RHEUMATIC

dr. Pandji M,SpPD,KEMD

TERMINOLOGI

Artralgia;keluhan rasa nyeri sekitar sendi,Px taa

Artritis ;kelainanan sendi obyektiv,berupa Px
inflamasi komplit
Mono artritis; artritis mengenai satu sendi saja
Oligo artritis/pauzi artikular;artritis yg nyerang
2 sp 4 sendi kecil DIP(distal inter falang)
PIP(proximal inter falang),MCP,MTP(me
tatarsofalangeal)

Cont terminologi

Poli artritis;artritis yg menyerang lbh 4 sendi kecil

Sinovotis;inflamasi sinovia sendi yg klinis nyata
Tenosinovitis;inflamasi sarung tendon
Tendinitis;inflamasi tendon
Bursitis;inflamasi bursa
Entesopati;inflamasi/kelainan entesis(tempat me
melekatnya ligamen,tendon,kapsul sendi ke
perios tulang

Musculoskeletal disorders

may manifest as acute, subacute, or chronic problems.

Pain and interference with daily activities are what
bring the patient to a physician and determine the
impact of the condition.
A general medical approach to the patient with
rheumatic complaints is :

an accurate history and a thoughtful physical examination.

only limited additional testing is required to diagnosis most
musculoskeletal disorders, but in some instances assessment
with a number of laboratory analyses, imaging studies, and
other disciplines may be necessary.

Examination Components
There are four essential steps in musculoskeletal physical
examination.
A. Inspection
Inspect for asymmetry, deformity, erythema, and swelling.
B. Palpation
Palpate for tenderness, warmth, synovial thickening and effusion,
bony hypertrophy, and crepitus.
C.Range of Motion
Take the joint through passive or active ROM (or a combination of
both

D. Special Testing
Perform an assessment of supporting structures (such as
ligaments and tendons) or for conditions particular to a
single region (such as Tinel's sign at the wrist for
detection of carpal tunnel syndrome).

Objective Joint Findings

A careful examination is critical in distinguishing
articular from periarticular conditions.
Joint tenderness alone is insufficient for diagnosis and
must be correlated with the finding of an objective,
visible, or palpable abnormality for a diagnosis of
arthritis to be made.
Joint redness (erythema) depends on the acuteness and
severity of the underlying inflammation, and its presence
may suggest the possibility of infection or crystalline
arthritis.

Joint warmth also depends on the acuteness of the

underlying inflammation.
Joint swelling is a definitive sign of arthritis and
may be caused by either a joint effusion (excess
synovial fluid) or an inflamed and swollen synovial
membrane (synovitis). Bony hypertrophy around a
joint (osteophytic swelling) is characteristic of
osteoarthritis. Crepitus refers to a continuous
grating sensation that is felt by the examiner's
hand during joint motion. Fine or velvety crepitus
may denote chronic proliferative synovitis,
whereas coarse crepitus may indicate either
roughening of the cartilage surface or complete
loss of hyaline cartilage.
Joint damage and deformity are usually signs of
prior arthritis or injury (ligamentous laxity, joint
subluxation, tendon rupture, or contracture

Range of Motion

Both active and passive ROM are important in assessing joint function.
Active ROM is patient-initiated movement of the joint; it tests
integrated function and requires intact innervation and muscle and
tendon function, as well as joint mobility.
Passive ROM is examiner-initiated movement of a joint; it tests only
joint mobility.
The combined use of passive and active ROM minimizes the need for
patient instruction and maximizes the speed and efficiency of the
examination.
Whenever joint motion is anticipated to be painful, it is best to first observe
active ROM, to appreciate the degree of pain and dysfunction, before gently
attempting passive ROM.

Extra-articular

Findings
Because
many
rheumatic
diseases
are
multisystem
disorders,
physical
examination may document
the presence of important
extra-articular features.
In
RA,
for
example,these
include
subcutaneous
nodules, digital vasculitis,
and other systemic features
as described

Classification
Clinical

evaluation
enables
the
establishment of which anatomic structures
are inflamed, which are damaged, and how
function is impaired.
Nine types of rheumatic involvement can be
identified as a framework for various
diagnostic possibilities or hypotheses to be
considered (see Fig. 277-1B ).
The
nine categories presented in the
following paragraphs are listed in Table 2771 along with typical diseases, examples of
useful diagnostic tests, and treatments..

