Chap 321

gideonjcaballes
• M.B., 45 year old female, married, Filipino, Roman Catholic admitted for
multiple joint pain and swelling.

• A year PTA, patient complained of body malaise and occasional fever

relieved with intake of Paracetamol.
• Later, this was associated with morning stiffness of hand joints relieved
after 15 minutes. No consults done.

• 6 months PTA, patient noted easy fatigability associated with swelling and
pain of the right hand joints involving the PIPs, MCPs and the wrist joint.
Took Diclofenac with temporary relief. Still no consult made. She then
noted involvement of the left wrist, MCPs and PIPs with persistence of
morning stiffness now lasting more than 2 hours.

• 4 months PTA, she noted swelling and pain of the elbow, shoulder and
knee joints with swelling and pain. There was limitation of motion of hand
joints with deformities.
• Consulted a local physician where laboratories taken revealed leukocytosis
and anemia on CBC, elevated BUA at 7.5 mg/dl.
• She was then given Allopurinol 300mg/day and Naproxen 500mg BID with
temporary relief.

• 2 months PTA, there was persistence of symptoms with patient having

difficulty in ambulation, as well as self-care and unable to perform
avocational activities.
• She also noted pain on both TMJ on mastication with limited mouth
opening. There was also limitation of extension of the neck and lumbar
flexion. (+) weight loss and anorexia

• A week PTA, patient was noted to have persistence of arthritis but now
associated with persistent fever and cough thus admitted.

• The patient is non-hypertensive, non-diabetic and non-asthmatic.

• No previous hospitalizations. No food and drug allergies. HFD includes
arthritis.
• She is an occasional smoker and an occasional alcoholic beverage drinker.
• The patient is a native of Zamboanga del Norte and worked as a
seamstress since 25 years old.

• Conscious, coherent, asthenic patient brought to ER per stretcher, not in

acute respiratory distress.
• Vital signs:
– BP: 140/80 mmHg
– PR: 110/min
– RR: 14/min
– Temp: 38.6 degrees C
– Wt: 40 kg
– Ht: 4’11”
• SKIN: generalized pallor, no rashes
• HEENT: pale palpebral conjunctivae, anicteric sclera, tenderness on palpation
of TMJ bilateral, mouth opening able to accomodate 2 fingerbreadths
• NECK: no lymphadenopathies, LOM on flexion and extension of cervical spine
• C/L: equal chest expansion, bibasilar rales, no wheeze
• CVS: distinct heart sounds, tachycardic, no murmurs
• ABDOMEN: flat, NABS, soft, no organomegaly
• GUT: no genital lesions, negative kidney punch sign
• BACK: unable to perform Schober’s test
Schober’s Test
• EXTREMITIES:
• swelling, tenderness and warmth of the MCPs, PIPs and DIPs with poor grip
bilateral; ulnar deviation of the fingers on the MCPs;
• flexion deformity of the PIPs and extension of DIPs
• swelling, tenderness and warmth of both wrists and elbows with LOM of flexion
and extension; radial deviation of wrists
• swelling, tenderness and warmth of the shoulder joints, unable to place hands
on the occiput
• swelling, tenderness and warmth of knees with LOM on flexion and extension
• swelling, tenderness and warmth of ankles and MTPs with positive grip test
• tenderness on both hips with LOM on internal and external rotation, adduction;
(+) FABERE test; tender SIJs
• presence of non-tender nodules on the dorsal aspect of proximal forearm
HIPS: Patrick’s test : flexion, abduction, external rotation, extension

swing the lower leg—medially for external rotation

at the hip and laterally for internal rotation.
VARIABLE RESULTS

Hematocrit (%) 28
White cell count (per mm3) 5000
Platelet count (per mm3) 259,000

BUN normal
Creatinine normal
AST (U/l) 68

ESR 110 mm/hr

Rheumatoid factor positive

Chest Xray interstitial infiltrates on both lung base

Xray Knees narrowed joint space with osteophytosis

Xray Hands periarticlar osteopenia with erosions on the ends of

MCPs and PIPs bilateral

Xray Cervical disc space narrowing

Xray Thoracolumbar spine osteophytosis with straightening of the lumbar lordosis
Xray Pelvis no erosions on SIJs

