RHEUMATIC

dr. Pandji M,SpPD,KEMD

05/22/15

SAMSUN NISAK WN_08B

TERMINOLOGI
2

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)

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Cont terminologi
3

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

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Musculoskeletal disorders
4

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.

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Examination Components
5

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
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Objective Joint Findings

A careful examination is critical in

articular from periarticular conditions.

distinguishing

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
6
arthritis.

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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).

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D. Special Testing

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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

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Range of Motion
8

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.

SAMSUN NISAK WN_08B

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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
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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
277-1 along with typical diseases,
examples of useful diagnostic tests, and
treatments..
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10

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11

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12

Synovitis
13

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

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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.

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ENTHESOPATHY

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
14

Crystal-Induced Synovitis
15

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.

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Joint Space Disease

16

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

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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
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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
18
cancer.

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OSTEOARTICULAR DISEASE

Inflammatory Myopathy
19

Inflammation and (usually painless) weakness of

the proximal skeletal muscles are characteristic
of inflammatory myopathies:

polymyositis,
dermatomyositis,
inclusion body myositis.

Elevated
creatine
kinase
levels,
electromyographic
abnormalities,
and
characteristic histologic abnormalities on muscle
biopsy are present in inflammatory myopathies

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Local and Regional Conditions

20

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

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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.

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GENERAL CONDITIONS

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.
21

22

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 .

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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

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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

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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

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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

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Medical Therapy
27

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

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I. NONSTEROIDAL ANTI-INFLAMMATORY
DRUGS

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.

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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.

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.
28

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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.

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II. GLUCOCORTICOIDS

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).

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Glucocorticoids have had a significant role

treatment of RA for more than half a century.

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

30

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Glucocorticoids remain among the most potent antiinflammatory 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
31
extra-articular manifestations, especially vasculitis and
scleritis

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III. DISEASE-MODIFYING ANTIRHEUMATIC

DRUGS

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.

32

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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.

33

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.

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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.
34

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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.

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METHOTREXATE.

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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]

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35

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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
36
leflunomide, as recommend for methotrexate.

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LEFLUNOMIDE.

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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]

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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

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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.

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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.

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39

40

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

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ANTI-TNF- DRUGS
41

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.

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ANAKINRA
42

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

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RITUXIMAB.
43

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.

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ABATACEPT.
44

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

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Treatment of Underlying Conditions

45

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

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Cardiovascular Disease
46

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.

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Osteoporosis
47

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 antiTNF 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

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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 =
disease-modifying antirheumatic drug; RA =
rheumatoid arthritis.

Important comorbid conditions include cardiovascular

disease, increased susceptibility to infections, and
osteoporosis
*

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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[*]
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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.

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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

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. Uric acid underexcretion 1. Primary

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

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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 low-dose salicylates) Lead toxicity with
nephropathy ATP = adenosine triphosphate; HGPRT =
hypoxanthine-guanine phosphoribo-syltransferase;
PRPP = phosphoribosylpyrophosphate

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Clinical Manifestations
54

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.

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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.

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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
hypoxanthine-guanine
phosphoribosyltransferase
(HGPRT) and milder forms of superactivity of 5phosphoribosyl
1-pyrophosphate
(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 Xlinked. 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

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