Rheumatoid Arthritis: Pathogenesis, Clinical Features, and Treatment

Rheumatoid Arthritis:
Pathogenesis, Clinical
Features, and Treatment
Arthur Kavanaugh, MD
John J. Cush, MD
Richard P. Polisson, MD, MHS
Contents
1. Pathogenesis
2. Epidemiology
3. Clinical Features
4. Prognosis
5. Therapy
6. Specific Antirheumatic Drugs
7. References
RHEUMATOID ARTHRITIS: PATHOGENESIS, CLINICAL FEATURES, AND TREATMENT 1

1. Pathogenesis
Rheumatoid arthritis (RA) is a chronic, destructive, The pathobiology of RA involves a complex interac-
inflammatory arthropathy manifested by articular tion of three different scientific domains: 1) a complex
and extra-articular features. RA has profound genetic predisposition to the disease plus some envi-
effects on patient function and morbidity and exacts ronmental stimulus; 2) a self-perpetuating, self-ampli-
a substantial economic burden from affected per- fying, intra-synovial immune response; and at the
sons. Although the pathology of the synovial inflam- final stage, 3) tissue injury mediated by pro-inflamma-
mation and cartilage destruction that occurs in tory cells, inflammatory effector molecules, and
patients with RA has been described for decades, degradative enzymes. In individuals with RA, this
many important developments in the understanding process is arthrotropic and produces a characteristic
of genetic influences and immunopathophysiologic pathologic lesion in the synovium as well as the hall-
mechanisms have recently been defined. Basic mark erosions of bone and destruction of cartilage at
research delineating the molecular mechanisms of the joint margin.
synovial inflammation has driven the development
of innovative therapies for patients with RA. Hope- The histopathology of RA synovium has been well
fully, new genomic and proteomic information will described. The synovial lining, the interstitium, and
allow further stratification identification of subsets the microvasculature are all involved. Early on in the
of RA patients who respond better, longer, and with process, the synovial lining, which includes both
fewer adverse reactions to targeted therapies. Type A (macrophage-like) and Type B (mesenchy-
mal or fibroblast-like) cells, becomes proliferative.
The synovial lining increases in cell number and
mass. Likewise, a diffuse and nodular inflammatory
cell infiltrate is observed in the interstitium. It
includes CD4+ and CD8+ lymphocytes, dendritic
cells, and other antigen presenting cells. In some
patients, the histologic appearance is quite dramatic,
showing focal aggregation of both T- and B-cells, as
well as the presence of germinal centers similar to
that which is seen in lymphoid tissues.
The synovium of the rheumatoid joint, although not

malignant, often times behaves as a local invasive
“tumor.” The microvasculature initially reveals
endothelial cell activation. As the process matures,
plasma cells and multinucleated giant cells appear,
and the vascular supply becomes exuberant. Finally,
the growing synovium appears as granulation tissue
as it advances to the hyaline cartilage at the margin of
the joint. A local effect of degradative enzymes and
activated osteoclasts produces the classic erosion at
the bone and cartilage margin. These enzymes may
also affect structures that are more distant, including
the tendons, ligaments, and other musculoskeletal
structures. Erosions are produced by bone and matrix
protein resorbing osteoclasts, which may be induced
and activated by cytokines released into the inflam-
matory milieu. Some of the scientific observations
that explain these phenomena are noted below.
2 EDUCATIONAL REVIEW MANUAL IN RHEUMATOLOGY

Genetics and Environmental Stimulus to RA over the years, conclusive evidence for any
single cause is lacking. Moreover, the dosage effect
Genetic contributions to the pathogenesis of rheuma- of HLA-DR in RA (ie, persons with 2 copies of the
toid arthritis (RA) are very complex. Genetic studies shared epitope containing MHC Class II allele are
in families of patients with RA suggest that monozy- more likely to have RA than those with a single copy)
gotic twins have a concordance rate for RA of argues against simple antigen presentation being the
between 15%-30%. Thus, genetic factors contribute relevant mechanism. More likely, presence of disease
to susceptibility but are not the whole story. Obvi- associated HLA-DR alleles modifies the T-cell-
ously, there must also be some triggering mechanism. receptor repertoire during thymic selection.
It is certain that RA is a polygenic disease in which
some genes may drive the initiation of the disease Other factors are also involved in the triggering of
while others may impact the response to therapy or RA in susceptible persons. One factor (not entirely
define disease severity and prognosis. extragenetic) is female sex. Particularly at younger
ages of onset, RA is more common in women than in
Approximately 2 decades ago, certain alleles of the men, with a ratio of about 3:1. Whether this differ-
HLA-DR4 locus were found to be associated with RA ence reflects hormonal differences, genetic factors
in Caucasian patients. Most scientific evidence now involved in the presence or absence of the Y chromo-
suggests that certain genes within the major histo- some, or genetic factors in the random inactivation of
compatibility complex (MHC), located on the short one X chromosome is not known. Another factor
end of chromosome 6 play the most significant role in may be the microbial flora (both pathogenic and com-
the initiation of the rheumatoid disease process. Sus- mensurate) to which persons are differentially
ceptibility to RA can be explained by the shared epi- exposed, as mentioned above. Finally, it is possible
tope hypothesis, ie, a 5-amino acid sequence found on that stochastic processes involved in the formation of
several HLA-DR4 alleles defines a structural domain the T-cell–receptor repertoire can, in a genetically
that confers susceptibility to RA. Recent studies sug- susceptible person, produce a propensity for disease,
gest that the clinical phenotype of RA (ie, destructive the inheritance of which does not follow the rules of
joint disease and extraarticular manifestations) is also Mendelian genetics. At some point, the susceptible
associated with certain genes within the MHC. Evi- host’s genome, interacting perhaps with some exoge-
dence also suggests that there are RA susceptibility nous factor, be it an infectious antigen or self-protein,
genes on other chromosomes that appear to correlate induces the next phase in pathogenesis.
with the phenotypic presentation of RA. Recently,
allelic variations in PTPN22, a gene that encodes a Intrasynovial Immune Response
tyrosine kinase involved in inhibition of T-cell activa-
tion, have been shown to be associated with RA. The presence of activated T-cells, increased concen-
trations of pro-inflammatory mediators, and endothe-
There are several ways HLA-DR alleles could confer lial activation within the synovium appear to impli-
susceptibility to RA. In the simplest scenario, a pep- cate an aberrant self-perpetuating and self-amplifying
tide derived for example from a microbial protein immune response central to the initiation and suste-
could bind to HLA-DR, and via standard antigen pre- nance of rheumatoid synovitis. Animal models of
sentation mechanisms trigger the proliferation of autoimmunity strongly support a role for the T-
antigen-specific T-lymphocytes. If the inciting cell–receptor recognition of MHC–peptide com-
microbe selectively infects synovial cells and the plexes in the initiation and propagation of autoim-
resulting immune response is unable to clear the mune disease. In most animal models, the specific
microbial infection, chronic synovial inflammation antigen responsible for the induction of autoimmunity
might ensue. Alternatively, antigen-specific T-cells is known (eg, type II collagen in collagen-induced
activated in response to a microbial peptide could arthritis) and the MHC molecules that bind the pep-
recognize a self-peptide derived from a protein that is tide antigen, as well as the T-cell receptors that recog-
selectively expressed in synoviocytes, a process nize the resulting complex, can be determined experi-
known as molecular mimicry. However, although mentally. Under these experimental conditions, inter-
myriad organisms have been proposed to predispose ventions that disrupt this quaternary complex (eg,

antibodies recognizing involved T-cell–receptor V RA has been clearly shown by the profound clinical
regions or specific MHC alleles) ameliorate autoim- effects of the anti-TNF therapies (ie, infliximab, etan-
mune disease. Both CD4+ and CD8+ T-cells can con- ercept, and adalimumab), on the signs, symptoms and
tribute to the initiation and propagation of autoim- structural damage that characterizes RA. Finally, the
mune disease in animal models. Often both cell types invasive nature of the RA pannus has suggested to
are required to produce disease. Although it is likely some observers that the tissue behaves like a locally
that human autoimmune disease is also initiated by invasive tumor. Indeed, growth factors such as TGF-
the recognition of self-MHC–peptide complexes by ␤ and FGF produced locally in the synovium by resi-
CD4+ or CD8+ T-cells, it is not yet possible to iden- dent macrophages and fibroblasts may provide the
tify triggering antigens. The identification of such drive for tissue expansion.
antigens would greatly facilitate the design of anti-
gen-specific therapies for human autoimmune dis- Certain autoantibodies are associated with RA. The
ease. Although the evidence implicating CD4+ T- most characteristic, certainly from a historical per-
cells in the initiation of RA is strong, an essential spective is rheumatoid factor (RF). The landmark
role for other cell types is certain. Activated discovery of RF which is present in approximately
macrophages found in synovial tissues are a major 75%-85% of people with RA, marked the begin-
source of cytokines such as tumor necrosis factor- ning of the understanding that RA is a systemic
alpha (TNF-␣), which suggests an important role for autoimmine disease. Although it is relevant to the
this inflammatory cytokine in this disease. Fibrob- diagnosis of RA, RF may be of greater value to the
lasts, mast cells and B-cells have also been shown to clinician in prognosis. Epidemiologic observations
be capable of significantly contributing to the gener- suggest that the presence of the RF is a marker that
ation of rheumatoid inflammation. predicts more serious disease. Rheumatoid factors
are autoreactive antibodies that bind to the Fc por-
Effector Molecules and Cartilage Damage tion of IgG molecules. RF is not specific for
rheumatoid arthritis, as it is observed in a host of
Once this biologic inflammatory process has matured, other autoimmune disorders or infectious diseases.
it appears to be regulated and amplified by inflamma- Also, by definition of how the test is performed, 5%
tory cells and their regulatory proteins, the most of the normal population will have a positive test
notable of which include the pro-inflammatory for RF. RF of isotypes indicative of class switching
cytokines. T-cells and antigen presenting cells directly (ie, IgG and IgA, rather than IgM) may be more
(by cell to cell contact) and indirectly (by other sig- specific, as are higher titers. Although the potential
nals) stimulate macrophages to secrete interleukin-1 contribution of RF to the pathogenesis of RA is
(IL-1) and tumor necrosis factor-alpha (TNF-␣), unclear, it has been suggested that RF may induce
among other inflammatory mediators. IL-1 and TNF- tissue damage by acting as immune complexes.
␣ or their mRNA have been identified in the serum, Over the years, a variety of other autoantibodies
synovial fluid, and tissues of patients with RA. Both of have been reported to be associated with RA,
these cytokines have broad biologic effects, including including antikeratin antibodies, antiperinuclear
the induction by synoviocytes of matrix metallopro- factor, and antifilaggrin antibody. It has been
teinases as well as the inhibition of tissue inhibitors of demonstrated that the antigen recognized in com-
metalloproteinases (TIMPs). In vivo and in vitro stud- mon by these antibodies is citrullinated protein.
ies have documented that recombinant IL-1 and TNF- Citrulline is a nonstandard amino acid created by
␣ injure normal hyaline cartilage. Chondrocytes, in the de-amination of arginine residues in proteins by
particular, enter a catabolic phase when exposed to the enzyme peptidyl arginine deiminase (PADI).
these cytokines, leading to an increase in collagenase Interestingly, in some populations, allelic varia-
production and a decrease in matrix protein synthesis. tions in the genes encoding PADI have been shown
TNF-␣ also induces adhesion molecules, eg, the intra- to correlate with RA. Tests for anti-CCP (cyclic cit-
cellular adhesion molecule 1 (ICAM-1), which may in rullinated peptide) antibodies are as sensitive as RF
turn affect the homing and trafficking of inflammatory for the diagnosis of RA and are more specific. Simi-
cells into the synovium. The “proof of concept” that larly, high titers of anti-CCP antibodies define
TNF is an important mediator in the pathobiology of patients with a more aggressive disease phenotype.