Synovial fluid analysis yellow, turbid, poor string sign

WBC: 20000 Seg: 75 Lymph 25
AFB smear and gram stain: no organisms seen
crystal studies: (-) for MSU crystals
diagnosis
• diagnosis of RA is based on signs and symptoms of chronic inflammatory
arthritis with laboratory and radiographic results providing supplemental
information

• 2010: American College of Rheumatology (ACR) and the European League

Against Rheumatism (EULAR) revised the 1987 ACR classification criteria
for RA (Table 321-1)

• the newly revised criteria yields a score of 0–10, with a score of 6 fulfilling
the requirements for definite RA
1987 ACR Criteria for RA
 RA diagnosis:
score of ≥6

Note: These criteria are aimed at classification of newly presenting patients who have at least 1 joint with definite clinical synovitis that is not better explained by another
disease.
Abbreviations: CCP, cyclic citrullinated peptides; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IP, interphalangeal joint; MCP, metacarpophalangeal joint;
MTP, metatarsophalangeal joint; PIP, proximal interphalangeal joint; RF, rheumatoid factor; ULN, upper limit of normal.
Rheumatoid Arthritis
• is a chronic inflammatory disease of unknown etiology
• most common form of chronic inflammatory arthritis
• marked by a symmetric, peripheral polyarthritis
• often results in joint damage and physical disability

• affects approximately 0.5–1% of the adult population worldwide

Rheumatoid Arthritis
• is a systemic disease with extraarticular manifestations:
– fatigue
– subcutaneous nodules
– lung involvement
– pericarditis
– peripheral neuropathy
– vasculitis
– hematologic abnormalities
clinical features
• incidence increases between 25 and 55 years of age, after which it
plateaus until the age of 75 and then decreases

• presenting symptoms typically result from inflammation of the joints,

tendons and bursae

• early morning joint stiffness > 1 hour and easing with physical activity
• earliest involved are small joints of the hands and feet

• initial pattern may be monoarticular, oligoarticular (2-4 joints) or

polyarticular (>5 joints), usually symmetric distribution
 ←TMJ

Rheumatoid Osteoarthritis
Arthritis

The joint distribution of the two most common types of arthritis are compared: rheumatoid arthritis (A) and osteoarthritis (B).
Rheumatoid arthritis involves almost all synovial joints in the body. Osteoarthritis has a much more limited distribution. Importantly, rheumatoid arthritis rarely, if ever,
involves the distal interphalangeal joints, but osteoarthritis commonly does.
clinical features
undifferentiated inflammatory arthritis
– some patients will present with too few affected joints and other
characteristic features to be classified as having RA

• undifferentiated arthritis most likely to be diagnosed later with RA have:

– higher number of tender and swollen joints
– (+) test for rheumatoid factor (RF) or anti-CCP antibodies
– higher scores for physical disability
clinical features
• wrists, metacarpophalangeal (MCP) and proximal interphalangeal (PIP)
joints are the most frequently involved
• distal interphalangeal (DIP) joint involvement may occur in RA but is
usually a manifestation of coexistent osteoarthritis
clinical features
• flexor tendon tenosynovitis is a frequent hallmark of RA and leads to
decreased range of motion, reduced grip strength, and "trigger" fingers
clinical features
• progressive destruction of the joints and soft tissues may lead to chronic,
irreversible deformities
• ulnar deviation results from subluxation of the MCP joints, with
subluxation of the proximal phalanx to the volar side of the hand
clinical features
• hyperextension of the PIP joint with flexion of the DIP joint ("swan-neck
deformity")
• flexion of the PIP joint with hyperextension of the DIP joint ("boutonnière
deformity")
clinical features
• thumb: subluxation of the first MCP joint with hyperextension of the first
interphalangeal (IP) joint ("Z-line deformity")
clinical features
• inflammation about the ulnar styloid and tenosynovitis of the extensor
carpi ulnaris may cause subluxation of the distal ulna, resulting in a
"piano-key movement" of the ulnar styloid
clinical features
• ankle and midtarsal regions are usually affected later in the course of
disease and predispose to pes planovalgus ("flat feet")

• large joints (knees and shoulders) are often affected in established disease
but may remain asymptomatic for many years after onset
clinical features
• atlantoaxial involvement of the cervical spine with progressive instability
of C1 on C2 has the potential to cause compressive myelopathy and
neurologic dysfunction
• prevalence of atlantoaxial subluxation is less than 10% of patients
clinical features
• unlike the spondyloarthritides, RA does not affect the thoracic and lumbar
spine except in very unusual circumstances

• radiographic abnormalities of the temporomandibular joint occur

commonly in patients with RA, but they are rarely associated with
significant symptoms or functional impairment
metacarpophalangeal and proximal interphalangeal joint swelling in rheumatoid arthritis.
A: A patient with early rheumatoid arthritis.
There are no joint deformities, but the soft tissue synovial swelling around
the third and fifth proximal interphalangeal (PIP) joints is easily seen.

