cells and
Antigen presenting cells (APC) interact. Basically, when a T-cell becomes stimulated
by an APC (i.e. dendritic cell (DC)) to produce antibodies and attack a specific antigen.
A molecular receptor crosstalk occurs between these two cell lines, CD28 a signal
produced by T-cells interacts with CD80 AND CD86 (also known as B7) in the APC.
This triggers the cellular response for T-cells to be activated. Once activated T-cells
display CTLA4, a CD28 analogue that binds to CD80, CD86, with 100x more affinity
than CD28. Abatacept is a fusion protein between CTLA4 and an immunoglobulin;
hence it is called CTLA4Ig (8). It acts as an antagonist of the molecular interaction
between CD28/CTLA4 and CD80/CD86/B7. It binds selectively to CD80/CD86 to
inhibit the activation of the CD28 and therefore the activation of T-cells.
This drug is given intravenously in three initial doses (day 0, week 2, and week 4),
followed by monthly infusions. The dose depends on body weight; a chart is presented
in table 1.





Table 1. Abatacept dosing range.

The serum half-life of the compound is 1316 days. Co-administration with
methotrexate, non-steroidal anti-inflammatory drug, and corticosteroids does not
influence abatacept clearance. Abatacept reduces the clinical signs and symptoms of
RA, including slowing of radiographic progression. (7). Abatacept can be used as
monotherapy or in combination with other DMARDs in patients with moderate or
severe RA who did not respond to other treatments; like anti-TNF. Its effective in early
RA; it reduces the clinical signs and symptoms for example slowing radiographic
progression.

In terms of the adverse effects of this drug it includes increased risk of infection, as with
other DMARDs, predominantly in the upper respiratory tract. Co-administration with
TNF- antagonists is not recommended due to the increased incidence of serious
infection. Since all of the T-cells and anti-pathogenic response pathways, will be
Weight Dose
<60 kg 500 mg
60-100 kg 750 mg
>60 kg 1000 mg
suppressed by these drugs. Hypersensitivity reactions have been reported, such as
anaphylaxis, but are rare (7).

Azathioprine
This molecule acts as an analogue of purines, as a prodrug for mercaptopurine, it
inhibits DNA synthesis of proliferating cells (fast division) such as T-cells, B-cells.
Through its major metabolite 6-thioguanine, which inhibits inosinic acid synthesis, it
suppresses immunoglobulin production, and interleukin-2 secretion. It displays a
bimodal metabolism where rapid metabolizers clearance for the drug is 4x faster than
in slow metabolizers. The metabolism of azathioprine is mediated by thiopurine
methyltransferase (TPMT). A frequency of 0.3% of the population possesses a low
TPMT activity in respect to the mean functional activity rate, and consequently a higher
myelosuppression (bone marrow suppression) risk by a high dose.

This compound has a used dose of 2 mg/kg/d, and can effectively treat: psoriatic
arthritis, reactive arthritis, polymyositis, systemic lupus erythematosus, and ehets
disease. The adverse effects of the drug include: gastrointestinal disturbances, and some
increase in infection risk and the previously mentioned bone marrow suppression. In
rare occasions: fever, rash, and hepatotoxicity signal acute allergic reactions (7).

Chloroquine and Hydroxychloroquine
Also known for their use as anti-malaria agent, and by unknown means it can
effectively treat RA. Some of the proposed hyphotesis towards what is the mechanism
of action of the drug are: suppression of T-lymphocyte response to mittogens, decrease
leukocyte chemotaxis, stabilization of lysosomal enzymes, inhibition of DNA and RNA
synthesis, and the trapping of free radicals.

These two are rapidly absorbed and 50% protein-bound in the plasma, and extensively
tissue-bound, particularly in melanin-containing tissues such as the eyes. The
metabolism occurs in the liver, the compounds have blood elimination half-lives of
approximately 45 days. Although antimalarial compounds improve symptoms, there is
no evidence that they alter bony damage in RA at their usual dosages (6.4 mg/kg/d for
hydroxychloroquine and 200 mg/d for chloroquine), and it takes from 36 months to
obtain a response on the patient.this group of compound are used for the treatment of
skin manifestations, serositis, and joint pains of systemic lupus erythematosus, and
jgrens syndrome.