2. Epidemiology 3. Clinical Features
RA occurs worldwide in virtually all ethnic groups, RA is characterized by symmetrical synovitis

with a prevalence estimated between 0.5% and 1%. involving multiple diarthrodial joints as well as
Notable exceptions include a prevalence of 5% or extra-articular features. Recent investigations have
more in certain North American indigenous popula- clarified the severe effects that RA can have on a per-
tions (eg, the Yakima and Pima tribes) and a very low son’s function and mortality. Epidemiologic and
prevalence in sub-Saharan Africa. It is significantly genetic studies have identified specific markers that
more common in females than in males (about 3:1 correlate with disease severity and prognosis. With
female: male ratio). Recently, an inception cohort the more widespread use of aggressive therapeutic
study in Rochester, Minnesota established the annual regimens, including accelerated doses of methotrex-
incidence rate at 75.3 per 100,000 with a point preva- ate, combination DMARD therapy, new DMARDs
lence of ~1%. There are some interesting epidemio- such as leflunomide, and the use of new biologic
logic trends from the Finnish Health Care system that response modifiers (etanercept, infliximab, adali-
suggest that over recent years the overall prevalence mumab, and anakinra, abatacept and rituximab),
of RA may be dropping and that it also may be occur- some of the manifestations of RA appear to be
ring later in life. changing. For example, it has been suggested that
features classically associated with very aggressive
Mortality rates of a cohort of 75 patients with RA fol- disease, such as rheumatoid vasculitis, are less com-
lowed over 15 years in a university hospital outpatient monly observed currently.
clinic have been reported to be 1.5- to 2-fold higher
than those of the United States population matched for In 1987, the criteria for the classification of RA were
age and gender. Similarly, an analysis of the Mayo revised by a committee of the American College of
Clinic and surrounding area population revealed that Rheumatology (ACR). These diagnostic criteria
although the life expectancy had increased in the gen- were not intended to establish a diagnosis clinically.
eral population from 1955 to the present, it had not Rather, they were designed to define homogeneous
changed for those patients with RA. Death most often cohorts of patients for clinical research (Table 1).
results from infection, heart disease, respiratory fail- Likewise, in 1991 the Steinbrocker criteria for the
ure, renal failure, or gastrointestinal disease rather classification of functional capacity in RA were
than from joint disease itself. Specifically, accelerated revised by another committee of the ACR (Table 2).
atherosclerotic disease may afflict RA patients. These criteria were designed to define the level of
Whether this is due to an inflammatory pathobiology clinical disability in RA patients, which is rapidly
or to exposure to antirheumatic drugs (ie, glucocorti- becoming an important clinical endpoint and stratifi-
coids) or both is unclear. A recent cohort study found cation variable in RA drug trials.
that greater number of involved joints, decreased
functional status, presence of comorbid cardiovascu- Clinical Presentation
lar disease, older age, and fewer years of formal edu-
cation were all significant predictors of mortality in Most patients with RA note a gradual onset of joint
RA. Five-year survival of those patients with the inflammation over weeks to months; however, 10%-
poorest functional status was 40%-60%, which is 20% may develop the classic joint stiffness, pain,
comparable to that of patients with three-vessel coro- and swelling of RA acutely. Some patients have a
nary artery disease or stage IV Hodgkin’s disease. waxing and waning course sometimes referred to as
Notably, it seems that effective therapies may have a “palindromic rheumatism”; it may be several years
positive effect on this trend, and it has been shown that before the chronic, persistent features of RA become
treatment with methotrexate and TNF-inhibitors may evident. Systemic symptoms, such as malaise,
positively impact survival among RA patients. fatigue, and weakness often accompany the signs
and symptoms of joint inflammation.
Based on cross-sectional studies of patients with RA,

elderly-onset RA with onset at age 60 years or older
has been considered to be a clinical entity distinct
from younger-onset RA. However, the evidence from

Table 1
1987 American College of Rheumatology Criteria for

the Classification of Rheumatoid Arthritis*
1. Morning stiffness in and around the joints lasting at least 1 hour before maximal improvement
2. At least 3 joint areas simultaneously have had soft tissue swelling or fluid (not bony overgrowth alone)
observed by a physician. The 14 possible areas are: right or left PIP, MCP, wrist, elbow, knee, ankle,
and MTP joints
3. At least 1 area swollen (as defined above) in a wrist, MCP, or PIP joint
4. Simultaneous involvement of the same joint areas (as defined in 2) on both sides of the body
(bilateral involvement of PlPs, MCPs, or MTPs is acceptable without absolute symmetry)
5. Subcutaneous nodules over bony prominences, extensor surfaces, or in juxta-articular regions,

observed by a physician
6. Demonstration of abnormal amounts of serum rheumatoid factor by any method for which the result
has been positive in less than 5% of normal control subjects
7. Radiographic changes typical of rheumatoid arthritis on posteroanterior hand and wrist radiographs,
which must include erosions or unequivocal bony decalcification localized in or most marked adjacent
to the involved joints (osteoarthritis changes alone do not qualify)
* For the diagnosis of RA, 4 of the 7 criteria are required.

MCP = metacarpophalangeal; MTP = metatarsophalangeal; PIP = proximal interphalangeal
Table 2
1991 American College of Rheumatology Revised Criteria

for Classification of Functional Status in Rheumatoid Arthritis*
Class I Completely able to perform usual activities of daily living (self-care,

vocational, and avocational)
Class II Able to perform usual self-care and vocational activities, but limited in
avocational activities
Class III Able to perform usual self-care activities, but limited in vocational and
avocational activities
Class IV Limited in ability to perform usual self-care, vocational, and avocational activities
* Usual self-care activities include dressing, feeding, bathing, grooming, and toileting. Avocational (recreational and/or
leisure) and vocational (work, school, homemaking) activities are patient-desired and age- and sex-specific.

observational studies has been conflicting. The clini- develop erosive damage even after 8 years or more of
cal presentation of elderly-onset RA may be similar to follow-up. Most studies involving an inception cohort
that of polymyalgia rheumatica, with an abrupt onset of patients suggest an overall, relatively linear rate of
of shoulder and hip joint inflammation. Other studies joint damage progression. The development of ero-
have found the anatomic distribution of joint inflam- sions correlates with the persistence of inflammation,
mation in patients with elderly-onset RA to be similar as evidenced by clinical measures of morning stiff-
to that of patients with younger-onset RA. Rheuma- ness, synovial swelling, and elevation of erythrocyte
toid nodules and serum rheumatoid factor have been sedimentation rate and other acute phase reactants.
observed less often in patients with elderly-onset RA Magnetic resonance imaging (MRI) visualizes and
than in those with younger-onset RA. Some authori- quantifies tissue or “synovial load” and also detects
ties believe that elderly-onset RA usually follows a early invasion of pannus into hyaline cartilage and
relatively benign course and generally responds well sub-chondral bone. There is also increasing interest in
to treatment. However, a recent study of consecutive the use of ultrasonography, which can visualize bony
patients who presented to a university hospital erosions, joint fluid, and synovial hypertrophy.
rheumatology clinic found few significant differences
between elderly-onset RA and younger-onset RA at A syndrome of “pseudo-thrombophlebitis” can be
the time of disease onset. seen in RA patients with active synovitis of the knee.
Typically, a swollen, warm, tender calf causes prob-
Joint Manifestations lems with weight bearing, and the physical examina-
tion findings clearly mimic that of deep venous
Morning gel describes a peculiar stiffness that is pro- thrombophlebitis. The cause is typically a large,
nounced in the morning or after periods of inactivity. draining popliteal cyst, and for this reason, noninva-
It plagues most patients with active inflammatory sive lower extremity studies of the deep venous sys-
arthritis, including those with RA. Its duration and tem are typically negative.
quality oftentimes provide the clues to early diagno-
sis of an inflammatory arthropathy. The clinical hall- The cervical spine is a common site of involvement in
mark of RA is a symmetrical polyarthritis involving RA. In autopsy studies, up to 50% of patients with RA
the proximal interphalangeal joints (PIPs), metacar- show some cervical spine involvement. There is a
pophalangeal joints (MCPs), wrists, elbows, shoul- direct relationship between cervical spine disease and
ders, hips, knees, ankles, and metatarsophalangeal the presence of erosive peripheral joint disease. Prolif-
joints (MTPs). Although fully expressed RA may erative synovitis can damage the ligaments and articu-
involve multiple joints, it normally begins in one or a lar cartilage of the cervical spine, causing several
few joints and typically evolves in an additive fash- types of cervical spine instability. These include: 1)
ion. The hands and wrists are affected in approxi- atlantoaxial subluxation in 50%-70% of patients; 2)
mately 90% of RA patients, and these joints may subaxial subluxation in 20%-25% of patients; and 3)
show unique changes over time. Early in RA, joint basilar invagination into the foramen magnum alone
tenderness and subtle swelling are observed, but or in combination with atlantoaxial subluxation in
after months to years the synovitis becomes prolifer- approximately 20% of patients. Symptoms of cervical
ative and destructive. The tissue within the joint spine involvement in RA include neck pain, occipital
becomes boggy to the touch, then typical joint defor- headache, and paresthesias in the extremities. Basilar
mities appear, including ulnar drift at the MCPs, invagination may cause symptoms of vertebrobasilar
rotatory subluxation at the wrist (ulnar styloid), and insufficiency, such as tinnitus, vertigo, visual distur-
the “swan-neck” (flexion of DIP, hyperextension of bances, and dysphagia. Spinal cord compression may
PIP) and “boutonniere” (hyperextension of DIP, cause weakness or paralysis. Assessment of the poten-
flexion of PIP) deformities. tial for neurologic injury is especially important in
patients with advanced RA requiring general anesthe-
Although over 70% of patients with RA display radio- sia because of the risk of cervical cord compression
graphic evidence of erosions adjacent to small joints during intubation. Plain lateral radiographs of the cer-
of the hands and feet within the first 2 years after diag- vical spine with gentle flexion and extension views are
nosis, about 25% of patients with early RA may not used to quantify the degree of instability.

Pleuropulmonary Manifestations rheumatoid nodules, lymphoid hyperplasia, or non-
specific cellular interstitial infiltrates have a better
Abnormalities of the pleura and lungs have been prognosis than patients with UIP.
detected by high-resolution computed tomography
(HRCT) in up to 75% of patients with RA. However, Pulmonary rheumatoid nodules may occasionally be
pleura inflammation is often asymptomatic and may visualized on routine radiographs and confused with
not be detected until chest radiographs are done for malignancy. Occasionally, these nodules may cavi-
other reasons. The prevalence of pleural effusion in tate. The unique entity of Caplan’s syndrome defines
RA is only about 5%. In some patients the pleural multiple pulmonary nodules with cavitation in coal
fluid glucose may be dramatically low compared to miners exposed to dust and other inhalants.
serum levels. Although it may present rarely before
arthritis is manifested, pleural effusion usually occurs Cardiac Manifestations
in individuals with active established RA. About one-
third of patients with RA with pleural effusions have Symptomatic cardiac involvement is rare in patients
coexisting interstitial lung disease. with RA; however, echocardiography has shown the
prevalence of asymptomatic cardiac involvement to
Interstitial pulmonary fibrosis occurs in 20%-40% of be higher than previously reported in autopsy studies.
patients with RA, more commonly in patients with In a study of patients with RA and no cardiac symp-
rheumatoid nodules and serum rheumatoid factor. It toms, there was a significantly increased prevalence
can be asymptomatic in its early stages because the of posterior pericardial effusion (57.1%), mitral valve
decreased physical activity of patients with RA may prolapse (34.3%), mitral valve thickening (22.9%),
be insufficient to induce dyspnea. The early radio- aortic root dilatation (34.3%), and aortic valve thick-
graphic changes of interstitial pulmonary fibrosis, ening (20.0%) compared to healthy persons.
consisting of ground-glass opacities predominantly in Myocarditis and endocarditis are not commonly
the lower lungs, may not be evident on conventional seen in patients with RA. Areas of focal myocarditis
plain radiographs but appear as high-attenuation are seen at autopsy but are clinically insignificant.
lesions at the periphery of the lungs on HRCT. Com- Arrhythmias secondary to involvement of the con-
pared to HRCT, pulmonary function testing, espe- duction system by myocarditis, vasculitis, or nod-
cially assessment of residual volume, is a more sensi- ules can occur but are exceedingly rare. Endocardial
tive but relatively nonspecific indicator of interstitial disease in the form of nonspecific valvulitis has been
pulmonary fibrosis in RA. Increased numbers of acti- observed in up to 70% of autopsied cases but is usu-
vated T-lymphocytes, predominantly T-helper ally asymptomatic and generally goes unrecognized
(CD4+) cells, are evident in the bronchoalveolar fluid during life. Rarely, valvular dysfunction may be
of patients with RA with interstitial pulmonary fibro- caused by rheumatoid nodules. Aortitis, most com-
sis, compared to patients with RA without lung dis- monly involving the thoracic aorta, was identified in
ease and healthy persons. Interstitial lung disease in 10 of 188 consecutive autopsied cases of patients
patients with RA may also be a complication of gold with RA and was associated with the presence of
or methotrexate therapy, and there have also been serum rheumatoid factor, subcutaneous nodules, and
anecdotal reports associated with the TNF inhibitors. rheumatoid vasculitis involving vessels other than
the aorta.
Because transbronchial biopsies do not provide
enough tissue for reliable diagnosis, the pattern of Felty’s Syndrome and
lung disease in patients with RA for whom treatment Pseudo-Felty’s Syndrome
for pulmonary symptoms is being contemplated is
best determined by open-lung biopsy. Various histo- Felty’s syndrome, which was reported in previous
logic patterns have been described, including pul- years in as many as 1% of patients with RA, was
monary rheumatoid nodules, usual interstitial pneu- originally described as the association of RA with
monitis (UIP), bronchiolitis obliterans with patchy leukopenia and splenomegaly. It was frequently
organizing pneumonia (BOOP), lymphoid hyperpla- associated with the presence of rheumatoid nodules,
sia, and cellular interstitial infiltrates. Patients with Sjögren’s disease, and other extra-articular manifes-