B: A patient with advanced rheumatoid arthritis with severe joint deformities

including subluxation at the metacarpophalangeal joints and swan-neck
deformities (hyperextension at the PIP joints).
clinical features
• extraarticular manifestations may develop during the clinical course of RA,
even prior to the onset of arthritis

• patients most likely to develop extraarticular disease have a history of

smoking, early onset of significant physical disability, and test positive for
serum RF

• subcutaneous nodules, secondary Sjögren's syndrome, pulmonary nodules

and anemia are the most frequently observed extraarticular
manifestations
extraarticular manifestations of
rheumatoid arthritis
constitutional signs and symptoms
• weight loss, fever, fatigue, malaise, depression, and in severe cases,
cachexia

• generally reflect a high degree of inflammation and may even precede the
onset of joint symptoms

• in general, the presence of a fever of >38.3°C (101°F) at any time during

the clinical course should raise suspicion of systemic vasculitis or infection
nodules
• 30–40% of patients
• more common in very active disease, (+) RF and radiographic evidence of
joint erosions

• firm, nontender
• adherent to periosteum, tendons, or bursae
• develop in areas subject to repeated trauma or irritation such as the
forearm, sacral prominences and Achilles tendon
• may also occur in the lungs, pleura, pericardium and peritoneum

• typically benign
• can be associated with infection, ulceration and gangrene
a rheumatoid nodule in a typical location on the extensor surface of the forearm is apparent in
this patient with seropositive, erosive rheumatoid arthritis
Sjögren's Syndrome
• secondary Sjögren's syndrome: presence of either keratoconjunctivitis
sicca (dry eyes) or xerostomia (dry mouth) in association with another
connective tissue disease, such as RA
• 10% of patients with RA have secondary Sjögren's syndrome
pulmonary
• pleural disease: most common pulmonary manifestation of RA
• pleuritic chest pain and dyspnea, pleural friction rub and effusion
• pleural effusions tend to be exudative

• diagnosis: high-resolution chest CT scan

• pulmonary function test: restrictive pattern

• interstitial lung disease (ILD) may also occur and is heralded by dry cough
and progressive shortness of breath

• presence of ILD confers a poor prognosis

cardiac
• the most frequent site of cardiac involvement in RA is the pericardium

• cardiomyopathy may result from necrotizing or granulomatous

myocarditis, coronary artery disease, or diastolic dysfunction

• rarely, the heart muscle may contain rheumatoid nodules or be infiltrated

with amyloid

• mitral regurgitation is the most common valvular abnormality

vasculitis
• rheumatoid vasculitis is seen most commonly in patients with long-
standing disease, a (+) RF and hypocomplementemia; incidence is rare,
occurring in no more than 1% of cases

• cutaneous signs include petechiae, purpura, digital infarcts, gangrene,

livedo reticularis and in severe cases large, painful lower extremity
ulcerations
lymphoma
• two- to fourfold increased risk of lymphoma in RA patients compared with
the general population

• most common histopathologic type is diffuse large B-cell lymphoma

• risk of developing lymphoma increases if the patient has high levels of

disease activity
 associated conditions that contribute
to morbidity and mortality in RA
cardiovascular disease
• the most common cause of death in patients with RA is cardiovascular
disease

• incidence of coronary artery disease and carotid atherosclerosis is higher

in RA patients

• congestive heart failure occurs at an approximately two-fold higher rate in

RA than in the general population

• elevated serum inflammatory markers appears to confer an increased risk

of cardiovascular disease
 associated conditions that contribute
to morbidity and mortality in RA
osteoporosis
• more common in RA
• prevalence rates of 20–30%

• inflammatory milieu of the joint probably spills into the rest of the body
and promotes generalized bone loss by activating osteoclasts