In terms of toxicity, because of the accumulation of this kind of compound in the optic
tissue, an elevated dosage such as 250 mg/d for chloroquine and greater than 6.4 mg/
kg/d for hydroxychloroquine can cause damage in the eyes. Therefore ophthalmologic
monitoring is advised. Other toxicities are dyspepsia, nausea, vomiting, abdominal pain,
rashes, and nightmares. There are no concerns relating to toxicity during pregnancy (7).

Cyclophosphamide
Similarly to Azathioprine, cyclophosphamide inhibits the synthesis of DNA, through its
functional domain of a phosphoramide mustard, it incorporates an alkyl group to DNA.
What provokes cross-linking between the two strands of DNA and consequently
prevents cell replication of rapidly dividing cell linaeages (such as lymphocytes). It
suppresses 30-40% T-cell and B-cell function. Activation to its cytotoxic form happens
in the liver by microsomal enzymes, P450 methabolizing enzyme converts it from
phosphamide to 4-hydroxycyclophosphamide.

The adverse effects include vomiting and nausea, cystitis can present itself and be
prevented with regular hydration. The via for administration is intravenous, with an
effective concentration of 2 mg/kg/d. Other uses for the compound are lupus
erythematosus, vasculitis, Wegeners granulomatosis, and other severe rheumatic
diseases (7).

Ciclosporin
This immunosuppressive drug is widely used in organ transplant procedures to prevent
rejection from the receiver. It successfully inhibits interleukin-1 and interleukin-2
receptor production and secondarily inhibits macrophageT-cell interaction and T-cell
responsiveness. It has initially extracted from tolypocladium inflatum (fungus) by Dr.
Hans Peter Frey, a Sandoz biologist, in Hardangervidda, Norway. Its a cyclic molecule
composed of 11 amino acids, but not synthetized by the ribosome (like other peptides
and proteins), another peculiarity of this molecule is that it contains a D-amino acid, not
regularly found in nature.

Its absorption is not very efficient, being incomplete and even erratic, although a micro
emulsion (using micelles and liposomes), improves its consistency and provides 20
30% bioavailability (F). Surprisingly, grapefruit juice increases cyclosporine
bioavailability by as much as 62%. This molecule is metabolized by CYP3A and
consequently is subject to a large number of drug interactions.

Cyclosporine is approved for use in RA, because of its immunosuppressive activity, it
retards the appearance of new bony erosions. Its usual dosage is 35 mg/kg/d divided
into two doses. Other uses of the compound are treating systemic lupus erythematosus,
polymyositis and dermatomyositis, Wegeners granulomatosis, and juvenile chronic
arthritis (7).

Leflunomide
Used to treat RA as well as psoriatic arthritis, this compound undergoes isomerization
to its active form A77-1726 as long as it reaches the plasma or as early as the intestine.
This strong agent inhibits dihydroorotate dehydrogenase, leading to a decrease in
ribonucleotide synthesis and the arrest at the G1 phase of cell growth. Thus affecting
primarily proliferating cells such as lymphocytes, it stops T-cell proliferation and
production of autoantibodies by B cells. Since this effect is so powerful, as a side effect
theres an increase in interleukin-10 receptor mRNA, decreased interleukin-8 receptor
type A mRNA, and decreased TNFdependent nuclear factor kappa B (NF-B)
activation.

It is very well absorbed as leflunomide with a half-life of 19 days, and A77-1726 (active
form) has approximately the same persistence rate and its subject to enterohepatic
recirculation (from the liver back to the intestine). Cholestyramine can enhance
leflunomide clearance by 50%.

Leflunomide as effective in the treatment of RA as methotrexate, it includes inhibiting
bony damage. Its been reported that a combined treatment of methotrexate with
leflunomide can improve RA in as much as a 46.2% ACR20 response, compared to
19.5% in patients only receiving methotrexate.