tations. Felty’s syndrome typically occurred in older Rheumatoid Nodules
patients with advanced erosive RA of at least 10 to
20 years’ duration. Almost all Caucasian patients Rheumatoid nodules occur in approximately 15% to
with Felty’s syndrome were positive for HLA-DR4. 40% of patients with RA and are associated with the
Serum rheumatoid factor is almost always present, presence of serum rheumatoid factor, erosive joint
usually in high titer, and antinuclear antibodies destruction, necrotizing vasculitis, and other extra-
(most commonly antihistone antibodies) are present articular manifestations of RA. They usually occur in
in 47%-100% of patients with Felty’s syndrome. The areas that are repeatedly subjected to friction or pres-
prevalence of Felty’s syndrome and some other sure, such as the extensor surface of the forearm or
severe extra-articular manifestations of RA appear the Achilles tendon; however, nodules may also
to be decreasing over recent years, possibly in con- develop in viscera such as the heart and lungs. Histo-
junction with the more common use of highly effec- logically, rheumatoid nodules contain a central area
tive treatment regimens. of necrosis encircled by palisading histiocytes,
which are surrounded by granulomatous tissue infil-
Large granular lymphocytes (LGLs) normally com- trated with lymphocytes.
prise 10%-15% of circulating peripheral blood
mononuclear cells. These LGLs contain azurophilic Patients receiving low-dose methotrexate therapy for
granules scattered in the cytoplasm and can be divided RA may develop accelerated rheumatoid nodule for-
into two subgroups: natural killer cells (CD3-, mation despite good control of joint inflammation.
CD16+, CD56+) and CD3+ LGLs (CD3+, CD16+, These nodules are usually smaller than 5 mm and are
CD56+), which are a subpopulation of T-cells. Both located on the fingers, although they may be present
subgroups of LGL are capable of non-MHC-restricted at other sites.
cytotoxicity and can secrete a variety of cytokines.
Patients with clonal or polyclonal proliferations of Malignancy
LGL, more commonly of CD3+ LGL, are considered
to have a form of chronic lymphoproliferative disease The overall incidence of cancer in patients with RA is
called the large granular lymphocyte syndrome. not increased; however, patients with RA have an
Many of these patients’ cells display restricted T- increased risk of developing lymphomas and lung
cell–receptor gene rearrangements, but a specific cancer, and a decreased risk for developing cancers of
common pattern of variable (V), diversity (D), and the colon, rectum, and stomach. The low risk of col-
joining (J) region T-cell receptor b-chain gene usage is orectal cancer among RA patients may be related to
not observed when different patients are compared. their common use of nonsteroidal anti-inflammatory
drugs (NSAIDs).
RA is the disease most frequently associated with the
LGL syndrome (up to 39% of patients). Patients with Patients receiving methotrexate therapy for RA have
the LGL syndrome and RA exhibit idiopathic neu- developed non-Hodgkin’s lymphoma, which may
tropenia and splenomegaly, a condition called pseudo- regress with the discontinuation of methotrexate
Felty’s syndrome. Because of an increased number of therapy, as occurs with lymphomas in patients
LGLs, the total leukocyte count may be normal in receiving immunosuppressive drugs after organ
patients with pseudo-Felty’s syndrome. Similar to transplantation. These reversible lymphomas are
patients with Felty’s syndrome, patients with pseudo- usually diffuse, large-cell lymphomas of B-cell lin-
Felty’s syndrome have serum rheumatoid factor and eage. Epstein-Barr virus genome and latent mem-
other autoantibodies and are susceptible to frequent brane protein have been detected in lymphomas of
infections. However, extra-articular manifestations patients with RA who were treated with methotrex-
and severe erosive arthritis are less common among ate alone or with cyclosporin A, suggesting that
patients with pseudo-Felty’s syndrome. immunosuppression may have contributed to the
development of these lymphoid neoplasms.
Recently, there has been some concern as to whether
patients treated with TNF inhibitors may be at
greater risk of developing lymphomas, particularly

4. Prognosis
non-Hodgkin’s lymphoma (NHL). Analysis of any The clinical expression of RA is usually established in
increased risk attributable to therapy is compounded the first 2 years, although the disability measures
by the fact that patients with severe RA are at greater almost always get worse with time. As mentioned pre-
risk of developing NHL than the general population, viously, mortality studies suggest that patients with
and the risk correlates with the severity and activity severe RA die at an accelerated rate due to infection,
of disease. Of note, this has been the subset of RA cardiopulmonary disease, and gastrointestinal bleed-
patients for whom TNF inhibitor therapy has been ing. Results from a recent observational study suggest
most widely utilized. At present, it seems that much that patients who are unresponsive to methotrexate
of the increased risk observed among patients treated may have a significantly higher mortality risk com-
with TNF inhibitors relates to the activity and sever- pared to those patients who do respond to methotrex-
ity of RA, but this bears close observation. ate. The presence of serum rheumatoid factor in
patients appears to best predict the subsequent devel-
opment of RA for patients presenting with undifferen-
tiated polyarthritis. Patients who have elevated titers
of serum rheumatoid factor and anti-CCP antibodies
early in the course of disease more often develop ero-
sive joint disease than patients who are seronegative.
High titers of rheumatoid factor are also associated
with the appearance of extra-articular manifestations.
Likewise, RA patients who have the HLA-DR4 hap-
lotype usually have a poorer clinical outcome.
Most patients with RA have a slowly progressive

course characterized by exacerbations and improve-
ments. Long-term studies have shown that fewer than
10% of patients with RA ever go into a prolonged
remission. Greater number of tender or swollen joints
at disease onset has been correlated with increased
disease activity and joint erosion. Lower socioeco-
nomic status and fewer years of formal education,
which is a component of or a surrogate marker for
lower socioeconomic status, have been associated
with higher morbidity and mortality in RA.
Defining markers of a bad prognosis early on in RA

facilitates therapeutic decision-making. Histori-
cally, second-line therapy was reserved for severe
refractory patients who had unremitting disease for
years. With recent evidence suggesting that erosions
appear early, there is a new emphasis on treating RA
patients earlier with second-line agents. Bad prog-
nostic features include: RF and anti-CCP seroposi-
tivity; evaluated markers of inflammation (ESR and
CRP); rheumatoid nodules; extra-articular features;
larger numbers of active joints; early functional
impairment; and early appearance of erosions.
These features should trigger the instinct to treat
more aggressively. However, as always, the patient
must be educated about the risks and benefits of
such approaches and participate actively in the deci-

5. Therapy
sion-making. Also, the above associations, while Background

certainly true for large groups of patients, may not
be applicable for a single patient: The exceptions RA is a chronic progressive disease, punctuated by
can prove the rule. periods of exacerbation and remission. Over 5 to 10
years, this “saw tooth” natural history leads to struc-
tural joint damage and deteriorating musculoskeletal
function. One subset of RA patients progress early
and inexorably to functional disability and total joint
replacement despite aggressive treatment. On the
other end of the clinical spectrum, some individuals
have mild RA with long periods of inactivity, a pauci-
articular disease expression, or a short course of active
arthritis followed by total remission. Although those
remitting patients have clinical findings that satisfy
published criteria for the diagnosis of RA during peri-
ods of active disease, many experts believe that they
may in fact not have RA but some other reactive,
inflammatory, self-limited arthropathy. Complicating
this clinical heterogeneity is a lack of simple surrogate
markers that indisputably predict long-term outcome
in every single patient; therefore, in practice, cus-
tomizing therapy by risk and benefit is difficult.
The history of anti-inflammatory drug development

dates to the early part of the 20th century, when bed
rest, painkillers, salicylates, and homeopathic reme-
dies were standard practice. In the late 1940s and early
1950s, corticosteroids were discovered. When admin-
istered to patients with RA, the dramatic improve-
ments they induced caused them to be considered
“miracle drugs.” Soon thereafter, appreciation of the
adverse effects related to their use tempered enthusi-
asm. Other than acetylsalicylic acid (aspirin), the first
of many NSAIDs, phenylbutazone, was developed
and also proved to be effective for patients with arthri-
tis. Interestingly, it was during this same time that
aminopterin, the parent compound of methotrexate,
was initially identified and administered successfully
to patients with RA. Soon thereafter, gold salts were
proven to be effective in the first prototype of a well-
designed trial of a disease-modifying antirheumatic
drug (DMARDs). Most recently, biologic drugs
specifically targeted to components of the immune
system have been introduced into the clinic.

Table 3
Clinical Evaluation of Rheumatoid Arthritis
Classification of Disease Activity
Slowly Progressive Aggressive
Swollen joints Few Many
ESR or CRP Normal or modestly elevated Markedly elevated
Radiographic erosions Absent May be present
Rheumatoid nodules Absent May be present
Extra-articular manifestations Absent May be present
Rheumatoid factor or anti-CCP Normal or modestly elevated Markedly elevated
Functional status Preserved Impaired
CRP = C-reactive protein; ESR = erythrocyte sedimentation rate.

Reprinted with permission from Lipsky, PE. Algorithms for the Diagnosis and Management of Musculoskeletal Complaints.
Dallas, Tex: The University of Texas Southwestern Medical Center at Dallas; 1996.
General Approach to Treatment Before 1989, when the early and widespread use of
methotrexate became commonplace, the treatment
Although RA treatment approaches are highly indi- pyramid of RA was popularized. During this period,
vidualized, according to practitioner experience and overly aggressive treatment with corticosteroids and
patient preference, several trends deserve mention. other second-line drugs was eschewed because of the
Controlling pain is a critical objective, but RA with concern for toxicity and because the disease was
active inflammation needs to be differentiated from regarded as nonfatal and only modestly disabling. Ini-
the mechanical pain that can arise with joint defor- tial drug therapy included months to years of high-
mity, because management strategies will differ. dose salicylates or NSAIDs superimposed on a broad
Specifically, pain from end-stage mechanical joint base of patient education, rest, modest exercise, and
problems may not necessarily require the use of the use of assistive devices. Only with the widespread
potentially toxic immunosuppressive drugs. The appearance of erosions on radiographs would second-
level of intensity of the therapeutic approach needs to line drugs be prescribed. During the 1980s, mean dis-
be developed with the cooperation of the patient. ease duration for many second-line drug trials was in
Treatment algorithms should always be used as a the 5- to 7-year range.
guideline to be modified by the actual clinical cir-
cumstances—not as a rigid treatment protocol. The Traditional Treatment Pyramid
critical step in determining treatment guidelines
involves differentiating slowly progressive from Prior to 1990, standard rheumatologic practice
aggressive disease as outlined in Table 3. involved a step-wise, conservative approach in the
early phases of the disease termed the RA treatment
pyramid. For the purpose of future discussion of RA

treatment algorithms, this pyramid will be described its negative aura as a cancer chemotherapy agent and
here. The driving philosophy was that more toxic, but randomized, controlled trials showed impressive effi-
perhaps more effective, drugs would only be used cacy. As observational studies suggested, due to con-
after a prolonged period of persistent inflammation, tinued long-term effectiveness and an acceptable toxi-
often after patients had developed erosive disease. At city profile in the real world of rheumatology practice,
the base of the pyramid lay the broad platform of methotrexate became the gold standard treatment for
physical medicine modalities, pain management, patients with moderate RA. Third, long-term epi-
patient education, and “watchful waiting.” The next demiologic studies now suggest that the conservative,
level involved prescribing salicylates and non- step-wise pyramid treatment approach leaves many
steroidal anti-inflammatory drugs (NSAIDs) to patients with smoldering disease for long periods of
reduce pain and suffering while optimizing exercise time, resulting in poor long-term functional outcome.
and physical therapy approaches and awaiting (hope- In addition, several studies have documented initia-
fully) spontaneous disease remission. After a period tion and significant progression of structural damage
of unremitting disease (often lasting for years) fol- early in the course of RA. Specifically, imaging tech-
lowed by structural damage, the disease modifying niques (especially MRI) have identified the presence
antirheumatic drugs (DMARDs) might be added as of early erosions and marrow effects of pannus in the
the third tier of the pyramid. The rationale for the absence of radiographic abnormalities, suggesting
delay here was that DMARDs (including intramuscu- that irreversible damage may occur long before tradi-
lar gold, methotrexate, and immunosuppressive tional outcome parameters are able to detect it. Fourth,
drugs) were only worth the risk of adverse events in several simple prognostic clinical measures have been
patients with chronic, progressive disease who were at linked to poor outcome. These include: 1) persistent
risk of joint destruction. For the unfortunate patient joint inflammation or multiple affected joints; 2) ele-
who did not respond to these modalities, the fourth vated titers of rheumatoid factor or anti-CCP antibod-
level of treatment would include experimental thera- ies; 3) radiographic erosions; 4) extra-articular fea-
pies (usually under scientific protocol). Finally, gluco- tures; and 5) early functional impairment. Finally and
corticoids (both systemic and intra-articular) could be most importantly, the advances in molecular and
used at all levels of the treatment pyramid for patients genetic medicine have elucidated a new understand-
at the early, middle, or later stages of disease. ing of RA pathogenesis that has now reached clinical
practice. In the last decade, 6 new biologic therapies
Early Aggressive Therapy that have revolutionized the RA treatment scheme
have been approved by regulatory authorities and
Because patients treated by the pyramid approach fre- introduced into the clinic. These include: the p75-sol-
quently suffered through years of smoldering disease, uble TNF-␣ receptor-Ig Fc piece fusion protein (etan-
a more aggressive approach has been embraced ercept); a chimeric monoclonal antibody to TNF-␣
recently. Although the rationale for this aggressive ligand (infliximab); a human anti-TNF-␣ antibody
treatment paradigm is being presently debated, (adalimumab); an interleukin-1 receptor antagonist
emerging practice patterns suggest that rheumatolo- (anakinra), an inhibitor of T-cell costimulation
gists are adopting this approach. Several events have (CTLA-4Ig; abatacept); and a chimeric monoclonal
forced a reevaluation of the traditional treatment pyra- antibody to the B-cell molecule CD20.
mid. First, the toxicities (especially gastrointestinal
and renal) of the traditional NSAIDs and salicylates These recent trends in rheumatology practice have
are now more apparent. Large databases of patients driven the concept of “inversion of the pyramid,” ie,
with RA and other musculoskeletal diseases suggest DMARDs and the newer drugs are instituted early in
an excessive rate of gastroduodenal ulcers, GI perfo- disease and in novel combinations in RA patients hav-
ration, or GI bleeding in individuals exposed chroni- ing poor prognostic features. Concomitantly, the use
cally to these drugs. So, the notion that these agents of NSAIDs would be used for “breakthrough” pain,
(used early and often in RA patients) have a “benign” general palliation, or perhaps not at all (if pain is well
toxicity profile is under increased scrutiny. Second, managed). NSAID drug holidays, therefore, are more
newer, more effective DMARD drugs are used earlier frequent, and hopefully, GI toxicity will be mini-
in patients with RA. Specifically, methotrexate shed mized. Likewise, COX-2 specific inhibitors, which