• chronic use of glucocorticoids and disability-related immobility also

contributes to osteoporosis

• hip fractures are more likely to occur in patients with RA and are
significant predictors of increased disability and mortality rate
 associated conditions that contribute
to morbidity and mortality in RA
hypoandrogenism

• men and postmenopausal women with RA have lower mean serum

testosterone, luteinizing hormone (LH) and dehydroepiandrosterone
(DHEA) levels than control populations
environmental factors
• cigarette smoking: most reproducible environmental links with relative risk
for developing RA of 1.5–3.5

• the risk from smoking is almost exclusively related to RF (+) and anti-CCP
antibody (+) disease

• a twin who smokes will have a significantly higher risk for RA than his or
her monozygotic co-twin who does not smoke
environmental factors
possible infectious etiology for RA:

• streptococci

• viruses such as Epstein-Barr virus (EBV)

– titers of IgG antibodies against EBV antigens in the peripheral blood
and saliva are significantly higher in patients with RA than the general
population
– EBV DNA has also been found in synovial fluid and synovial cells of RA
patients

• mycoplasma and parvovirus B19

diagnosis
• The new classification criteria differ in several ways from the older criteria:
– new criteria include a positive test for serum anti-cyclic citrullinated
peptide antibodies (anti-CCP) -- carries greater specificity for RA
diagnosis than a positive rheumatoid factor test
– new criteria does not take into account rheumatoid nodules or
radiographic joint damage since these findings occur rarely in early RA

• the new 2010 ACR-EULAR criteria are "classification criteria" as opposed

to "diagnostic criteria"
– serve to distinguish patients at the onset of disease with a high
likelihood of evolving into chronic disease with persistent synovitis and
joint damage

• radiographic joint erosions or subcutaneous nodules may inform the

diagnosis in the later stages
laboratory features: RF
• IgM, IgG, and IgA isotypes of rheumatoid factor (RF) occur in sera from
patients with RA, although the IgM isotype is the one most frequently
measured by commercial laboratories

• serum IgM RF has been found in 75–80% of patients with RA; therefore, a
negative result does not exclude the presence of this disease
• serum RF may also be detected in 1–5% of the healthy population

• RF is also found in other connective tissue diseases, such as primary

Sjögren's syndrome, systemic lupus erythematosus, and type II mixed
essential cryoglobulinemia, as well as chronic infections such as subacute
bacterial endocarditis and hepatitis B and C
laboratory features: anti-CCP
• serum anti-CCP antibodies has about the same sensitivity as serum RF for
the diagnosis of RA
• but its diagnostic specificity approaches 95%, so a positive test for anti-
CCP antibodies in the setting of an early inflammatory arthritis is useful for
distinguishing RA from other forms of arthritis

• there is some incremental value in testing for the presence of both RF and
anti-CCP, as some patients with RA are positive for RF but negative for
anti-CCP and visa versa
• presence of RF or anti-CCP antibodies also has prognostic significance,
with anti-CCP antibodies showing the most value for predicting worse
outcomes
synovial fluid analysis
• synovial fluid from patients with RA reflects an inflammatory state
• synovial fluid white blood cell (WBC) counts can vary widely, but generally
range between 5000 and 50,000 WBC/3 compared to <2000 WBC/ for a
non-inflammatory condition such as osteoarthritis
• the overwhelming cell type in the synovial fluid is the neutrophil
• synovial fluid also contains RF and anti-CCP antibodies and immune
complexes, as well as by-products of complement activation
• the analysis of synovial fluid is most useful for confirming an inflammatory
arthritis (as opposed to osteoarthritis), while at the same time excluding
infection or a crystal-induced arthritis such as gout or pseudogout
arthrocentesis of the knee
joint imaging
• valuable tool for diagnosing RA and for tracking progression of joint
damage

• plain x-ray is the most common imaging modality, but it is limited to

visualization of the bony structures and inferences about the state of the
articular cartilage based on the amount of narrowing of the joint space