Diarrhea is a common side effect of leflunomide, approximately 25% of patients show
this undesired effect. But only about 35% discontinue the drug because of this effect.
Increase in liver enzymes concentration also presents. These and other side effects can
be avoided or decreased by lowering the dosage. Other adverse effects associated with
the drug are mild alopecia, weight gain, and increased blood pressure, and rarely
leukopenia and thrombocytopenia can occur. This drug is contraindicated in pregnancy
(7).

Mycophenolate mofetil
This is an immunosuppressant used in transplant therapy and a prodrug of
mycophenolic acid, the later is the active form of the compound. Which is a reversible
inhibitor of inosine monophosphate dehydrogenase (IMPDH), one of the enzymes
catalyzing purine biosynthesis (adenine and guanine), necessary for the growth of T-
cells and B cells. As with other purine biosynthesis inhibitors, other cell lineages are
able to proliferate without purines using a different pathway and are thus able to escape
the effect. It also interferes with leukocyte adhesion to endothelial cells through
inhibition of E-selectin, P-selectin, and intercellular adhesion molecule 1.

Some of the side effects that can present are aggressive, such as myelosuppression.
Mycophenolate mofetil is effective in the treatment of renal diseases due to systemic
lupus erythematosus, and is effective in vasculitis and Wegeners granulomatosis too.
The commonly used dosage is 2 g/d to treat RA (7).
Rituximab
This molecule is a chimeric monoclonal antibody that targets CD20 B lymphocytes.
Built by genetic engineering through the fusion of a human immunoglobulin (IgG1) and
a murine anti-CD20 antibodys variable region. CD20 is expressed in many of the B cell
lineages as well as in lymphoma cells (blood cancer cells), but not in the hematopoietic
lineage. Thus its a good marker to selectively target and destroy -cells and
lymphomas. This process takes place through cell-mediated and complement-dependent
cytotoxicity as well as stimulation of cell apoptosis. Depletion of B lymphocyte (B-
cells) levels reduces inflammation by preventing the presentation of antigens to T
lymphocytes and inhibiting the secretion of proinflammatory cytokines. The reduction
in B-cell population occurs as soon as the drug is administered, it takes about 6 months
for the B-lymphocyte population to replenish to its typical level. This drug rapidly
depletes peripheral B cells although this reduction neither correlates with efficacy nor
with toxicity.

This fusion monoclonal antibody is given as two intravenous infusions of 1 g, separated
by 2 weeks. It may be repeated every 69 months, if needed, without loosing potency or
effectivity. Pretreatment with glucocorticoids (intravenous) 30 minutes prior to infusion
(i.e. 100 mg of methylprednisolone) decreases the occurrence and severity of
inconvenient infusion reactions.

Rituximab has shown assistance in the treatment of RA. It is indicated and approved for
the treatment of moderate to severe RA when combined with methotrexate in patients
with an inadequate response to TNF-antagonists. Approximately 30% of the patients
develop rash in the skin with the first 1 g treatment; which decreases to about 10% with
the second infusion and progressively decreases with each new administration. These
rashes are mild and do not usually require discontinuation of therapy, although urticarial
(severe rashes) or anaphylactoid reactions (pre-anaphylactic reaction), prevent further
therapy. Immunoglobulins (particularly IgG and IgM) may decrease with repeated
dosages of rituximab, what increases the risk of infection; still this is not directly
associated with the decreases in Igs. Rituximab is not associated with activation of
tuberculosis or lymphomas, which gives the drug relative advantage over other
DMARDs. Other adverse effects, such as cardiovarcular difficulties are rare (7).