Synovitis

Inflammation of the synovial membrane lining

of the joint is typical of inflammatory
polyarthritides such as RA and other
autoimmune diseases.
Persistent synovitis in RA may lead to
irreversible joint damage

ENTHESOPATHY

The enthesis is the anatomic transition zone where

tendons, ligaments, and joint capsules attach to
bone.
Inflammation in this region is the hallmark of the
family
of
spondyloarthropathies,
of
which
ankylosing spondylitis is the prototype.
Other members of this group include reactive
arthritis associated with enteric or urethral
infection,
the
arthropathy
associated
with
inflammatory bowel disease, and psoriatic arthritis.
In ankylosing spondylitis, the sacroiliac joints and
apophyseal joints of the spine show characteristic
inflammation with a tendency to bony ankylosis
(axial predominance), whereas in psoriatic arthritis
there
is
frequently
enthesitis
with
an
oligopolyarthritis (peripheral predominance

Crystal-Induced Synovitis
Crystals of monosodium urate (gout), calcium
pyrophosphate (pseudogout), or hydroxyapatite are
capable of inducing an acute inflammatory reaction in
both synovial fluid and synovium.
Acute crystalline arthritis usually affects only one or at
most a few joints at a time.
Joint aspiration and synovial fluid analysis for crystals
using polarized light microscopy establish the diagnosis.
Calcium pyrophosphate deposition disease (CPPD) is often
associated with the radiologic appearance of
chondrocalcinosis of hyaline cartilage.

Joint Space Disease

Septic arthritis may develop from hematogenous spread of

microorganisms into the joint space, through local
extension from adjacent soft tissues or by joint
penetration.
Joint infections are usually associated with intense pain
even at rest, and the diagnosis is confirmed by joint
aspiration with Gram stain and culture of the synovial
fluid.
A joint prosthesis increases susceptibility to infection in
that joint. Blood in the joint space, known as hemarthrosis,
may result from microfractures, coagulopathy, or tumor

Cartilage Degeneration
OA is defined as loss of articular cartilage with a
bony response leading to the formation of
osteophytes.
Primary

OA is thought to be caused by biochemical

abnormalities in the cartilage that predispose to
microfissures in the surface and subsequent
degeneration of the cartilage.
Secondary OA may develop as a consequence of
inflammatory conditions such as RA, ankylosing
spondylitis, septic arthritis, and CPPD. Previous
trauma and joint hypermobility are other
mechanical factors that may predispose to OA

OSTEOARTICULAR DISEASE
Osteopenia/osteoporosis may complicate many
rheumatic conditions
Osteonecrosis, which results from collapse of the
bony end plate due to vascular insufficiency, causes
secondary crushing and fragmentation of the
overlying articular cartilage.
Osteonecrosis may be idiopathic or associated with
systemic conditions such as sickle cell disease or
liver disease; it may occur after treatment with
high-dose corticosteroids.

Inflammation of the periosteum, known as

periostitis, may be associated with hypertrophic
pulmonary osteoarthropathy and clubbing.
This syndrome may be a clue to underlying lung
cancer.

Inflammatory Myopathy

Inflammation and (usually painless) weakness of

the proximal skeletal muscles are characteristic of
inflammatory myopathies:

polymyositis,
dermatomyositis,
inclusion body myositis.

Elevatedcreatinekinaselevels, electromyographic
abnormalities, and characteristic histologic
abnormalities on muscle biopsy are present in
inflammatory myopathies

Local and Regional Conditions

Nonarticular disorders such as tendonitis,

bursitis, and neck and low-back strains are very
common regional problems.
They usually respond to

analgesics or nonsteroidal anti-inflammatory drugs,

physical therapy,
protective splints,
injection of corticosteroids

GENERAL CONDITIONS

These nonarticular or extra-articular disorders are

not usually associated with arthritis.
This group includes polymyalgia rheumatica,
complex regional pain syndrome/reflex sympathetic
dystrophy, and fibromyalgia.
Polymyalgia rheumatica usually affects Caucasians
older than 50 years of age and causes proximal
muscle pain in the neck, shoulders, and hips, with
significant morning stiffness and a high erythrocyte
sedimentation rate.
It is sometimes associated with giant cell (temporal)
arteritis.
Fibromyalgia usually manifests in individuals
younger than 50 years of age; is associated with
widespread arthralgia and myalgia (deceptively
inflammatory-sounding),
morning
stiffness,
significant fatigue, and nonrestorative sleep. It is
accompanied by the presence of tender points.