• MRI and ultrasound techniques offer the added value of detecting

changes in the soft tissues such as synovitis, tenosynovitis, and effusions
as well as greater sensitivity for identifying bony abnormalities
plain radiography
• classically in RA, the initial radiographic finding is juxtaarticular
osteopenia
• other findings include soft tissue swelling, symmetric joint space loss, and
subchondral erosions, most frequently in the wrists and hands (MCPs and
PIPs) and the feet (MTPs)
• advanced RA may reveal signs of severe destruction, including joint
subluxation and collapse
X-ray demonstrating progression of erosions on the proximal interphalangeal joint (PIP)
The radiographic features of rheumatoid arthritis and osteoarthritis are compared with regard to large joint involvement.
A: Symmetric loss of cartilage space that is typical of inflammatory arthritis such as rheumatoid arthritis. Note that both the medial and lateral compartments are severely
narrowed. Despite this severe narrowing, there is very little in the way of subchondral sclerosis or osteophyte formation since these repair mechanisms are generally shut off
in active rheumatoid arthritis.
B: Complete loss of the cartilage in the medial joint compartment with significant subchondral sclerosis and osteophyte formation. The lateral compartment in this patient is
not involved. These features are typical of osteoarthritis.
magnetic resonance imaging
• MRI offers the greatest sensitivity for detecting synovitis and joint
effusions, as well as early bone and bone marrow changes
• these soft tissue abnormalities often occur before osseous changes are
noted on x-ray

• presence of bone marrow edema has been recognized to be an early sign

of inflammatory joint disease, and can predict the subsequent
development of erosions on plain radiographs as well as MRI scans

• cost and availability of MRI are the main factors limiting its routine clinical
use
ultrasound
• has the ability to detect more erosions than plain radiography, especially
in easily accessible joints

• less clear, however, is the ability of ultrasound to reliably detect synovitis,

including increased joint vascularity indicative of inflammation

• the usefulness of ultrasound is dependent on the experience of the

sonographer; however, it does offer the advantages of portability, lack of
radiation, and low expense relative to MRI, factors that make it attractive
as a clinical tool
clinical course
• the natural history of RA is complex and affected by a number of factors
including age of onset, gender, genotype, phenotype (i.e., extraarticular
manifestations or variants of RA), and comorbid conditions
• there is no simple way to predict the clinical course

• as many as 10% of patients will undergo a spontaneous remission within 6

months (particularly seronegative patients)

• vast majority of patients will exhibit a pattern of persistent and

progressive disease activity that waxes and wanes in intensity over time
• a minority of patients will show intermittent and recurrent explosive
attacks of inflammatory arthritis interspersed with periods of disease
quiescence
clinical course
• an aggressive form of RA may occur in an unfortunate few with inexorable
progression of severe erosive joint disease

• disability results from both a disease activity–related component that is

potentially reversible with therapy and a joint damage–related component
owing to the cumulative and largely irreversible effects of cartilage and
bone breakdown

• early in the course of disease, the extent of joint inflammation is the

primary determinant of disability, while in the later stages, the amount of
joint damage is the dominant contributing factor
clinical course
• overall mortality rate in RA is two times greater than the general
population
– ischemic heart disease being the most common cause of death
followed by infection

• median life expectancy shortened by an average of 7 years for men and 3

years for women

• at higher risk for shortened survival are those with systemic extraarticular
involvement, low functional capacity, low socioeconomic status, low
education and chronic prednisone use
• joint inflammation is the main driver of joint damage and is the most
important cause of functional disability in the early stages
treatment of RA
• medications used for the treatment of RA may be divided into broad
categories:
– nonsteroidal anti-inflammatory drugs (NSAIDs)
– glucocorticoids, such as prednisone and methylprednisolone
– conventional disease-modifying anti-rheumatic drugs (DMARDs)
– biologic DMARDs

• while disease for some patients with RA is managed adequately with a

single DMARD, such as methotrexate, the situation entails in most cases
the use of a combination DMARD regimen that may vary in its
components over the treatment course depending on fluctuations in
disease activity and emergence of drug-related toxicities and
comorbidities
DMARDs Used
For The Treatment of
Rheumatoid Arthritis