Sulfasalazine
Sulfasalazine (SSZ) is metabolized and degraded to: sulfapyridine and 5-aminosalicylic
acid. It is suggested that sulfapyridine is the active compound in the treatment of RA.
Some authorities think that sulfasalazine also has an effect. The mechanism of action
involves the decrease of IgA and IgM rheumatoid factor. Suppression of T-cell response
as well as inhibition of in vitro B-cell proliferation has been documented. Other in vitro
studies showed that sulfasalazine inhibits the release of inflammatory cytokines,
including those produced by monocytes or macrophages (i.e. interleukins-1, -6, and -12,
TNF-). These findings suggest a possible (but not definitive) mechanism of action of
sulfasalazine, clinically used against RA.

Sulfasalazine is administered orally and not very efficiently absorbed, only about 10
20% of the administered dose is absorbed, nonetheless a fraction undergoes
enterohepatic recirculation into the bowel where it is reduced by intestinal bacteria to
sulfapyridine and 5-aminosalicylic acid. Sulfapyridine is well absorbed, 5-
aminosalicylic acid remains unabsorbed. A fraction of sulfasalazine is excreted
unchanged in the urine whereas sulfapyridine is excreted after hepatic acetylation and
hydroxylation.

Sulfasalazines half- life is 617 hours. The effectiveness of this drug against RA is
extensively recorded, it reduces radiologic disease progression. It has been used in
juvenile chronic arthritis, ankylosing spondylitis and uveitis. The usual dose is 23 g/d.

This compound is relatively toxic, 30% of patients discontinue the drug because of
toxicity. Some adverse effects are: nausea, vomiting, headache, and rash. Rare effects
could include: hemolytic anemia and methemoglobinemi. Neutropenia (low
concentration of neutrophils) occurs in 15% of patients, while thrombocytopenia (low
population of platelets) is very rare. Pulmonary toxicity and positive double-stranded
DNA are occasionally seen, but drug-induced lupus is rare. In men, reversible infertility
occurs, but not in women. The drug does not appear to be teratogenic (7).

TNF- locking Agents
Cytokines, from the greek cyto=cell, kinos=movement are inter-signaling moleculas
that range from: chemokines, interferons, interleukins, and lymphokines, to tumor
necrosis factors. These are produced by: macrophages, B lymphocytes (B-cells), T
lymphocytes (T-cells) and mast cells, as well as endothelial cells, fibroblasts, and
stromal cells. They play a central role in the immune response and consequently in RA.
A wide range of cytokines have been associated to RA, because of their relative high
expression profile in the joints, and damaged tissue. TNF- is particularly important in
the overall pathway regulation and is important in the inflammatory response.
TNF- affects cellular functions by affecting the equilibrium in the inner molecular
pathways via activation of specific membrane-bound TNF receptors (i.e. TNFR1,
TNFR2). Three drugs interfering with TNF- have been approved for the treatment of
RA and other rheumatic diseases: Adalimumab, Infliximab, Etanercept.

Adalimumab
Adalimumab is a human antibody, more precisely IgG1 anti-TNF monoclonal antibody
(Figure 2). It binds to TNF- and prevents its interaction with the TNF-receptor (p55
and p75) laying on the cell surface. The inhibition of this cell signal down regulates
macrophage and T-cell activity.

The means for administration of this drug are subcutaneous and the half-life is 10 20
days. When co-administered with methotrexate, the clearance is decreased by
approximately 40%. The usual dose is 40 mg every week, but the dose can be increased
to increase the response. In psoriasis, the dose is 80 mg at week 0, 40 mg at week 1, and
then 40 mg every other week thereafter.

The compound has been approved for the treatment of many immune diseases
including: RA, ankylosing spondylitis, psoriatic arthritis, juvenile idiopathic arthritis,
plaque psoriasis, and Crohns disease. It decreases the rate of formation of new
erosions, and effective as monotherapy. In can also be used in combination with
methotrexate and other DMARDs.