The pathogenetic mechanisms and feedback

loops associated with structural damage to the
cartilage structure and associated alteration in
chondrocyte function are demonstrated in
Figure 283-1 .

TABLE 283-2 -- RECOMMENDATIONS FOR

PHARMACOLOGIC MANAGEMENT OF
OSTEOARTHRITIS OF THE HIP AND KNEE [*]
ORAL Acetaminophen
Nonselective NSAID plus misoprostol or a proton pump
inhibitor[]
COX2-selective inhibitor
Nonacetylated salicylate
Other pure analgesics
Glucosamine and/or chondroitin sulfate
Tramadol
Opioids

CLASSIFICATION CRITERIA FOR RHEUMATOID ARTHRITIS[*]

1. Morning stiffness (1 hr)
2. Swelling (soft tissue) of three or more joints
3. Swelling (soft tissue) of hand joints (PIP, MCP, or wrist)
4. Symmetrical swelling (soft tissue)
5. Subcutaneous nodules
6. Serum rheumatoid factor
7. Erosions and/or periarticular osteopenia in hand or wrist joints seen on
radiograph *
Criteria 1 through 4 must have been continuously present for 6 wk or longer,
and criteria 2 through 5 must be observed by a physician
. A classification as rheumatoid arthritis requires that four of the seven criteria
be fulfilled. MCP = metacarpophalangeal; PIP = proximal interphalangeal

TABLE 285-3 -- DIFFERENTIAL DIAGNOSIS OF

RHEUMATOID ARTHRITIS
Disorder Subcutaneous Nodules Rheumatoid Factor -Viral
arthritis (hepatitis B and C, parvovirus, rubella, others)
- Bacterial endocarditis
+ Rheumatic fever +
- Sarcoidosis + + Reactive arthritis - - Psoriatic arthritis - Systemic lupus erythematosus
+ Primary Sjgren's syndrome
+ Chronic tophus gout + - Calcium pyrophosphate disease - Polymyalgia rheumatica - - Osteoarthritis (erosive) - - - = not
present; + = frequently present; = occasionally present

EXTRA-ARTICULAR MANIFESTATIONS OF RHEUMATOID ARTHRITIS

Skin Nodules,
fragility,
vasculitis,
pyoderma gangrenosum
Heart Pericarditis,
premature atherosclerosis, vasculitis, valve disease, and valve ring nodules
Lung Pleural effusions, interstitial lung disease, bronchiolitis obliterans,
rheumatoid nodules, vasculitis Eye Keratoconjunctivitis sicca, episcleritis,
scleritis, scleromalacia perforans, peripheral ulcerative keratopathy Neurologic
Entrapment neuropathy, cervical myelopathy, mononeuritis multiplex
(vasculitis), peripheral neuropathy Hematopoietic Anemia, thrombocytosis,
lymphadenopathy, Felty's syndrome Kidney Amyloidosis, vasculitis Bone
Osteopenia

Medical Therapy

In the treatment of RA, three types of medical

therapies are used:
I.
II.
III.

NSAIDs,
glucocorticoids,
DMARDs (both conventional and biologic).

Initial combination therapy appears to be

preferred over monotherapy

I. NONSTEROIDAL ANTI-INFLAMMATORY
DRUGS

NSAIDs are important for the symptomatic relief they provide to

RA patients; however, they play only a minor role in altering the
underlying disease process.

Therefore, NSAIDs should rarely, if ever, be used to treat RA

without the concomitant use of DMARDs. Many clinicians waste
valuable time switching from one NSAID to another before
starting DMARD therapy.
Much has been written about the gastrointestinal toxicity of
NSAIDs, and these concerns are particularly relevant to RA
patients, who often have significant risk factors including age
and concomitant steroid use.

Therefore, cyclooxygenase-2 (COX2)-selective agents have been a

popular choice for patients with RA. The recent evidence
linking these agents to increased cardiovascular toxicity has
been particularly troubling for patients with RA, who are
already at high risk for myocardial infarction.

Therefore, if COX2-selective agents are used,

they should be kept at a low dose.
Consideration should be given to low-dose
aspirin prophylaxis in RA, but this may
increase the gastrointestinal toxicity of
NSAIDs.
The use of concomitant misoprostol or
proton pump inhibitors should be considered
in all patients with RA who are taking
NSAIDs.
Additionally, the potential for NSAIDs to
decrease renal blood flow and to increase
blood pressure should be kept in mind.