Figure 1
Medical management of rheumatoid arthritis
Diagnosis
Initial Evaluation
Slowly Progressive Aggressive

Disease Disease
Initiate NSAIDs · Initiate NSAIDs

· Strongly Consider
- Oral Corticosteroids
Outcome Assessment - Methotrexate
Acceptable · Continued
Outcome Assessment
Response Disease Activity
· Unacceptable
Toxicity
Acceptable · Continued Disease Therapy
Response · Progressive Disability
Continue · Progressive Joint Damage
Consider: · Unacceptable Toxicity
Therapy
· Another NSAID
· Low Dose Oral
Corticosteroids Continue
· Intra-articular Corticosteroids Therapy
Reevaluate: · Hydroxychloroquine
· Control Disease Activity Consider:
· Functional Capacity · Altered Dosage of
· Joint Damage Methotrexate
· Drug Toxicity · Intra-articular Corticosteroids
· Another DMARD
· Combination DMARDs
· Biologic Agent
· Immunosuppressive agent
· Investigational Agent
· Continued Disease Activity
Outcome Consider
· Progressive Disability
Assessment Methotrexate
· Progressive Joint Damage
show an improved safety profile, are now widely Specific Therapeutic Approaches
used. It has been theorized that this new approach
would both maximize benefit and minimize toxicity. Most rheumatologists agree that the judicious use of
Recent observations involving drug retention rate in NSAIDs or COX-2 specific drugs are still the useful
rheumatology practice suggests that this practice pat- adjuncts, particularly during the early stages of active
tern is finding its way into clinics. Based on published RA for both slowly progressive and aggressive dis-
evidence, the medical management of RA is schema- ease. Full doses should be used and careful follow-up
tized in Figure 1. Critical to therapeutic success is arranged so that second-line drugs can be prescribed
constant vigilance and systematic follow-up to evalu- when appropriate. Full doses of aspirin are accept-
ate effectiveness and toxicity. In this scheme, able but infrequently used because of poor patient
methotrexate is central. The newer drugs, anti-TNF compliance and significant long-term tolerability
agents, and other biologic agents may eventually be problems. Chronic NSAID use in RA has never been
used in a different niche as post-marketing surveil- shown to retard radiographic progression, and in
lance information becomes available. addition, NSAIDs may cause gastropathic side
effects in high-risk patients. These drugs do, how-
ever, partially reduce the pain and suffering that are
the hallmark of the disease.

Table 4
Rheumatoid Arthritis: Medical Management of Rheumatoid Arthritis with

Disease-Modifying Antirheumatic Drugs
Slowly Progressive Disease Aggressive Disease
Consider in NSAID-nonresponsive patients Consider early in course of disease
Hydroxychloroquine Methotrexate, leflunomide
Sulfasalazine* Intramuscular gold (rarely used now)
Minocycline* Hydroxychloroquine
Sulfasalazine*
For patients refractory to the above, consider:
Etanercept, infliximab, or adalimumab
Combinations of DMARDs*
Cyclosporine*
Anakinra
For patients refractory to TNF inhibitors, consider:
Abatacept
Rituximab
* Not approved by the FDA for use in rheumatoid arthritis.

DMARD = disease-modifying antirheumatic drug; NSAID = nonsteroidal anti-inflammatory drug.
Reprinted with permission from Lipsky, PE. Algorithms for the Diagnosis and Management of Musculoskeletal Complaints.
Dallas, Tex: The University of Texas Southwestern Medical Center at Dallas; 1996.
If erosions appear early or if the disease shows disease as “bridge therapy” and then tapered as the
aggressive features that are unabated despite NSAID disease comes under control with drug treatment.
use, then a decision to use a single second-line drug The early use of low-dose corticosteroids was shown
should be made within 3 months or less (Table 4). to retard radiographic progression; however, no
Thus careful follow-up is crucial. Consideration long-term effect was observed on other key clinical
should be given to use hydroxychloroquine or sul- parameters such as functional status, and the long-
fasalazine if the disease is slowly progressive. On term sequelae are still of concern. In most practices
the other hand, if aggressive clinical features are in the United States, certain older DMARDs have
obvious (erosions, sustained disease activity with become uncommon. Thus, because of adverse
multiple joint involvement, or extra-articular fea- effects related to their use, the introduction of newer
tures), then methotrexate alone or perhaps in combi- agents and other factors, rheumatologists infre-
nation with hydroxychloroquine or sulfasalazine quently use parenteral gold, oral gold, azathioprine
might be a favored approach. Prednisone or equiva- and D-penicillamine.
lent is typically used during periods of very active

The biggest change in RA treatment in the last 5 years patients did achieve low disease activity on 2 succes-
involves the use of multiple second-line agents concur- sive visits, treatment was tapered (to a minimum of
rently. Until recently this approach had been consid- MTX 10 mg/week over the first 2 years, and off all
ered overly aggressive and highly toxic. However, sev- therapy after the second year). Data from the 1 year
eral well-designed, randomized, controlled trials of and 2 years of follow-up showed that patients in
combination chemotherapy have shown improved groups 3 and 4 achieved low disease activity and even
outcomes. Almost all effective combination regimens remission quicker than did those in groups 1 and 2,
use methotrexate as the cornerstone. Combinations of although as might have been expected given the study
methotrexate plus sulfasalazine and hydroxychloro- design with its mandatory changes in therapies, clini-
quine (or leflunomide, or cyclosporine) have all cal efficacy was comparable across all groups by 2
proven more efficacious than monotherapy. Most years. However, the progression of joint damage mea-
importantly, adverse effects with the combination sured radiographically was less in groups 3 and 4
approaches were comparable to those of monotherapy. through the first 2 years of the study. Preliminary
The new TNF-␣ inhibitors have profound rapid effects assessment at year 3 has suggested that a substantial
on the clinical signs and symptoms of RA as well as on number of patients can have their therapy tapered or
mood and constitutional symptoms. In addition, they even discontinued while maintaining low levels of dis-
also retard structural damage and improve quality of ease activity. This suggests that early aggressive ther-
life. While there has been a marked trend towards apy may be able to change the course of RA.
increasing use of these agents, eg, patients with earlier
stages of disease, their ultimate practice niche is still Surgery
evolving. At present, etanercept, infliximab, and adali-
mumab are most widely used for patients who fail to Appropriately timed reconstructive orthopedic
respond to methotrexate or who cannot take it because surgery is an invaluable treatment strategy for selected
of comorbid diseases. Interestingly, recent data sug- patients with RA. Generally, surgery is most effective
gests that patients failing one TNF inhibitor, whether for patients with RA with the following conditions:
due to loss of efficacy or adverse effects, can still impending tendon rupture in the hand and wrist (ten-
achieve meaningful clinical responses when switched don repair); functional limitation due to end-stage
to another TNF inhibitor. For patients failing TNF arthritis in large or weight-bearing joints (total joint
inhibitors or perhaps for those with contraindications replacement of hip, knee, shoulder); joint instability
to their use, the new biologic agents abatacept and rit- or intractable pain with routine use (fusion of thumb,
uximab may be tried. wrist, ankle, cervical spine).
A study in early RA from the Netherlands has pro- Outcome Assessment

vided some insight as to the relative efficacy of various
treatment approaches. In this study, known as the BeSt The optimal method for measuring outcome in the
trial, 508 patients with early RA (defined as < 2 years treatment of patients with RA has always been an area
of arthritis) were randomized to one of 4 treatment of discussion. Standard outcome parameters in RA
arms: 1) sequential monotherapy (beginning with treatment trials include: tender and swollen joint
methotrexate [MTX]); 2) step-up combination therapy counts; global assessments of disease activity; assess-
(also beginning with MTX); 3) initial combination ment of pain by the patient; measurement of the acute
therapy with MTX, sulfasalazine (SSZ) and high dose phase response (eg, with the erythrocytsedimentation
prednisone (as was used in the earlier COBRA study); rate [ESR] or C-reactive protein [CRP]); assessment
and 4) initial combination therapy with MTX plus of functional status (eg, using the Health Assessment
TNF-inhibitor (infliximab). In all arms, the goal was Questionnaire [HAQ]) and assessment of joint dam-
low levels of disease activity. At their 3 monthly fol- age; quantifying periarticular erosions; and joint space
low-up visits, patients not achieving this goal, defined narrowing on radiographs.
by a disease activity score (DAS) of 2.4 or less, were
required to have their treatment altered according to an Because individual measures are inexact, a trend has
algorithm specific for each group. Eventually, groups been to use composite measures that incorporate sev-
1, 2, and 3 could end up on MTX plus TNF inhibitor. If eral aspects of disease activity, and require important

6. Specific Antirheumatic Drugs
improvements in a majority for a “response” to be NSAIDs and Salicylates

achieved. The most commonly used are the response
criteria developed by the ACR which require 20% or Mechanisms of action. Prostaglandins increase vas-
more improvement in a variety of measures (com- cular permeability and sensitivity to bradykinins,
monly called “ACR20 response”) and the disease thereby enhancing inflammation and increasing sensi-
activity score (DAS) and its modifications (eg, tivity to pain. NSAIDs inhibit the production of
DAS28). These composite indices are standard in prostaglandins of the E series, including the formation
clinical trials and are increasingly becoming more of prostacyclin and thromboxane, resulting in com-
widely used in practice. plex effects on vascular permeability and platelet
aggregation. In the inflammatory cascade, polyunsat-
This issue of quantifying outcome is important, urated fatty acids (including arachidonic acid), which
because if measures are insensitive to change or do are constituents of all cell membranes and exist in
not describe clinically relevant conditions, then evalu- ester linkage with glycerols of phospholipids, are
ations of therapies both in practice and in rigidly converted to prostaglandins or leukotrienes through the
designed trials will be extremely difficult. It may be action of phospholipase A2 or phospholipase C. Free
that treatment in RA will follow the treatment arachidonic acid acts as a substrate for the
paradigm in oncology, such as induction of remis- prostaglandin H (PGH) synthetase complex (PGHS),
sion/maintenance and relapse/reinduction strategy. which includes both cyclooxygenase and peroxidase.
One might then envision the newer, emerging biologic These catalyze the conversion of arachidonic acid to the
therapies to be used in conjunction with established unstable cyclic-endoperoxide intermediates, PGG2 and
synthetic drugs. Emerging data suggest that this PGH2, which then are converted to the more stable
indeed may be the case. PGE2 and PGF2 compounds by specific synthetases
that exist in specific tissues. NSAIDs specifically
Because the TNF inhibitors have been shown to be inhibit cyclooxygenase activity and thereby reduce the
capable of stopping the progression of radiographic conversion of arachidonic acid to PGG2.
joint damage—a level of disease control previously
considered unachievable—this has become increas- One of the most important advances in the area of
ingly utilized. Indeed, measures of radiographic inflammation involves recent elucidation of
damage are standard in clinical trials now, and cyclooxygenase (COX) biology. Accumulated evi-
arresting such damage has become a goal in the dence now suggests that there are at least 2 related iso-
treatment of RA. forms of the cyclooxygenase enzymes. They possess
significant homology in those amino acid sequences
considered important for catalysis of arachidonic acid.
The most important differences between the two iso-
forms are in their regulation and expression of the
enzymatic activity. To date, a constitutive form has
been described, prostaglandin synthetase H1 (PGHS-
1 or COX-1), which is inhibited by all of the available
NSAIDs to varying degrees (depending on the applied
experimental model system used to measure the drug
effects). COX-1 is expressed variably in most tissues;
it has been described as a “housekeeping enzyme”
that regulates normal cellular processes and is stimu-
lated by hormones or growth factors. It is thought to
be important in maintaining the integrity of the gastric
and duodenal mucosa, and its inhibition is considered
the basic cause of many of the toxic effects of the
NSAIDs. The other isoform is an inducible, highly
regulated enzyme, prostaglandin synthetase H2
(PGHS-2 or COX-2), which is usually undetectable.