The risk of bacterial infections increases when using this drug, as well as macrophage-
dependent infections (tuberculosis and other opportunistic pathogens) is increased when
using this drug. But as in other TNF- and lymphocyte activity blockers, this effect is
not severe enough to stop the treatment. Patients should be screened for latent or active
tuberculosis before starting adalimumab or other TNF-blocking agents, to prevent
development of this pathogen. It is not clear if the incidence of lymphomas is increased
by adalimumab. It has been shown that double-stranded DNA (dsDNA) antibodies and
antinuclear antibodies (ANAs) has been documented to present themselves when using
adalimumab, but clinical lupus and other severe autoimmune responses are extremely
rare. Leukopenia (decreased population of white blood cells) and vasculitis
(inflammation of the blood vessels), seemingly associated with adalimumab, have been
reported.

Infliximab
Infliximab is a chimeric IgG1 monoclonal antibody comprising a human IgG1 heavy
chain and a murine variable region (25% mouse, 75% human) that binds with high
affinity to either soluble or membrane bound TNF- (Figure 2). Its mechanism of action
is tough to be similar to the one of adalimumab.

Infliximab is given as an intravenous infusion at a dose of 310 mg/kg, although the
usual dosage is 35 mg/kg every 8 weeks. There is a relationship between the serum
concentration and the degree of the effect. And individual clearances vary significantly
among patients. The half-life is approximately 912 days, and there is no accumulation
even after repeated dosing at 8-week intervals. After several dosing sessions, infliximab
causes the secretion of human antibodies against the chimeric region of the drug in up to
62% of patients. Simultaneous therapy with methotrexate noticeably decreases the
prevalence of human antichimeric antibodies.

Infliximab is approved for: RA, ankylosing spondylitis, psoriatic arthritis, and Crohns
disease. But also other diseases such as: psoriasis, ulcerative colitis, juvenile chronic
arthritis, Wegeners granulomatosis, giant cell arteritis, and sarcoidosis. In patients with
RA, infliximab with methotrexate as adjuvant decreases the rate of formation of new
erosions more than methotrexate alone, in a 1224 months time realm. Even with
methotrexate is commonly used alongside with infliximab, a number of other DMARDs
can be used as in co-administration, such as: antimalarials, azathioprine, leflunomide,
and cyclosporine, can be used as background therapy for this drug.

Like other TNF-blocking agents, infliximab is associated with an increased incidence
of bacterial infections, including upper respiratory tract infections. Infliximab can be
associated with activation of latent (lysogenic) tuberculosis, and patients should be
tested for latent or active tuberculosis before starting therapy. There is no evidence for
an increased incidence of solid malignancies (tumours) and it is not clear if the
incidence of lymphoma is increased with infliximab. Demyelinating syndromes (loosing
myelin and degradation of neural tissue) have been deocumented; patients with multiple
sclerosis should not use infliximab. Additionally, cases of leukopenia, hepatitis,
activation of hepatitis B, and vasculitis have been documented. Occurrence of positive
ANA and ds-DNA antibodies secretion is presented too, although clinical lupus
erythematosus remains an extremely rare occurrence and the presence of ANA and
dsDNA does not contraindicate the use of infliximab. Infusion site reactions are
correlated to anti-infliximab antibodies secretion. These kind of reactions occur in
approximately 311% of patients treated with infliximab. The combined use of
antihistamines and H2 blocking agents has been shown to avoid some of these adverse
effects.

Etanercept
This drug is a recombinant fusion protein consisting of two soluble TNF receptor (p75)
domains linked to the heavy chain portion of human IgG1 (Figure 2); it binds to TNF-
molecules and also inhibits lymphotoxin-.

This drug is administered subcutaneously in a dosage of 25 mg two times per week or
50 mg weekly. For psoriasis, 50 mg are given twice weekly for 12 weeks followed by
50 mg weekly. This molecule is slowly absorbed, with peak plasma concentration at 72
hours after drug administration. Etanercept has a serum elimination half-life of
aproximately 4.5 days. It has been reported that 50 mg of etanercept, given once a week
or 25 mg twice a week have the same effect (same area under the curve and minimum
serum concentrations).