II. GLUCOCORTICOIDS

Glucocorticoids have had a significant role

treatment of RA for more than half a century.

in

the

Indeed, RA was chosen as the first disease to be treated

with this new therapy, partly because it was thought that
RA was a disease of glucocorticoid deficiency (an issue
that remains unresolved).

As was the case with the first patient treated in 1948,

glucocorticoids are dramatically and rapidly effective in
patients with RA. Not only are glucocorticoids useful for
symptomatic improvement, but they significantly decrease
the radiographic progression of RA.
However, the toxicities of long-term therapy are extensive
and potentially devastating. Therefore, the optimal use of
these drugs requires an understanding of several
principles

Glucocorticoids remain among the most potent anti-inflammatory

treatments available; for this reason and because of their rapid onset
of action, they are ideally suited to help control the inflammation in
RA while the much slower-acting DMARDs are starting to work.
Prednisone, the most commonly used glucocorticoid, should rarely
be used in doses higher than 10 mg/day to treat the stiffness and
articular manifestations of RA.
This dose should be slowly tapered to the lowest effective dose, and
the concomitant DMARD therapy should be adjusted to make this
possible.
Glucocorticoids should rarely, if ever, be used to treat RA without
concomitant DMARD therapy.

The paradigm is to shut off inflammation rapidly with

glucocorticoids and then to taper them as the DMARD is taking
effect (bridge therapy).
In all patients receiving glucocorticoids, strong measure should be
taken to prevent osteoporosis. Bisphosphonates have been shown to
be particularly effective in this regard. Higher doses of
glucocorticoids may be necessary to treat extra-articular
manifestations, especially vasculitis and scleritis

III. DISEASE-MODIFYING ANTIRHEUMATIC

DRUGS
DMARDs are a group of medications that have the ability to
greatly inhibit the disease process in the synovium and
modify or change the disabling potential of RA. In most
cases, these drugs have the ability to halt or slow the
radiographic progression of RA.
Conventional DMARDs
Included in this group of medications are

methotrexate,
sulfasalazine (Azulfidine),
gold,
antimalarials (Plaquenil and others),
leflunomide (Arava),
azathioprine (Imuran),
minocycline.

It is critically important that clinicians

and patients understand that
conventional DMARDs take 2 to 6
months to exert their maximal effect,
and all require some monitoring ( Table
285-7 ). Therefore, other measures such
as glucocorticoid therapy may be
needed to control the disease while
these medications are starting to work.

All of these DMARDs have been shown to be effective in

treating both early and more advanced RA that remains
active.
Until additional research elucidates factors that allow
selection of the best initial therapy for each patient, the
choice will depend on patient and physician concerns about
toxicity and monitoring issues, as well as the activity of
disease and comorbid conditions.
The critical factor is not which DMARD to start first but
getting the DMARD therapy started early in the disease
process.

METHOTREXATE.

Methotrexate is the preferred DMARD of most

rheumatologists, in part because patients have a more
durable response, and because, with correct monitoring,
serious toxicities are rare.
Methotrexate is dramatically effective in slowing
radiographic progression and is usually given orally in
doses ranging from 5 to 25 mg/week as a single dose.
This once-a-week administration is worthy of emphasis;
prior experience with daily therapy in psoriasis has
demonstrated the importance of allowing the liver time
to recover between doses.
Oral
absorption
of
methotrexate
is
variable;
subcutaneous injections of methotrexate may be effective
if oral treatment is not.

Side effects of methotrexate include oral ulcers, nausea,

hepatotoxicity,
bone
marrow
suppression,
and
pneumonitis. With the exception of pneumonitis, these
toxicities respond to dose adjustments. Monitoring of
blood counts and liver blood tests (albumin and aspartate
aminotransaminase [SGOT] or alanine aminotransferase
[SGPT]) should be done every 4 to 8 weeks, with dosage
adjustments as needed.
Renal function is critical for clearance of methotrexate;
previously stable patients may experience severe
toxicities when renal function deteriorates. Pneumonitis,
although rare, is less predictable and can be fatal,
particularly if the methotrexate is not stopped or is
restarted.
Folic acid, 1 to 4 mg/day, can significantly decrease most
methotrexate toxicities without apparent loss of efficacy.
If methotrexate alone does not sufficiently control disease,
it is combined with other DMARDs.
Methotrexate in combination with virtually any of the
other DMARDs (conventional or biologic) has been shown
to be more effective than either drug alone.[2]