The expression of COX-2 is increased during states of have also been described. Nitric oxide synthetase,
inflammation or experimentally in response to mito- once induced by cytokines and other pro-inflamma-
genic stimuli. For example, in fibroblasts, various tory mediators, produces nitric oxide in large
growth factors, phorbol esters, and interleukin-1 amounts, leading to increased signs of inflammation
(IL-1) stimulate the expression of COX-2; in mono- such as vasocongestion, increased cytotoxicity, and
cyte–macrophage systems, endotoxin stimulates it. increased vascular permeability.
The expression of COX-2 is inhibited by glucocorti-
coids. Orally active NSAIDs and salicylates inhibit There is interesting evidence about the effects of
both isoforms of cyclo-oxygenase, thereby reducing prostaglandins on cellular function. It has recently
the synthesis of prostanoids at sites of inflammation as been described that prostaglandins inhibit apoptosis
well as the “housekeeping” arachidonate mediators in (programmed cell death) and that NSAIDs, through
renal parenchyma and gastric mucosa. inhibition of prostaglandin synthesis, reestablish the
return to a more normal cell cycle in some cell sys-
Arachidonic acid can also serve as a substrate for 5- or tems. Thus, the suggestion is that in vitro
12-lipoxygenase. These enzymes catalyze the conver- prostaglandins are important modulators of apoptosis
sion of arachidonic acid to biologically active and that NSAIDs may alter this mechanism, thus
leukotriene and hydroperoxyeicosatetraenoic acids altering cell-cycle changes.
(HETEs). Although none of the currently available
NSAIDs inhibit 5-lipoxygenase directly, several In summary, the literature is replete with reports of
NSAIDs may indirectly reduce leukotriene levels by purported biologic efforts of NSAIDs; however, the
shunting arachidonic acid back into the triglyceride role and importance of these prostaglandin- and non-
pool. Several new compounds may have inhibitory prostaglandin-mediated processes in clinical inflam-
effects on both cyclooxygenase and lipoxygenase. It mation are not entirely clear.
remains to be seen whether these effects will be bio-
logically important at the clinical level. Pharmacology. All NSAIDs are well absorbed from
the gastrointestinal tract, and because they are weakly
Data suggest that NSAIDs have other effects that may acidic, they become tightly bound to serum proteins.
be pertinent to their clinical effects; they inhibit acti- Therefore, alterations of circulating free drugs may
vation and chemotaxis of neutrophils as well as occur when NSAIDs are co-administered with other
reduce the elaboration of toxic oxygen radicals from protein-bound drugs or in patients with hypoalbu-
stimulated neutrophils. There is also evidence that minemia. In general, most NSAIDs are metabolized
several NSAIDs scavenge superoxide radicals. in the liver and by-products excreted in the urine.
NSAIDs are lipophilic, becoming incorporated in the Some NSAIDs are excreted in the bile and the urine.
lipid bilayer of cell membranes and thereby interrupt- Others have prominent enterohepatic circulation.
ing protein-protein interactions that are important for NSAIDs should be used with caution and vigilance in
signal transduction. Specific NSAIDs have been the patient with liver or renal dysfunction.
shown to inhibit proteoglycan synthesis by chondro-
cytes in vitro. There are in vitro data and a few case Plasma half-life of the NSAIDs is highly variable; this
reports to suggest that the use of some NSAIDs accel- pharmacokinetic heterogeneity reflects the wide vari-
erates cartilage damage in OA, although few investi- ability in dosing regimens. In general, the NSAIDs
gators believe the data to be compelling enough to (and COX-2 specific anti-inflammatory drugs) with
preclude the use of NSAIDs as standard therapy for the longest half-lives (eg, piroxicam, nabumetone,
OA. Some NSAIDs have been shown to affect T-lym- oxaprozin, and rofecoxib) are administered once
phocyte function experimentally. Another newly daily; others (eg, ibuprofen) have short half-lives, and
described biologic effect of NSAIDs not directly are administered 4 times per day in order to achieve a
related to prostaglandin synthesis involves the inter- biologic and clinical effect. Some NSAIDs are lipid
ference with neutrophil-endothelial cell adherence, soluble, readily penetrate the CNS, and occasionally
which is a critical step in the inflammation pathway. cause side effects like HA, mentation difficulties, and
The effects of the NSAIDs on nitric oxide metabolism mood alterations.

Table 5
Nonsteroidal Anti-Inflammatory Drugs and Dose Ranges by Chemical Classification
Daily Recommended Plasma

Chemical Category Drug (trade name) Adult Dose (mg) Half-Life (hrs)
Carboxylic acids Acetylsalicylic acid (aspirin) 1300-5000 4-15
Choline magnesium 1500-3000 4-15

Salicylate (Trilisate®)
Salsalate (Disalcid®) 1500-3000 4-15
Diflunisal (Dolobid®) 500-1500 7-15
Propionic acids Ibuprofen (Motrin®) 1600-3200 2
Naproxen (Naprosyn®) 500-1000 13
Fenoprofen (Nalfon®) 1200-3200 3
Ketoprofen (Orudis®) 150-300 2
Flurbiprofen (Ansaid®) 200-300 3-9
Oxaprozin (Daypro®) 600-1800 40-50
Acetic acids Indomethacin (Indocin®) 75-200 3-11
Tolmetin (Tolectin®) 800-1600 1
Sulindac (Clinoril®) 300-400 16
Diclofenac (Voltaren®) 100-200 1-2
Etodolac (Lodine®) 600-1200 2-4
Ketorolac (Toradol®)* 20-40 2
Fenamic acids Mefenamic acid (Ponstel®)† 500-1000 2
Meclofenamic acid (Meclomen®) 200-400 2-3
Enolic acids Roxicam (Feldene®) 10-20 30-86
Naphthylkanones Nabumetone (Relafen®) 500-1000 19-30
COX 2 inhibitors Celecoxib (Celebrex®) 200-400
Rofecoxib (Vioxx®) 12.5-25

Valdecoxib (Bextra®) 10-20
* Used for management of acute pain (not recommended for use for more than 21 days).
† Used for management of pain or dysmenorrhea (not recommended for more than 7 days).

Clinical use. Overall, the magnitude of therapeutic Two strategies presently exist to prevent GI ulcera-
effects of NSAIDs is similar when studied in population. The first involves the concomitant use of miso-
tions of arthritis patients in clinical trials. However, prostol, a methylated, orally-active prostanoid. Ran-
wide variability in response to particular NSAIDs has domized controlled trials and large post-marketing,
been observed in individual patients. These drugs do population-based outcomes studies have proven that
not appear to retard the development or progression of misoprostol reduces the risk of serious GI complica-
chondral erosions. However, NSAIDs do offer pallia- tions including perforation, ulcers, and bleeding by up
tion with respect to pain and suffering, as attested to to 50%. However misoprostol at high doses itself pro-
by the “flare” phenomena frequently observed in clin- duces annoying GI side effects including abdominal
ical trials when these drugs are withdrawn from pain and diarrhea. Recently, a combination of
patients with active RA. Despite the recent philosoph- diclofenac (an NSAID) and misoprostol (in daily
ical change regarding the traditional treatment pyra- doses lower than label suggestion) reduced the fre-
mid, NSAIDs are routinely used in RA patients to quency of NSAID-induced ulcers by 60%-80%, while
reduce the symptoms of pain. Most practitioners now showing significant symptomatic efficacy. The sec-
recognize that they are purely soothing for muscu- ond strategy builds upon the elucidation of the 2 sepa-
loskeletal symptoms, but do not provide a “disease- rate isoforms of cyclo-oxygenase, COX-1 and COX-
modifying” biologic effect, and have significant atten- 2. Specific inhibitors of COX-2, the isoform induced
dant toxicity. Thus, there is increasing vigilance by biologic mediators of inflammation, have been
regarding their use. As a class of drug, NSAIDs, espe- developed into anti-inflammatory drugs that are selec-
cially over-the-counter NSAID preparations, are used tive, and do not inhibit COX-1, when used in physio-
routinely in primary care practice. The NSAIDs and logic doses.
typical dosages and regimens are outlined in Table 5.
Three COX-2 specific inhibitors, celecoxib, rofe-
Adverse effects. Adverse effects of traditional COX- coxib, and valdecoxib, had been approved by various
1 inhibiting NSAIDs are a major issue, especially in regulatory agencies both in the United States and
patients at high risk for toxicity. GI side effects in par- around the world. Several other COX-2 inhibitors,
ticular are a major reason for discontinuing NSAIDs. including etoricoxib and lumaricoxib, progressed
Large databases suggest a hierarchy of toxicity, with through late phases of the drug development pathway
tolmetin and indomethacin exhibiting the most toxic- and were even approved in a number of countries. In
ity and ibuprofen and nonacetylated salicylates the clinical trials and in the clinic, all the COX-3
least. Large population-based epidemiologic studies inhibitors successfully achieved their main clinical
suggest that patients exposed to NSAIDs exhibit a 3- advantage, namely the control of signs and symptoms
10 fold higher risk of GI toxicity and death than those of arthritis while reducing gastrointestinal complica-
who are not exposed. GI side effects range in severity tions typical of nonselective NSAIDs, particularly
from mild dyspepsia and flatulence to death from NSAID gastropathy. However, the use of COX-2
massive GI blood loss or visceral perforation. Com- inhibitors was dramatically altered when it was shown
plicating the surveillance issue for side effects is the that patients treated with rofecoxib experienced sig-
observation that up to 40% of patients with docu- nificant complications of atherosclerotic cardiovascu-
mented gastroduodenal erosive disease may not com- lar disease more often than patients treated with older
plain of symptoms. Although observations gleaned NSAIDs. Subsequently, rofecoxib was removed from
from randomized controlled trials may not reflect the the market worldwide, valdecoxib was withdrawn by
true natural history in large populations, endoscopic its manufacturer, and drugs in development had their
studies in short-term trials have identified gastroduo- plans put on hold. At present, celecoxib remains the
denal ulcers with a frequency of 15%-30%. Risk only COX-2 inhibitor approved for use in the US and
factors for GI adverse events in the RA population many other countries. Analysis of this area is dynamic
include age, concomitant use of NSAIDs, prior and evolving.
NSAID related side effects, and level of disability.

Glucocorticoids corticoids also produce significant metabolic effects
elsewhere. Generally speaking, they are catabolic and
Since their discovery in the late 1940s by Hench and induce breakdown of protein, diminished utilization
colleagues at the Mayo Clinic, glucocorticoids have of glucose, and alterations in lipids, thereby facilitat-
been used to treat patients with RA. Although early ing premature atherosclerosis.
observations suggested that these compounds exhib-
ited profound clinical effects in patients with RA, the Pharmacology. Glucocorticoids are well-absorbed
long-term adverse event profile severely limited the from the gastrointestinal tract. Once absorbed, the
widespread and prolonged usage of these drugs. drug binds to corticosteroid binding globulin (CBG)
Because of the disastrous side effects observed in the and albumin. Glucocorticoids are metabolized largely
early 1950s, some academic centers and private by the liver, where they are hydroxylated, conjugated,
rheumatologists avoided the use of these drugs for any and then excreted in the urine. Prednisone is an inac-
patient with RA. What followed was a profound tive steroid, but once absorbed it is converted in the
antipathy on the part of rheumatologists to use gluco- liver to prednisolone. The half-life and biologic
corticoids for nonfatal inflammatory diseases. Gradu- effects of various glucocorticoid preparations are
ally, these agents were accepted as short- or intermedi- highly variable. Differences in plasma half-life and
ate-term “bridge therapy” for active RA while await- other factors contribute to significant differences in
ing disease amelioration by second-line agents. In clinical potency. Most practitioners divide glucocorti-
addition, several studies have now shown that treat- coids into 3 groups according to their duration of
ment with corticosteroids can slow the progression of action. Short-acting glucocorticoids (8-12 hours)
radiographic joint damage in RA. include cortisol and cortisone; intermediate-acting
glucocorticoids (12-36 hours) include prednisone,
Since those early days, the practice pendulum has prednisolone, and methylprednisolone; and finally,
swung back, and glucocorticoids are now routinely long-acting glucocorticoids (36-72 hours) include
but cautiously prescribed for patients with active RA. dexamethasone.
Mechanism of action. The mode of action of gluco- Clinical use. Low dosages of glucocorticoids co-
corticoids is complex. They bind specifically to a administered with NSAIDs and DMARDs are used
cytoplasmic receptor, which belongs to a super family routinely as “bridge therapy” for some patients with
of regulatory proteins (including the estrogen and very active RA. In that setting, the plan is to first
vitamin D receptors). The glucocorticoid-receptor quickly extinguish the signs and symptoms of the
complex migrates to the nucleus and then affects gene “flare” phenomena, but then to always taper gluco-
transcription. Glucocorticoids have profound and pro- corticoid treatment once the DMARD takes effect. In
tean anti-inflammatory effects caused by the suppres- some patients with chronic progressive disease, long-
sion of immunomodulating proteins, including IL-1, term low-dose glucocorticoid treatment is required to
IL-6, TNF-␣, interferon-gamma, and GMCSF. In maintain the disease at a certain level of control and
addition, glucocorticoids inhibit the production and to secure a reasonable quality of life. Glucocorticoids
expression of pro-inflammatory prostaglandins and are also used intermittently over 1-2 weeks in doses
leukotrienes, inducible nitric oxide synthase, plas- tapering rapidly from 20 mg per day for patients
minogen activator, and adhesion molecules (ICAM- experiencing a “flare” of RA.
1). Glucocorticoids also modulate cellular physiology
by reducing neutrophils at sites of inflammation; New information now exists regarding the magnitude
decreasing the number and function of and durability of these effects as well as the potential
monocytes/macrophages (perhaps by affecting for retarding cartilage damage and structural deterio-
chemokine physiology); suppressing antigen present- ration of the joint. In 1995, Kirwan showed that low-
ing cells; and inhibiting the number of circulating dose glucocorticoids resulted in a reduction of pro-
lymphocytes and their functions, including the prolif- gression of a joint damage in patients with RA who
erative response to mitogens, cytokine production, were taking second-line antirheumatic drugs. One
and immunoglobulin production. In addition, gluco- hundred and twenty-eight RA patients with average
disease duration of less than 2 years were randomized