Etanercept has been approved for the treatment of: RA, juvenile chronic arthritis,
psoriasis, psoriatic arthritis, and ankylosing spondylitis. The followed strategy is either
as monotherapy or alongside with methotrexate. More than 70% of patients taking
etanercept take methotrexate too. Etanercept has a stronger effect over the rate of
formation of new erosions than that of methotrexate alone. It has also been used to treat
other rheumatic syndromes such as: scleroderma, Wegeners granulomatosis, giant cell
arteritis, and sarcoidosis.


Bacterial infection risk is slightly increased, particularly on soft tissue and septic
arthritis. Activation of latent tuberculosis can also occur, but etanercept shows lower
probability than treatment with other TNF-blocking agents. Nonetheless, patients must
be tested for latent or active tuberculosis before proceeding with the administration of
this medication. In the same sense, opportunistic infections can occur when using
etanercept. The occurrence of tumours is not favored, but as with other TNF-blocking
agents checkups must be performed to prevent the appearance of lymphomas. Still their
incidence may not be increased when comparing it with other DMARDs or active RA in
itself. While positive ANAs and dsDNAs may be found in patients receiving this drug,
these findings are not sufficient enough to stop the administration of etanercept if
clinical lupus symptoms do not occur. Also, injection site reactions can occur in 20
40% of treated patients, but they rarely result in suspension of therapy. Anti-etanercept
antibodies secretion is present in up to 16% of treated patients, but they do not interfere
with efficacy or toxicity (7).

Corticosteroids
Corticosteroids are widely used for the treatment of RA, around 6070% of patients
who have this disease go through this kind of treatment. They can efficiently stop new
bone erosions; thats the main motive for choosing corticosteroids therapy against RA.
Since this molecule is an endogenous hormone, the use of it as a drug can have very
strong and deleterious effects on the patient. This is a very relevant signaling molecule
in the endocrine system and it regulates a wide variety of homeostatic functions.
Nonetheless this therapy is commonly used to treat serious extra-articular
manifestations of RA such as pericarditis and eye degeneration or during periods of
exacerbation. And thus the use of these compounds as therapeutic agents has been very
controversial. Still, its use is widely popularized and distributed along the globe.

Glucocorticoids have become a central agent for the treatment of many inflammatory,
immunologic, hematologic, and other disorders such as RA. Many therapies for a wide
variety of disease involve corticosteroids either as monotherapy or in combinatory
approaches. This has stimulated the development of many synthetic steroids with anti-
inflammatory and immunosuppressive activity. Synthetic corticosteroids are particularly
prefered over natural ones for the treatment of these diseases, because of their relative
selectivity and increased efficacy.

Steroids for pharmacological purposes are usually synthesized from cholic acid
obtained from cattle or steroid sapogenins found in plants. Further modifications of
these initial steroids have led to the production and marketing of a large variety of
synthetic steroids. These have specific characteristics that are both pharmacologically
and therapeutically relevant (Figure 3).

This spectrum of synthetic corticosteroids is classified according to their relative time of
action inside the body. In most cases rapidly and completely absorbed when given by
mouth. Although they are transported, metabolized, and excreted in a fashion similar to
that of the endogenous steroids, there are significant differences surrounding the
pharmacokinetics of synthetic corticosteroids.

Catalytic modifications such as conjugations in the glucocorticoid molecule influence
its affinity and the pharmacodynamics when interacting with glucocorticoid and
mineralocorticoid receptors. As well as affecting the: protein binding affinity, side chain
stability, rate of elimination, and metabolic products. Some modifications that present
with administering corticosteroids that prolong the half-life by more than 50% are:
halogenation at the 9 position, unsaturation of the 12 bond of the A ring, and
methylation at the 2 or 16 position. The -1 compounds are excreted in free form
without modifications. In some cases where the agent given is a prodrug, other
modifications involve the activation of the molecule; for example, prednisone is rapidly
converted to the active product prednisolone in the body.

The mechanisms of action of the synthetic steroids are similar to those of cortisol. They
bind to the specific intracellular receptor proteins, which in turn interact with specific
promoters and thus regulate the transcription of target genes (via inactivation of heat
shock proteins). This produces cellular responses, which lead to systemic effects.
Depending on the type of steroid (i.e. glucocorticoid to mineralocorticoid) the effect and
different ratios of potency vary among these.