LEFLUNOMIDE.
Leflunomide, a pyrimidine antagonist, has a very long half-life
and is most commonly started at 10 to 20 mg/day orally.
A loading dose of 100 mg/day for 3 days was previously
recommended, but because it increases diarrhea, the most
common toxic effect of this drug, loading treatment is no longer
advocated. Diarrhea responds to dose reduction, and doses of
leflunomide of 10 to 20 mg three to five times per week are
frequently used.
Also, because of its long half-life and its teratogenic potential,
women wishing to become pregnant who have previously
received leflunomide, even if therapy was stopped years ago,
should have blood levels drawn.
If toxicity occurs or if pregnancy is being considered,
leflunomide can be rapidly eliminated from the body by
treatment with cholestyramine.
Laboratory monitoring for hematologic and hepatic toxicity
should be done during treatment with leflunomide, as
recommend for methotrexate.

ANTIMALARIAL DRUGS.
The antimalarial drugs hydroxychloroquine
(Plaquenil) and chloroquine are frequently used
for the treatment of RA.
They have the least toxicity of any of the
DMARDs and do not require monitoring of
blood tests.
Yearly monitoring by an ophthalmologist is
recommended to detect any signs of retinal
toxicity (rare).
Hydroxychloroquine is the most commonly used
preparation and is given orally at 200 to 400
mg/day. These drugs are frequently used in
combination with other DMARDs, particularly
methotrexate.[2]

SULFASALAZINE.
Sulfasalazine has been the most commonly
used DMARD in Europe. It is an effective
treatment when given in doses of 1 to 3
g/day.
Monitoring
of
blood
counts,
particularly white blood cell counts, in the
first 6 months is recommended.
MINOCYCLINE.
Minocycline, 100 mg twice daily, has been
shown to be an effective treatment for RA,
particularly when used in early, RF-positive
disease. Chronic therapy (longer than 2
years) with minocycline may lead to
cutaneous hyperpigmentation

GOLD.
Gold, the oldest DMARD, when given
intramuscularly, remains an extremely
effective therapy for a small percentage of
patients.
It is less commonly used because of its slow
onset of action, need for intramuscular
administration,
frequent
monitoring
required (complete blood count and
urinalysis), and frequent toxicities.
Toxicities include skin rashes, bone marrow
suppression, and proteinuria.

Biologic DMARDs

Recent research has continued to elucidate the central role

that cytokines, most notably TNF- and IL-1, play in the
pathophysiology of RA.

This has led directly to the development and clinical use of

biologic agents directed against TNF-1 (etanercept [3] [Enbrel],
infliximab [4] [Remicade], adalimumab [5] [Humira]) and IL-1
(anakinra [Kineret]).

Two other biologicals have recently been approved: rituximab

(Rituxan) and abatacept (Orencia). All RA patients receiving
biologic therapies should be monitored by a rheumatologist,
and their physicians should be aware of the risk for infections
that are often atypical.

Currently, biologic agents should not be used in combination

with each other, because all studies to date have shown a
significant increase in infections

ANTI-TNF- DRUGS

This category of drugs includes etanercept, a recombinant TNF

receptor fusion protein that is administered by subcutaneous injection
at 50 mg once weekly.

Infliximab is a mouse/human chimeric monoclonal antibody against

TNF- that is given intravenously (3 to 10 mg/kg) every 4 to 8 weeks.

Adalimumab is a human monoclonal antibody against TNF- that is

given subcutaneously at 40 mg every other week.

All three anti-TNF agents have been shown to be highly effective

against both clinical symptoms and radiographic progression of RA,
particularly when used in combination with methotrexate. A rapid
onset of action (days to weeks) is apparent and is a significant
advantage that these treatments have over conventional DMARDs.

Current disadvantages include cost and long-term toxicities, in

particular infections (especially tuberculosis and others), and
malignancies, [6] as well as heart failure, rare demyelinating, and
autoimmune syndromes.

ANAKINRA

Anakinra, a recombinant human IL-1 receptor

antagonist, is given subcutaneously at 100 mg/day.
It has been shown to be effective against signs and
symptoms of RA as well as radiographic
progression.
Its onset of action is somewhat slower and less
dramatic than that of the TNF inhibitors.
Toxicities include injection site reactions and
pneumonia (especially in patients with asthma

RITUXIMAB.