in double-blind fashion to either placebo or low-dose Table 6
prednisolone. All patients were receiving stable doses
of NSAIDs or second-line antirheumatic agents. Clin- Side Effects of Corticosteroid Therapy
ical improvement of the signs and symptoms of RA in
the prednisolone group was greater than in the
placebo group after the first year of therapy but disap- Very common, should be
peared at 2 years. However, at 2 years, the erosion considered in all patients
scores were significantly better in the prednisolone
group compared to the placebo group. Kirwan’s obser- Osteoporosis
vations were the first to define a potential “disease Increased appetite
modifying” capability of glucocorticoids. Centripetal obesity
Impaired wound healing
Building upon that evidence, a recent 2-year double- Increased risk of infection
blind randomized placebo-controlled trial was com- Suppression of hypothalamic-pituitary axis
pleted in patients with early RA who were not concur- Arrest of normal growth in children
rently exposed to second-line antirheumatic drugs.
Similar to the Kirwan study, the glucocorticoid group Frequently seen
showed more clinical improvement than the placebo
group early on in the observation period, but the dif- Myopathy
ference between the groups was insignificant at 6 and Osteonecrosis
12 months. However, radiologic outcome showed sig- Hypertension
nificant reduction in erosion and joint space narrow- Thin fragile skin, striae, purpura
ing scores in the prednisone group versus the placebo Edema
group. These observations suggest that glucocorti- Hyperlipidemia
coids may have “structure-modifying” effects despite Psychiatric symptoms, particularly euphoria
the potential for long-term toxicity. Diabetes mellitus
Posterior subcapsular cataracts
Given the recent additions to the pharmacologic
armamentarium to treat glucocorticoid-induced Uncommon, but important to recognize early
osteoporosis and glucocorticoid-associated gastroin-
testinal side effects, the concern about long-term side Glaucoma
effects has been mitigated to some extent. However, Silent intestinal perforation
given all of the other potential adverse effects of glu- Peptic ulcer disease
cocorticoids, these agents should always be used Gastric hemorrhage
judiciously. A thorough discussion of risk benefit and Hypokalemic alkalosis
appropriate concern for patient expectations should Hyperosmolar nonketotic coma
be part of the decision-making process when using
these drugs. Rare
Adverse effects. The adverse effects of glucocorti- Hirsutism

coids are legion and are noted in Table 6. For the Panniculitis
most part, these side effects are dose- and duration- Secondary amenorrhea
dependent. Of particular importance in the Impotence
rheumatic disease population are immune suppres- Epidural lipomatosis
sion, and osteoporosis. Other side effects may also
be seen in RA patients, including aggravated hyper- Modified from Behrens TW, Goodwin JS. Glucocorticoids.
In: McCarty D, Koopman W, eds. Arthritis and Allied Con-
tension, glucose intolerance, stimulation of cataract
ditions. 11th ed. Philadelphia, Pa: Lea & Febiger;
growth, difficulties with wound healing and, occa- 1989:604-21.
sionally, CNS effects ranging from mild emotional
lability to frank psychosis.

The effect of glucocorticoids on bone mineral density tonin ((intranasal and parenteral)), PTH hormone,
is probably the most vexing complication for RA estrogen replacement for women, and testosterone
patients exposed to these compounds, especially replacement for hypogonadal men), are the key
because many of these patients are post-menopausal therapeutic agents that may reduce bone mineral
women. Bone mineral density loss in these patients density loss.
can range from 4%-10% per year, and even low-dose
glucocorticoid therapy may cause significant osteo- Acetaminophen
porosis in some patients. Most of the bone loss occurs
early. Glucocorticoids cause osteoporosis via several Acetaminophen has analgesic and antipyretic proper-
mechanisms, including stimulation of osteoclastic ties. The exact mechanism of action is unknown, but it
bone resorption, reduction of calcium absorption, may have both peripheral and central actions. This
reduction in sex hormone production, and finally, a medication is well absorbed after oral administration
direct negative effect on bone formation. and may be effective within 30 to 60 minutes. The
half-life and duration of action is approximately 4
Strategies to minimize glucocorticoid-associated hours. This drug is metabolized in the liver and
osteoporosis have been developed recently and excreted in the urine. Overall, it is safe and produces
include calcium supplementation as a base with less gastrointestinal dyspepsia and bleeding than the
vitamin D. In addition, drugs that reduce osteoclas- NSAIDs. Acetaminophen is used routinely in RA
tic bone resorption, (eg, the biphosphonates, calci- patients to manage pain due to mechanical joint prob-
lems. This agent may cause hepatotoxicity in patients
Table 7
Monitoring Drug Therapy in Rheumatoid Arthritis
Recommended monitoring strategies for drug treatment of rheumatoid arthritis*
Toxicities Monitoring
Requiring Baseline System Review/
Drugs Monitoring† Evaluation Examination Laboratory
Salicylates, Gastrointestinal CBC, creatinine, Dark/black stool, CBC yearly, LFTs,

nonsteroidal anti- ulceration AST, ALT dyspepsia, nausea creatinine testing
inflammatory and bleeding or vomiting, abdominal may be required‡
drugs pain, edema,
shortness of breath
Hydroxy- Macular damage None unless patient Visual changes,

chloroquine is over age 40 or consider funduscopic
has previous eye and visual fields every
disease 12 months
Sulfasalazine Myelosuppression CBC, and AST Symptoms of CBC every 2-4

or ALT in patients myelosuppression§, weeks for first 3
at risk, consider photosensitivity, rash months, then
G6PD every 3 months
(continued on next page)

Table 7 (continued)
Monitoring Drug Therapy in Rheumatoid Arthritis
Toxicities Monitoring
Requiring Baseline System Review/
Drugs Monitoring† Evaluation Examination Laboratory
Methotrexate Myelosuppression, CBC, chest Symptoms of CBC, platelet

hepatic fibrosis, radiography myelosuppression§, count, AST
cirrhosis, pulmonary within past year, shortness of breath, albumin, creatinine
infiltrates or fibrosis hepatitis B and C nausea/vomiting, every 4-8 weeks
serology in high- lymph node swelling
risk patients, AST
or ALT, albumin,
alkaline phosphatase,
and creatinine
Leflunomide Hepatoxicity, myelosuppression, diarrhea (same as methotrexate for last 3 columns)
Gold, Myelosuppression, CBC, platelet count, Symptoms of CBC, platelet

intramuscular proteinuria creatine, urine myelosuppression§, count, urine
dipstick for protein edema, rash, oral dipstick every 1-2
ulcers, diarrhea weeks for first 20
weeks, then at the
time of each (or
every other) injection
Gold, oral Myelosuppression, CBC, platelet count, Symptoms of CBC, platelet

proteinuria urine dipstick for myelosuppression§, count, urine
protein edema, rash, diarrhea dipstick for protein
every 4-12 weeks
Corticosteroids Hypertension, BP, chemistry panel, BP at each visit, Urinalysis for

(oral <10 mg of hyperglycemia bone densitometry polyuria, polydipsia, glucose yearly
prednisone or in high-risk patients edema, shortness of
equivalent) breath, visual changes,
weight gain
*CBC = complete blood cell count (hematocrit, hemoglobin, white blood cell count) including differential cell and platelet
counts; ALT = alanine aminotransferase; AST = aspartate aminotransferase; LFTs = liver function tests; BP = blood pressure.
† Potential serious toxicities that may be detected by monitoring before they have become clinically apparent or harmful to
the patient. This list mentions toxicities that occur frequently enough to justify monitoring. Patients with comorbidity, con-
current medications, and other specific risk factors may need further studies to monitor for specific toxicity.
‡ Package insert for diclofenac (Voltaren®) recommends that AST and ALT be monitored within the first 8 weeks of treat-
ment and periodically thereafter. Monitoring of serum creatinine should be performed weekly for at least 3 weeks in
patients receiving concomitant angiotensin-converting enzyme inhibitors or diuretics.
§ Symptoms of myelosuppression include fever, symptoms of infection, easy bruisability, and bleeding.
American College of Rheumatology Ad Hoc Committee on Clinical Guidelines: Guidelines for monitoring drug therapy in
rheumatoid arthritis. Arthritis Rheum. 1996;39:723-31. Reprinted with permission of the American College of Rheumatology.

with preexisting liver dysfunction. The issue of renal trial of hydroxychloroquine showed it to be signifi-
dysfunction secondary to acetaminophen has cantly more effective than placebo in patients with
received significant attention. A case-control study early RA. Clinical effects are usually observed at 8 to
(telephone sampling method) examining 716 patients 12 weeks; starting dosage is 400 mg/d in divided
with end stage renal disease from all causes and 361 doses, with a dose reduction to 200 mg/d at 8 to 12
age-similar controls from the same geographic area weeks if a good response is observed.
suggested that an average intake of acetaminophen of
more than one pill per day and a cumulative intake of Adverse effects. Adverse events are common and
1000 or more pills in a lifetime were associated with probably dose related, thus providing some ratio-
an increased risk of end stage renal disease. This nale for the lower doses presently in use. Gastroin-
study should be interpreted with caution due to testinal intolerance with dyspepsia, diarrhea, and
potential limitations, including recall bias, confound- nausea are common; however, gastrointestinal
ing factors associated with acetaminophen use in the bleeding is not a usual sequelae of these symptoms.
cases that were not examined in the study, and the Peripheral neuropathic symptoms, myopathy, and
lack of control over accuracy of the information skin rashes (including exfoliative dermatitis) have
reported by telephone interview. The true risk of also been reported. Of most concern is the potential
acetaminophen use in the development of end stage for ocular toxicity, which includes central effects on
renal disease remains unknown. visual accommodation, corneal deposits, and
retinopathy. The latter is associated with permanent
DMARDs visual loss, but at the doses prescribed today, this
side effect is very rare in clinical practice. Symp-
Antimalarial Drugs toms include central scotomata, peripheral field
Mechanism of action and pharmacology. The anti- deficits, or frank blindness. Regular ophthalmologic
malarial drugs, chloroquine and hydroxychloroquine, examination (according to American Academy of
are 4-aminoquinolones. Quinine, a related compound, Ophthalmology Guidelines), which should include
has been used since the 1800s to treat rheumatic dis- visualization of the macula for pigmented stippling
eases. These drugs are well absorbed from the gas- as well as peripheral field testing to a red test object,
trointestinal tract; hydroxychloroquine is excreted in may define a state of premaculopathy that predicts
the feces and chloroquine in the urine. Although the the eventual irreversible changes (Table 7).
exact mechanisms of action have not been completely
elucidated, the antimalarial drugs have been shown to Sulfasalazine
inhibit the release of IL-1 by monocytes. They inhibit Sulfasalazine is 5-aminosalicylic acid linked by a
lysosomal enzyme release by stabilizing lysosomal diazo bond to the antibacterial sulfonamide, sulfapyri-
enzymes, and they retard phagocyte chemotaxis and dine. In Western Europe, it has been used since the
lymphocyte blastogenesis. They have also been 1940s for patients with RA. Because of its favorable
shown to inhibit phospholipase A2, a critical enzyme effects and relative lack of toxicity, it is now more
in the prostaglandin cascade. widely used in the United States, especially in early
mild RA.
Clinical use. Although antimalarial drugs fell out of
favor for the treatment of rheumatic diseases in the Mechanism of action. The exact mechanism of action
1950s because of the retinal toxicity that was observed of sulfasalazine is poorly understood and is compli-
with long-term and high-dose therapy, these drugs cated by the fact that the metabolites, 5-aminosalicylic
have made a comeback in recent years. Several con- acid and sulfapyridine, are also biologically active.
trolled trials have proven hydroxychloroquine to be Most compelling is the fact that the parent molecule,
effective for patients with mild SLE whose manifesta- sulfasalazine, can inhibit 5-lipoxygenase, thus reduc-
tions are primarily dermatitis and arthritis. These ing production of leukotrienes. It has also been shown
drugs are also used in early RA (usually before to inhibit lymphocyte mitogenesis and nuclear factor
methotrexate, parenteral gold, and anticytokine ther- kappa B, a transcription factor important in the genetic
apy), or in more aggressive RA as combination regulation of inflammatory pathways.
chemotherapy with methotrexate. A recent controlled