The use of these drugs for extended periods of time, like the time realm required for
effective treatment of RA, leads to serious and disabling toxic effects. There is
controversy over whether or not many of these side effects occur at doses below 7.5
mg/d prednisone equivalents, although many experts thinks that even 35 mg/d can
cause these undesired effects in susceptible individuals when this class of drugs is used
over prolonged periods of time.

For RA, when prednisone (a synthetic corticosteroid) is required for long-term therapy,
the dosage should never exceed 7.5 mg a day, and gradual reduction of the dose should
be performed. Alternate-day corticosteroid therapy is usually not effective when using it
for RA. Other rheumatic diseases in which corticosteroids have been used comprise:
vasculitis, systemic lupus erythematosus, Wegeners granulomatosis, psoriatic arthritis,
giant cell arteritis, sarcoidosis, and gout. Intra-articular (injected directly in the joints)
corticosteroids are often effective to ease painful symptoms and which is preferable
than to increase the dosage of systemic medication, even when is more painful for the
patient (7).

Parenteral gold
Parenteral gold has been demonstrated to affect the activity of B and T lymphocytes as
well as polymorphonuclear leukocytes/ganulocytes (PMN) function. Injectable gold
was the first DMARD to have shown some benefits in treating RA, established in a
clinical trial. It still represents an important standard for comparing the efficacy of other
second-line agents. However, newer therapies, such as the mentioned above:
methotrexate and sulfasalazine, are equally efficacious but less toxic, making the
current use of parenteral gold much less frequent.

Bone marrow dysfunction and proteinuria from membranous glomerulonephritis require
that a complete blood count (CBC) and urinalysis be performed before every dosage of
this agent. There are other toxicities with this compound, such as stomatitis and rash. A
limited number of patients can tolerate parenteral gold for long terms, but this is usually
not the case. Therefore, gold salts should still be only in the circumstance of a patient
with progressive disease, especially when other DMARDs have not been beneficial (4).

Auranofin
Auranofin is another gold therapy, and the only gold-salt preparation that can be taken
orally. Sulfhydryl-containing organic gold compounds have been used in the treatment
of RA with benefit since the 1920s. Gold metabolism is complex and yields several
metabolites, which vary in concentration in among specific tissues. No specific site or
mechanism of action has been conclusively identified. Compared with parenteral gold,
auranofin is less toxic but probably less effective too. This has been reported in a
comparative study where injectable gold but not auranofin appeared to reduce the rate
of bony erosions. The time for a visible clinical response for auranofin ranges from 3-6
months after initiation of therapy. This time frame is somewhat longer than is typically
seen with parenteral gold.

Diarrhea is a common toxic effect but generally responds to a reduction in dose.
Mucosal ulcerations and skin rashes occur with a frequency similar to that seen with
injectable gold. While bone marrow dysfunction and proteinuria (increase in the
concentration of microalbumin in urine) are distinctly less common. A monthly CBC
and urinalysis (test urine) are required for adequate monitoring of the treatment.
Application of auranofin is most often considered in the patient with mild disease and a
favourable prognosis, and who is not adequately responding to NSAIDs alone (4).

Minocycline
Minocycline is an antibiotic of the tetracycline family that was recently reported to be
successful for RA in a large, multicentre trial study. It appeared to be efficacious in a
patient population with very early and mild stages of the disease. The mechanism of
action in RA is not clear but, in addition to their well-known antimicrobial properties,
the tetracyclines have demonstrated anti-collagenase activity. This is proposed to be
associated with its efficacy against RA.

Minocycline is generally well tolerated although dizziness is not unusual, abnormal
liver function tests have been observed as well. Until this drug has been studied in a
population with more severe disease, the use of minocycline should probably be
restricted to patients with early and mild RA (4).