Rituximab is a chimeric monoclonal antibody that

targets CD20 + B cells and is given intravenously in
two infusions of 500 to 1000 mg spaced two weeks
apart.
This results in marked reductions in circulating B cells
for 6 to 12 months and significant clinical responses.
The need for and timing of further courses is
determined by the patient's ongoing response.
Rituximab has been used for years to treat B cell
lymphoma.

ABATACEPT.

Abatacept is made by genetically fusing the

external domain of human CTLA4 to the heavychain of human IgG1 and binds both CD80 and
CD86 on antigen presenting cells thus inhibiting
T cells from receiving their second signal via
CD28.
It is administered intravenously 10 mg/kg on
days 1, 15, 30 and then monthly

Treatment of Underlying Conditions

Optimal care of patients with RA requires

recognition of the associated comorbid
conditions, including :

an increased risk of cardiovascular death,

osteoporosis,
infections (especially pneumonia),
certain cancers

Cardiovascular Disease

Increasingly, cardiovascular disease is being recognized as the

cause of much of the excess mortality in RA.
A number of factors contribute to this mortality:

sedentary lifestyle,
glucocorticoid therapy,
treatments that increase homocysteine levels, such as methotrexate and
sulfasalazine.

However, recently a strong association between chronic inflammation

and cardiovascular disease was identified, and it is likely that this may be
the most significant factor. Therapies that control RA earlier and better
can be expected to decrease cardiovascular morbidity and mortality.
Clinicians should consider RA a risk factor for cardiovascular disease
and should aggressively address other cardiovascular risk factors in their
rheumatoid patients.

Osteoporosis

Osteoporosis is common in patients with RA, and early treatment results in

long-term dividends.
Patients with RA are at an increased risk for infections, and some forms of
treatment further increase this risk.
Patients should be cautioned to seek medical attention early for even minor
symptoms suggestive of infection, especially if receiving anti-TNF therapy.
All patients with RA should receive a pneumococcal vaccine at appropriate
intervals and yearly influenza vaccinations. Finally, patients with RA have
an increased risk of lymphoma.
Occasionally, B-cell lymphomas are associated with immunosuppression
and regress after immunosuppression is discontinued. RA patients have
significantly decreased risk (odds ratio, 0.2) of developing colon cancer.
This is thought to be secondary to chronic inhibition of COX by NSAIDs

TABLE 285-5 -- KEYS TO OPTIMIZE OUTCOME OF

TREATMENT OF RA
Early, accurate diagnosis
Early DMARD therapy
Strive for remission in all patients
Monitor carefully for treatment toxicities
Consider and treat comorbid conditions [*] DMARD = diseasemodifying antirheumatic drug; RA = rheumatoid arthritis.

Important comorbid conditions include cardiovascular

disease, increased susceptibility to infections, and
osteoporosis
*

TABLE 285-6 -- GUIDELINES FOR USE OF GLUCOCORTICOIDS

Avoid use of glucocorticoids without DMARDs
Prednisone >10 mg/day is rarely indicated for articular disease
Taper to the lowest effective dose
Use as bridge therapy until DMARD therapy is effective
Remember prophylaxis against osteoporosis DMARD = diseasemodifying antirheumatic drug.

TABLE 285-7 -- CAVEATS FOR MONITORING DMARD

THERAPIES[*]

TABLE 285-7 -- CAVEATS FOR MONITORING DMARD THERAPIES [*]

Medication Caveats Prednisone Use as bridge to effective DMARD therapy, prophylaxis
for osteoporosis? (see Table 285-6 ) Hydroxychloroquine Keep dosage lower than 6.5
mg/kg/day; yearly eye checkup by ophthalmologist Sulfasalazine CBC for neutropenia,
initially every month, then every 6 mo Methotrexate CBC and SGOT/SGPT every 48
wk; many toxicities respond to folic acid or small dose reduction; if pneumonitis, stop
and do not restart; decreasing renal function may precipitate toxicities; absolute
contraindication in pregnancy Leflunomide CBC and SGOT/SGPT evert 48 wk; long
half-life may require cholestyramine washout; absolute contraindication in pregnancy
TNF inhibitors If fevers or infectious symptoms of any kind, stop until symptoms
resolve; aggressively work-up and treat possible infections; may precipitate congestive
heart failure, demyelinating syndromes, or lupus-like syndromes CBC = compete blood
count; DMARD = disease-modifying antirheumatic drug; SGOT = serum glutamate
oxaloacetate transaminase (aspartate aminotransferase); SGPT = serum glutamate
pyruvate transaminase (alanine aminotransferase); TNF = tumor necrosis factor.