Conventional DMARDs

Biologic DMARDs
DMARDs Used
For The Treatment of
Rheumatoid Arthritis Biologic DMARDs
NSAIDs
• NSAIDs were formally viewed as the core of all other RA therapy, but they
are now considered to be adjunctive therapy for management of
symptoms uncontrolled by other measures
• NSAIDs exhibit both analgesic and anti-inflammatory properties
• the anti-inflammatory effects of NSAIDs derive from their ability to
nonselectively inhibit cyclooxygenase (COX)-1 and COX-2
• although the results of clinical trials suggest NSAIDs are roughly equivalent
in their efficacy, experience suggests that some individuals may
preferentially respond to a particular NSAID
• chronic use should be minimized due to the possibility of side effects,
including gastritis and peptic ulcer disease as well as impairment of renal
function
glucocorticoids
• may be administered in low-to-moderate doses to achieve rapid disease
control before the onset of fully effective DMARD therapy, which often
takes several weeks or even months
• a 1–2 week burst of glucocorticoids may be prescribed for the
management of acute disease flares, with dose and duration guided by
the severity of the exacerbation
• chronic administration of low doses (5–10 mg/d) of prednisone (or its
equivalent) may also be warranted to control disease activity in patients
with an inadequate response to DMARD
• if a patient exhibits one or a few actively inflamed joints, the clinician may
consider intraarticular injection of an intermediate-acting glucocorticoid
such as triamcinolone acetonide
glucocorticoids
• osteoporosis ranks as an important long-term complication of chronic
prednisone use

• prevention of glucocorticoid-induced osteoporosis with a bisphosphonate

in any patient receiving 5 mg/d or more of prednisone for greater than 3
months
DMARDs
• have the ability to slow or prevent structural progression of RA
• conventional DMARDs include hydroxychloroquine, sulfasalazine,
methotrexate, and leflunomide; they exhibit a delayed onset of action of
approximately 6–12 weeks
• methotrexate is the DMARD of choice for RA and is the anchor drug for
most combination therapies
– approved for the treatment of RA in 1986 and remains the benchmark
for the efficacy and safety of new disease-modifying therapies
– methotrexate has been shown to stimulate adenosine release from
cells, producing an anti-inflammatory effect
• leflunomide, an inhibitor of pyrimidine synthesis, has similar efficacy to
methotrexate; effective as monotherapy or in combination with
methotrexate and other DMARDs
physical therapy
• all patients should receive a prescription for exercise and physical activity
• dynamic strength training, community-based comprehensive physical
therapy, and physical-activity coaching (emphasizing 30 minutes of
moderately intensive activity most days a week) have all been shown to
improve muscle strength and perceived health status
• foot orthotics for painful valgus deformity decreases foot pain and
resulting disability and functional limitations
• judicious use of wrist splints can also decrease pain; however, their
benefits may be offset by decreased dexterity and a variable effect on grip
strength
surgery
• may improve pain and disability in RA—most notably the hands, wrists,
and feet, typically after failure of medical therapy with varying degrees of
reported long-term success
• for large joints, such as the knee, hip, shoulder, or elbow, total joint
arthroplasty is an option for advanced joint disease
• silicone implants are the most common prosthetic for MCP arthroplasty,
and are generally implanted in patients with severe decreased arc of
motion, marked flexion contractures, MCP joint pain with radiographic
abnormalities and severe ulnar drift
• synovectomy and limited fusion are offered for the early rheumatoid wrist,
but they are used much less frequently now compared to the past
because of the availability of improved DMARD therapies
• Arthrodesis and total wrist arthroplasty are reserved for patients with
severe disease that have substantial pain and functional impairment
pregnancy
• Up to 75% of female RA patients will note overall improvement in
symptoms during pregnancy, but often will flare post-delivery
• flares during pregnancy are generally treated with low doses of
prednisone; hydroxychloroquine and sulfasalazine are probably the safest
DMARDs to use during pregnancy

• methotrexate and leflunomide therapy are contraindicated during

pregnancy due to their teratogenicity in animals and humans
• the experience with biologic agents has been insufficient to make specific
recommendations for their use during pregnancy

• most rheumatologists avoid their use in this setting; however, exceptions

are considered depending on the circumstances
elderly patients
• RA presents in up to one-third of patients after the age of 60
• studies suggest that conventional DMARDs as well as biologic agents are
equally effective and safe in younger and older patients
• due to comorbidities, many elderly patients have an increased risk of
infection
• gradual decline in renal function may raise the risk for side effects from
NSAIDs and some DMARDS, such as methotrexate
• renal function must be taken into consideration before prescribing
methotrexate, which is mostly cleared by the kidneys
• methotrexate is usually not prescribed if serum creatinine is greater than
2 mg/dl