Penicillamine
Penicillamine acts as a chelator of divalent cations, it is structurally similar to cysteine.
While it has been shown to impair antigen presentation, to diminish globulin synthesis
and to inhibit PMN myeloperoxidase, no certain mechanism of action is known
specifically for RA. Comparable with gold in terms of its efficacy, the use of
penicillamine as other anti-RA drugs is often limited by toxicity.

In addition to immune complexinduced glomerulonephritis (inflammation of small
blood vessels in the kidneys called glomeruli) and bone marrow suppression, a number
of autoimmune syndromes are also reported. Monthly monitoring is required and
consists of a CBC, a urinalysis and careful clinical evaluation. The use of penicillamine
has decreased considerably, particularly in the US, with the advent of agents such as
methotrexate and sulfasalazine, which have comparable potency with better tolerability
(4).


As an overall view of the diversity of options available for the treatment of RA: the first
line of treatment in early RA often involves MTX monotherapy. For example The North
American Cohort of Patients with Early RA (SONORA). This includes patients with
symptoms for >3 but <12 months, indicated that MTX was the most frequently
prescribed DMARD, being taken by more than half of patients (10). A study by Stenger
et al. has shown that early aggressive drug treatment, using SSZ and/or MTX, reduced
the C-reactive protein (CRP) level, and significantly reduces radiographic progression
in RA (11).

If this first option is not effective, then more aggressive DMARDs or non-modifying
drugs are supplied and tested in the patient. This comes with a tradeoff between toxicity
and efficacy. Since, almost all cases of effective anti-RA drugs come along with a
strong side effect or toxicity. This correlation is produced mainly by the nature of the
disease. Because treatment of RA involves the use of drugs that involve prevention of
inflammation and immune suppression, this entire set of compound will show a very
toxic effect. The mechanisms of action of these agents are deeply associated to
preventing normal host defense mechanisms. This is the main reason why many
compounds designed to effectively treat RA show so dramatic adverse effects.

Recent Methotrexate vs. Placebo Treatment studies; a double-blind, placebo-controlled,
randomized, multicentre trial in 110 participants with undifferentiated RA, was
conducted to determine whether participants would benefit from treatment with MTX.
After 30 months, the group taking MTX showed somewhat less radiographic
progression (12). This is just an example of the effect of placebo in broad terms in
DMARDs, and can be extrapolated to all agents of this group. It is very noticeable the
time frame needed for a positive effect to be appreciated. This is the second reason for
the high toxicity of DMARDs. Since these compound require a long period of time for
effective treatment of RA. Combined with the controversial mechanisms of action, it
results in a strong toxicity response in a high frequency of patients. Still the toxic
adverse effects are patient-dependent, and each individual should be accounted as a
particular case. This is the motive why treating this disease required long periods of
time. First, analysis of the symptoms and tests performance will provide with a correct
identification of the progression stage of the disease, towards then being able to select
the most favorable approach among the different available therapies for RA.

In conclusion, the use of DMARDs is the only effective treatment today for stopping
RA. Since these compounds do not eradicate the disease but only stop its development,
they usually require a long period of time and this is correlated to a high degree of
toxicity. There are a variety of agents comprising this group and they are categorized
according to their nature and degree of toxicity. Depending on both the patients
particular profile and the stage of the disease, the correct DMARD can be identified for
use. Low toxicity compound are regularly used for early stages of the disease, whereas
highly toxic agents are preferred for aggressive forms of RA. The first line of treatment
against this illness both for its efficacy and relatively low toxicity is MTX, but other
agents might be used depending on the mentioned criteria.

Further development of more specific and less toxic agents might appear with years to
come. By using molecular biology techniques combined with genetic engineering, new
agents can be produced. For example, the use of chimeric antigen receptors (CARs)
against RA has not been exploited yet, but surely soon will be.

Figure 1. Algorithm based on the European League Against Rheumatism to
generate recommendations on the treatment of rheumatoid arthritis management.
By Smolen et al.

Figure 2. Structures of approved anti-TNF DMARDs for treating RA. By Katzung
et al.

Figure 3. List of corticosteroids in general, both synthetic and natural. By Katzung
et al.

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