Pharmacology. Because of its insolubility, sul- by individual practitioners. Subsequently, it was sys-
fasalazine is poorly absorbed in the stomach and small tematically evaluated and proven efficacious in several
bowel. In the colon, the diazo bond is reduced by bac- large, randomized, controlled trials in the 1980s.
teria, thus liberating 5-aminosalicylic acid, most of Today, its clinical utility in the treatment of patients
which remains in the colon and is excreted in the with RA is undisputed, and it stands alone as the gold
feces. Sulfapyridine is absorbed, metabolized in the standard second-line antirheumatic drug against which
liver, and excreted in the urine. others are compared. Even the new TNF inhibitors are
typically added to methotrexate “partial responders” or
Clinical use. Sulfasalazine is widely used in after methotrexate has failed or caused toxicity.
patients with early mild RA, and most long-term
studies suggest a favorable efficacy profile. Most Mechanism of action. At the cellular level,
recently, sulfasalazine has also been shown to be methotrexate is transported across the cell membrane,
marginally effective in patients with the seronega- binds to dihydrofolate reductase, reduces intracellular
tive spondyloarthropathies, especially in those with folate pools, and inhibits purine synthesis. Intracellu-
psoriatic arthritis. It apparently has little effect on lar methotrexate is metabolized to polyglutamates,
axial spine disease. It is commonly prescribed as part which serve to amplify inhibition of dihydrofolate
of a combination chemotherapy protocol with reductase. The antimetabolic effects of methotrexate
hydroxychloroquine and methotrexate. The starting can be reversed with exogenously applied reduced
dosage is usually 500 mg twice a day, with gradual folates, such as leucovorin (folinic acid).
escalation to a total of 3 g/d in two divided doses.
In patients with RA, methotrexate may not function as
Adverse effects. Adverse effects are common but it does in cancer patients receiving antimetabolite
usually minor in magnitude or severity. Most long- chemotherapy. Indeed, its prompt clinical effects sug-
term RA studies of sulfasalazine have recorded very gest inhibition of inflammation as a possible mecha-
few serious adverse events. Previous sulfa allergy nism of action. However, methotrexate does not
precludes its use, and glucose-6-phosphate dehy- inhibit cyclooxygenase. It does inhibit IL-1 and
drogenase (G6PD) screens may be considered in leukotriene-4 (LTB4), and reduces levels of prote-
appropriate patients. Gastrointestinal intolerance, olytic enzymes. Methotrexate, by virtue of the bio-
including nausea and abdominal discomfort, are logic effects of intracellular polyglutamates, may
usually seen in the first 2 to 3 months of therapy and induce extracellular expression of adenosine, which in
may be minimized by gradually increasing the dose. turn may have an inhibitory effect upon cells that par-
Cutaneous adverse events include urticaria, pruri- ticipate in inflammation.
tus, maculopapular rash, and photosensitive erup-
tion. As with any sulfa drug, serum sickness or toxic Pharmacology. Unlike most other second-line
epidermal necrolysis rarely can be seen. Leukope- antirheumatic drugs, methotrexate’s pharmacokinetic
nia and neutropenia, which are usually clinically profile and mechanisms of action have been well stud-
insignificant, are observed in 1% to 5% of exposed ied. In low oral doses, the drug is well absorbed, with
patients; therefore, periodic hemogram screening is peak plasma levels occurring in 1 to 2 hours; at higher
suggested (Table 7). doses, however, the fraction of drug absorbed actually
decreases because of saturation of carrier-mediated
Methotrexate gastrointestinal absorption. In addition, the presence
of food may decrease bioavailability. When the drug
Methotrexate is a methylated analogue of tetrahydro- is given parenterally, its pharmacokinetic profile is
folate and inhibits dihydrofolate reductase. Its history somewhat different. Methotrexate is protein bound
as an antirheumatic drug dates to 1950, when a case and may be displaced by other protein-bound drugs,
series of patients with inflammatory arthritis improved including NSAIDs. Methotrexate is excreted in the
significantly after taking aminopterin, a drug related to urine by a process of filtration, reabsorption, and tubu-
methotrexate. Although it remained in use for psoria- lar secretion, and thus blood levels might be affected
sis, methotrexate was largely abandoned as a treatment by drugs that interfere with these processes.
for RA until the 1970s, when it began to see limited use

Clinical use. Widely utilized in many connective tis- 2 months during therapy with methotrexate (Table 7).
sue and autoimmune diseases, methotrexate has been A significant fall in serum albumin or persistent eleva-
shown to be an excellent steroid-sparing agent. It is tion of liver function tests may warrant a liver biopsy
effective in the spondyloarthropathies, psoriatic if therapy is to be continued. Dosages must be low-
arthritis, inflammatory myopathies, systemic vasculi- ered for patients with renal insufficiency.
tis, and nonrenal SLE. However, it has been most
extensively studied in patients with RA. Multiple Bone marrow suppression manifested as pancytope-
short-term and long-term studies have shown supe- nia is an infrequent but clinically significant adverse
rior clinical efficacy. Patients with RA take event in patients with RA. Macrocytosis may be a
methotrexate for years, attesting to its favorable effi- harbinger of this toxicity, and concomitant renal insuf-
cacy-to-toxicity profile. In most studies, methotrex- ficiency resulting in increased levels of and prolonged
ate produces a predictable response at 6 to 8 weeks, exposure to methotrexate may predispose to marrow
which peaks at 6 months and then requires gradually toxicity. Folinic acid (leucovorin rescue) effectively
increasing dosages of the drug in order to maintain reverses this.
the improvement. Although methotrexate may not
produce remission in many patients, it may retard An acute hypersensitivity to pneumonitis has been
radiographic progression. Dosing usually begins at observed in approximately 1%-2% of patients and at
7.5 to 10 mg orally per week, with gradual increases times may be severe or even fatal. Clinical character-
up to maximum dosage of 20 to 25 mg orally per istics include dry cough, fever, dyspnea, and severe
week depending on clinical response. If the clinical hypoxemia. Radiographs show diffuse interstitial
effect is suboptimal or if gastrointestinal adverse prominence or frank infiltrates and occasional
effects occur, methotrexate at similar doses can be adenopathy. Because methotrexate may predispose
given parenterally. Most recently it has been tested in patients to opportunistic organisms, infection must be
combination with other antirheumatic drugs, such as ruled out and the drug stopped. Patients usually
hydroxychloroquine and sulfasalazine in combina- respond to symptomatic support and drug withdrawal.
tion, and with cyclosporine alone.
Finally, methotrexate is a known teratogen, and the
Adverse effects. Adverse events may be classified as characteristic fetal abnormalities in babies of mothers
minor and major. Minor adverse effects, which are exposed to this drug have been termed “aminopterin
common, include stomatitis, gastrointestinal upset, syndrome.” The children exhibit craniofacial dys-
headache or minor central nervous system distur- plasias, mental retardation, and cardiovascular anoma-
bance, and elevations of levels of liver transaminases. lies. Methotrexate is also a potent abortifacient; in
All of these minor adverse effects may be averted by combination with misoprostol, it was shown to be an
concomitant use of folic acid. Alternatively, changing effective abortion-inducing therapy. Thus, methotrex-
dose, dose regimen, or route of administration may ate should never be given to pregnant or lactating
also reduce these annoying side effects. mothers. Although there exists little consensus regard-
ing an algorithm to discontinue methotrexate if a preg-
The more serious or major side effects include liver nancy is desired, conventional wisdom suggests that
toxicity, which is especially well described in the past the drug should be discontinued in women for at least
among patients with psoriasis. In patients with RA, 3 months (to include at least two ovulatory cycles)
mild transient elevation of liver function tests is com- before conception. Methotrexate in doses used for RA
monly observed, but serious liver disease, including probably does not have significant effect on fertility or
cirrhosis, is extremely rare. Risk factors for serious sterility, although this is poorly studied.
liver disease may include other contributors to liver
dysfunction, such as alcohol, diabetes mellitus, non-
alcoholic fatty liver disease, and other medications.
Briefly, complete blood count, renal function, liver
function, and serum albumin are monitored every 1 to

Cyclosporine potential for adverse reactions (see below) even at the
lower doses, cyclosporin A use is decreasing as the
Mechanism of action. Cyclosporine, a metabolic anti-TNF inhibitors penetrate routine practice.
product of fungal organisms, has immunologic
activity affecting calcium-associated signaling Adverse effects. Toxic effects of cyclosporin A
events in the regulation of cytokine gene expres- include: nausea; anorexia; flushing; headaches;
sion. Cyclosporine inhibits T-cell interaction with tremors; sleep disturbance; hypertrichosis; gingival
macrophages, reduces IL-2 synthesis, prevents pro- hyperplasia; hypertension; and hyperuricemia. Renal
duction of IL-1 receptor, and suppresses synthesis insufficiency may result from reversible acute toxic-
and release of IL-2 by CD4+ cells. Recent studies ity likely to be due to vasoconstriction or from
also indicate that cyclosporine increases chronic nephropathy with findings of interstitial
insulin–like growth factor and bone GLA (gamma- fibrosis, tubular atrophy, and vasculopathy. Baseline
carboxyglutamic acid) protein and may stimulate renal insufficiency, age above 30 years, and higher
the androgen axis. Growth of bone marrow-derived dosing place the patient at increased risk for these
B-lymphocytes, myeloid, and erythroid cell lines side effects. Potassium-sparing diuretics should be
are not inhibited by cyclosporine. avoided, because cyclosporine may cause hyper-
kalemia. Frequent monitoring of blood pressure,
Pharmacology. Cyclosporine is lipophilic and may blood chemistries, and leukocyte counts, as well as
be given orally or intravenously. Absorption of oral urinalysis should be done. Because the potential for
doses of cyclosporine is variable. It is bound to malignancy exists in patients treated with
plasma proteins, lipoproteins, and erythrocytes. Vol- cyclosporin A, appropriate long-term monitoring of
ume of distribution includes tissues that accumulate these patients is important.
higher concentrations than serum, such as body fat,
liver, spleen, pancreas, kidneys, lungs, and lymph Leflunomide
nodes. The drug is metabolized in the liver to multi-
ple metabolites (some of which have immunosup- Leflunomide was initially developed to prevent trans-
pressive activity) by cytochrome P450 mixed func- plant rejection; it was developed clinically for RA
tion oxidase. Drug interactions may occur, and grape- patients as an alternative to methotrexate and sul-
fruit juice may increase cyclosporin A serum levels. fasalazine. It was approved by regulatory authorities
Ketoconazole and diltiazem raise cyclosporine lev- for use in patients with active RA.
els, whereas phenytoin, phenobarbital, and rifampin
may lower drug levels. The drug must be carefully Mechanism of action. The active metabolite of
administered in patients with renal dysfunction, and leflunomide inhibits dihydroorotate dehydrogenase,
combination with other potentially nephrotoxic med- thereby interfering with pyrimidine synthesis. The
ications such as NSAIDs are discouraged or done down-stream is inhibition of activated lymphocytes
with considerable caution and monitoring. (T-cells and B-cells) and other cells that participate
in the inflammatory process. In animal models, it
Clinical use. Use of cyclosporin A in rheumatologic inhibits the expression of adjuvant and collagen-
conditions has thus far included RA, Sjögren’s dis- induced arthritis and allograft rejection. It inhibits
ease, Behçet’s-related inflammatory eye disease, T-cell proliferation and B-cell antibody formation.
SLE, scleroderma, polymyositis, and systemic vas- Leflunomide also inhibits tyrosine kinases,
culitis. Dosages of <5 mg/kg daily reduce potential for although the in vivo clinical effect of this action is
side effects. A number of combination therapy studies not completely elucidated.
have been reported, among them a study comparing
the use of cyclosporin A to placebo in RA patients Pharmacology. Leflunomide is orally administered,
who were inadequately controlled with low-dose shows good bioavailability, and has a long plasma
weekly oral methotrexate. This study showed a signif- half-life of roughly 2 weeks. It is highly protein bound,
icant drug effect compared to placebo, although con- metabolized in the liver, exhibits significant enterohep-
cerns about this continue. However, because of the atic circulation, and is excreted by the kidney and gut.