TABLE 294-1 -- HYPERURICEMIA: CAUSES AND

CLASSIFICATION[*]
A. Uric acid overproduction 1. Primary hyperuricemia
Idiopathic HGPRT deficiency (partial and complete) PRPP
synthetase superactivity 2. Secondary hyperuricemia
Excessive dietary purine intake Increased nucleotide turnover
(e.g., myeloproliferative and lymphoproliferative disorders,
hemolytic diseases, psoriasis, and Paget's disease of bone)
Accelerated ATP degradation Ethanol abuse Glycogen
storage diseases (types I, III, V, VII) Fructose ingestion,
hereditary fructose intolerance Hypoxemia and tissue
underperfusion Severe muscle exertion ?
Hypertriglyceridemia (via metabolism of excess acetate

. Uric acid underexcretion 1. Primary

hyperuricemia Idiopathic (influenced by
gender and ethnicity) Familial juvenile
hyperuricemic nephropathy

2. Secondary hyperuricemia Diminished glomerular

filtration rate Enhanced tubular urate reabsorption
Dehydration Diuretics Insulin resistance (metabolic
syndrome) Inhibition of tubular urate secretion
Competitive anions (e.g., keto and lactic acidosis)
Mechanism incompletely defined Hypertension
Hyperparathyroidism Hypothyroidism Certain drugs
(e.g., cyclosporine, pyrazinamide, ethambutol, and lowdose salicylates) Lead toxicity with nephropathy ATP =
adenosine triphosphate; HGPRT = hypoxanthine-guanine
phosphoribo-syltransferase; PRPP =
phosphoribosylpyrophosphate

Clinical Manifestations

Gout is classically manifested as recurrent attacks of acute

arthritis characterized by often excruciatingly painful articular
and periarticular inflammation, including erythema and edema
of the skin that can mimic bacterial cellulitis.
Acute gouty arthritis is typically monarticular or
oligoarticular. Stereotypical involvement of the first MTP
joint is termed podagra. Acute polyarticular gout can also
occur, particularly in the elderly and in transplant patients
taking cyclosporine.
This manifestation can be associated with substantial systemic
leukocytosis and temperature elevation mimicking sepsis.
Chronic gouty inflammation and proliferative, erosive arthritis
in gout can also mimic rheumatoid arthritis.

Goutytophi can involve not only the synovium and

cartilage of joints but also subchondral bone and soft
tissues, including the olecranon bursa, the first MTP
joint bursa, and the helix of the ear.
Olecranon bursitis may occur in association with gout,
but tophi in the olecranon bursa often remain
clinically quiescent.
Uric acid urolithiasis is a common manifestation of
gout, particularly in acid urine. Excessive excretion of
uric acid in the urinary tract also promotes calcium
oxalate urolithiasis.
Interstitial
nephropathy, characterized by the
deposition of monosodium urate in the renal medulla
at physiologic pH, is currently a rare manifestation of
gout, largely because of advances in recognition and
treatment of gout and hypertension.

Onset of gout (with or without tophaceous crystal

deposits) in early adulthood and a high incidence of uric
acid urinary tract stones constitute the common clinical
phenotype in both partial deficiency of hypoxanthineguanine phosphoribosyltransferase (HGPRT) and milder
forms
of
superactivity
of
5-phosphoribosyl
1pyrophosphate (PP-ribose-P) synthetase.
Severe HGPRT deficiency is associated with spasticity,
choreoathetosis, mental retardation, and self-mutilation
(Lesch-Nyhan syndrome).
In some subjects, regulatory defects in PP-ribose-P
synthetase are accompanied by sensorineural deafness
and neurodevelopmental defects. The genes for both
HGPRT and PP-ribose-P synthetase are X-linked. Thus,
homozygous males are affected, and postmenopausal gout
and urinary tract stones can occur as the phenotype of
carrier females.
Hyperuricemia in prepubertal boys always suggests the
need to determine whether one of these enzymatic defects
is the etiology