Clinical use. In 3 12-month phase III controlled clini- frequent monitoring should be done if the patient
cal trials involving 1839 patients, leflunomide was shows elevations of liver transaminases. If elevations
found to be significantly superior to placebo, and are observed, the dose should be reduced or stopped
equivalent to methotrexate and sulfasalazine in reduc- and liver function tests should be repeated until they
ing the signs and symptoms of active RA. The onset of are normal. Persistently abnormal or any severe eleva-
action of leflunomide appeared to be earlier than with tion of liver transaminases (ie, >3 x upper level of nor-
the other active comparator treatments. Importantly, mal) should prompt withdrawal of the drug. In the
in these same trials, leflunomide retarded the progres- early trials, infections were infrequent and were
sion of radiographic erosions, but this structural modi- equally prevalent across methotrexate and sul-
fication effect was similar in magnitude to that fasalazine treatment groups. Leflunomide is terato-
observed in both methotrexate and sulfasalazine treat- genic and contraindicated for pregnant women; thus,
ment groups. It has also been shown to improve qual- it should be used with great caution in women of
ity of life. childbearing potential.
In practice, the use of leflunomide increased after its Tumor Necrosis Factor Inhibitors:
introduction, particularly among patients who failed Etanercept, Infliximab and Adalimumab
methotrexate or who were not considered candidates
for the anticytokine treatments. A loading dose of 100 In many animal models of arthritis, and in in vitro and ex
mg po qd for 3 days was recommended in the past, but vivo experiments assessing human rheumatoid tissue,
its use has decreased as a means to minimize side TNF-␣ has been proven to be of profound importance in
effects. Some people begin with the maintenance dose driving inflammation in the RA synovium. Transgenic
of 20 mg po qd. Dosage reduction to 10 mg po qd is mice transected with the human TNF-␣ gene develop
occasionally a useful strategy when adverse effects chronic arthritis, and the treatment of these animals with
are encountered. Individual practitioners are now either the TNF-␣ receptor fusion proteins or the mono-
experimenting with leflunomide in combination with clonal antibody to TNF-␣ have abrogated the disease in
other second-line agents. vivo. TNF-␣ induces other pro-inflammatory cytokines,
(including IL-1 and IL-6), stimulates production of
Adverse effects. Side effects seen with leflunomide matrix metalloproteinases (eg, collagenase), and
include reversible alopecia, skin rash, diarrhea, and increases expression of adhesion molecules.
liver transaminase elevations. The pivotal trials of
leflunomide for RA showed that approximately 15% Etanercept
of patients had mild elevations of liver transami- Etanercept is a dimeric fusion protein of the extracel-
nases (1.2-2.0 x upper limit of normal). Severe ele- lular p75 soluble TNF-␣ receptor linked to IgG1. It
vations (ie, >3 times the upper limit of normal) were specifically binds to TNF-␣ and prevents its interac-
only seen in approximately 1%-4 % of patients in tion with the TNF-␣ receptor.
these trials. Many of the hepatic adverse events
occurred early in the treatment phase (usually within Pharmacology. It is administered subcutaneously,
the first 6 months). Many of the patients who had either 25 mg twice per week or 50 mg once a week.
severe hepatic reactions to leflunomide were taking After a single 25 mg injection, the median half-life is
other medications that may have been hepatotoxic or 115 hours.
had significant comorbid diseases that might have
contributed to the outcome. Clinical use. Etanercept has shown profound effi-
cacy in a number of double-blind randomized con-
The general recommendations for monitoring liver trolled trials. In the first Phase III trial of 234 patients
function in patients taking leflunomide are similar to with active RA, an impressive reduction of clinical
the guidelines developed for monitoring RA patients signs and symptoms was observed in the etanercept
taking methotrexate therapy. It is now recommended group compared to placebo. In another Phase III study
that ALT and AST be measured prior to drug initia- of 6 months duration, RA patients who were inade-
tion, monthly for 6 months, and finally, every 1 to 3 quately controlled with methotrexate were random-
months thereafter if the drug is well tolerated. More ized to either etanercept or placebo. The addition of

etanercept markedly improved the clinical status of Adalimumab
RA patients compared to those who received placebo. Adalimumab is a human IgG1 monoclonal antibody
to TNF-␣ that specifically binds to circulating and
Adverse effects. As with all TNF inhibitors, there cell-bound TNF, thereby inhibiting its biologic
there is concern regarding the potential for immune effects.
suppression and increased risk of infection. In clinical
trials, while overall infections were observed more Pharmacology. Adalimumab is given subcutaneously
commonly, there was no increase in the frequency of and has a half-life of approximately 13 days. It is given
severe infections. As with all TNF inhibitors, the at dose of 40 mg every other week, with the potential to
development of autoantibodies, in particular ANA increase weekly doses.
and anti-dsDNA, was observed in higher frequency in
etanercept-treated patients compared with placebo. Clinical use. The efficacy of adalimumab in patients
However, development of clinical lupus is rare. with active RA has been shown in several randomized
placebo controlled trials, both in conjunction with
Infliximab methotrexate and as monotherapy.
Infliximab is a chimeric IgG1 monoclonal antibody to
TNF-␣, thereby inhibiting its biologic effects in the Adverse effects. As with all TNF inhibitors, there is a
synovium. concern regarding the potential for immune suppres-
sion and increased risk of infection. In clinical trials,
Pharmacology. It is administered intravenously, and while overall infections were observed more com-
after a single intravenous administration of 3 mg/kg, monly, there was no increase in the frequency of severe
the half-life is 8 to 9.5 days. Infliximab is approved for infections. As with all TNF inhibitors, the develop-
use, in conjunction with concomitant methotrexate, at ment of autoantibodies, in particular ANA and anti-
doses of 3 to 10 mg/kg given every 4 to 8 weeks. dsDNA, was observed in higher frequency in etaner-
cept-treated patients compared with placebo. Develop-
Clinical use. Infliximab was initially approved by ment of clinic lupus is rare.
FDA for treating patients with active Crohn’s disease.
The efficacy of infliximab in patients with active RA Interleukin-1 Receptor
despite concomitant therapy with methotrexate was Antagonist Anakinra
evaluated in several randomized placebo-controlled
trials. Infliximab at 3 mg/kg was profoundly superior Interleukin-1 (IL-1) is a pro-inflammatory cytokine
to placebo in reducing the signs and symptoms of RA. that contributes to synovial inflammation, in part by
The usual dose regimen is 3 mg/kg by intravenous the induction of other inflammatory cytokines and pro-
infusion at 0, 2, and 6 weeks, followed by 3 mg/kg tein-degrading enzymes such as collagenase. Anakinra
intravenously every 8 weeks. Infliximab should be (IL-1ra) is a homologue of the naturally occurring IL-1
given to RA patients taking methotrexate, and dosage receptor antagonist (IL-Rra) that competes with IL-1
adjustment of up to 10 mg/kg can be made if there is for binding to type 1 IL-1 receptors.
insufficient clinical response.
Pharmacology. Anakinra, which is given typically as
Adverse effects. As with all TNF inhibitors, there is a a daily subcutaneous injection, has a half-life of
concern regarding the potential for immune suppres- approximately 4-6 hours.
sion and increased risk of infection. In clinical trials,
while overall infections were observed more com- Clinical uses. Anakinra has been shown to be effec-
monly, there was no increase in the frequency of tive in several double blind placebo controlled trials. In
severe infections. As with all TNF inhibitors, the general, the extent of responses observed with
development of autoantibodies, in particular ANA anakinra is less than that seen with TNF inhibitors.
and anti-dsDNA, was observed in higher frequency in
etanercept-treated patients compared with placebo. Adverse events. The overall safety profile of this
Development of clinical lupus is rare. agent seems to be acceptable with the most frequent
adverse events being injection site reactions. Infec-

tions are always a concern because of the active pro- Pharmacology. In RA, rituximab is typically given
inflammatory nature of IL-1; however, significant as 2 intravenous infusions of 1,000 mg, given 2
increase in frequencies of opportunistic infections weeks apart over 3-4 hours. Preinfusion corticos-
were not seen in the clinical studies. In a study in teroids (eg, 100 mg methylprednisolone) are com-
which anakinra was used in combination with the monly used and seem to increase the tolerability of
TNF inhibitor etanercept, a significantly greater num- the first dose particularly. Following treatment with
ber of serious infections developed; therefore, combi- rituximab, there is a profound and long-lasting deple-
nation therapy is not recommended. tion of circulating ␤-cells. Because not all patients
respond, this cannot be used as a marker of efficacy.
T-cell Costimulation Inhibitor Abatacept
Clinical use. The efficacy of rituximab has been
Abatacept, previously known as CTLA-4-Ig, is a shown in several studies in RA. Its initial approval in
fusion protein consisting of the extracellular portion RA was for patients who had failed previous treat-
of the T-cell molecule CTLA-4 linked with the Fc ment with TNF inhibitors.
piece of human IgG1 that has been modified so as to
not activate complement. CTLA-4 is a natural Adverse effects. As with all immunomodulatory
inhibitor of the interaction between CD28, a key agents, patients treated with rituximab should be
stimulatory molecule on T-cells, and its ligands observed for signs and symptoms of infection,
CD80 and CD86 on antigen presenting cells. although in clinical trials these occurred only slightly
more commonly than in the comparison arms. While
Pharmacology. Abatacept is given as an intravenous infusions of rituximab appear to be better tolerated in
infusion over 30 minutes once a month, after an initi- RA as compared to lymphoma, infusion related side
ation phase of treatment at weeks 0, 2 and 4. The dose effects can occur and can be severe.
is weight based, approximating 10 mg/kg.
Clinical use. The efficacy of abatacept has been

shown in RA patients who had active disease despite
concomitant MTX or who have failed previous treat-
ment with TNF inhibitors.
Adverse effects. As with all immunomodulatory

agents, patients treated with abatacept should be
observed for signs and symptoms of infection,
although in clinical trials these occurred only slightly
more commonly than in the comparison arms. In a
study in which abatacept was used in combination
with the TNF inhibitor etanercept, a significantly
greater number of serious infections developed;
therefore, combination therapy is not recommended.
␤-cell Inhibitor Rituximab
Rituximab is a chimeric monoclonal antibody

directed against CD20, a molecule whose expression
is limited to ␤-cells. Rituximab was approved as a
treatment for non-Hodgkin’s lymphoma in 1997.
Because of the role of ␤-cells in various autoimmune
diseases, it has been under study in several rheumatic
diseases.

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Rheumatoid Arthritis: Pathogenesis, Clinical Features, and Treatment

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Rheumatoid Arthritis: Pathogenesis, Clinical Features, and Treatment

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Rheumatoid Arthritis:

6. Specific Antirheumatic Drugs

RHEUMATOID ARTHRITIS: PATHOGENESIS, CLINICAL FEATURES, AND TREATMENT 1

The synovium of the rheumatoid joint, although not

2 EDUCATIONAL REVIEW MANUAL IN RHEUMATOLOGY

RHEUMATOID ARTHRITIS: PATHOGENESIS, CLINICAL FEATURES, AND TREATMENT 3

4 EDUCATIONAL REVIEW MANUAL IN RHEUMATOLOGY

RA occurs worldwide in virtually all ethnic groups, RA is characterized by symmetrical synovitis

Based on cross-sectional studies of patients with RA,

RHEUMATOID ARTHRITIS: PATHOGENESIS, CLINICAL FEATURES, AND TREATMENT 5

1987 American College of Rheumatology Criteria for

5. Subcutaneous nodules over bony prominences, extensor surfaces, or in juxta-articular regions,

* For the diagnosis of RA, 4 of the 7 criteria are required.

1991 American College of Rheumatology Revised Criteria

Class I Completely able to perform usual activities of daily living (self-care,

6 EDUCATIONAL REVIEW MANUAL IN RHEUMATOLOGY

RHEUMATOID ARTHRITIS: PATHOGENESIS, CLINICAL FEATURES, AND TREATMENT 7

8 EDUCATIONAL REVIEW MANUAL IN RHEUMATOLOGY

RHEUMATOID ARTHRITIS: PATHOGENESIS, CLINICAL FEATURES, AND TREATMENT 9

Most patients with RA have a slowly progressive

Deﬁning markers of a bad prognosis early on in RA

10 EDUCATIONAL REVIEW MANUAL IN RHEUMATOLOGY

sion-making. Also, the above associations, while Background

The history of anti-inﬂammatory drug development

RHEUMATOID ARTHRITIS: PATHOGENESIS, CLINICAL FEATURES, AND TREATMENT 11

Clinical Evaluation of Rheumatoid Arthritis

Classification of Disease Activity

Slowly Progressive Aggressive

Swollen joints Few Many

ESR or CRP Normal or modestly elevated Markedly elevated

Radiographic erosions Absent May be present

Rheumatoid nodules Absent May be present

Extra-articular manifestations Absent May be present

Rheumatoid factor or anti-CCP Normal or modestly elevated Markedly elevated

Functional status Preserved Impaired

CRP = C-reactive protein; ESR = erythrocyte sedimentation rate.

12 EDUCATIONAL REVIEW MANUAL IN RHEUMATOLOGY

RHEUMATOID ARTHRITIS: PATHOGENESIS, CLINICAL FEATURES, AND TREATMENT 13

Medical management of rheumatoid arthritis

Slowly Progressive Aggressive

Initiate NSAIDs · Initiate NSAIDs

14 EDUCATIONAL REVIEW MANUAL IN RHEUMATOLOGY

Rheumatoid Arthritis: Medical Management of Rheumatoid Arthritis with

Slowly Progressive Disease Aggressive Disease

Consider in NSAID-nonresponsive patients Consider early in course of disease

Hydroxychloroquine Methotrexate, leflunomide

Sulfasalazine* Intramuscular gold (rarely used now)

For patients refractory to the above, consider:

Etanercept, infliximab, or adalimumab

For patients refractory to TNF inhibitors, consider:

* Not approved by the FDA for use in rheumatoid arthritis.

RHEUMATOID ARTHRITIS: PATHOGENESIS, CLINICAL FEATURES, AND TREATMENT 15

A study in early RA from the Netherlands has pro- Outcome Assessment

16 EDUCATIONAL REVIEW MANUAL IN RHEUMATOLOGY

improvements in a majority for a “response” to be NSAIDs and Salicylates

RHEUMATOID ARTHRITIS: PATHOGENESIS, CLINICAL FEATURES, AND TREATMENT 17

18 EDUCATIONAL REVIEW MANUAL IN RHEUMATOLOGY

Nonsteroidal Anti-Inflammatory Drugs and Dose Ranges by Chemical Classification

Daily Recommended Plasma