Rheumatoid Arthritis

What should be evaluate

Deske Muhadi
Div. Reumatologi - Penyakit Dalam
FK USU
History of RA
 Rheumatoid Arthritis (RA)
Definition
Year/Milestone Finding
2
Pre-Columbian Old Analysis of skeletal remains not consistent with criteria The National Cancer Institute accurately describes rheumatoid arthritis (RA)
World (Europe) for establishing the presence of RA. Disease most likely as “an autoimmune disease that causes pain, swelling, and stiffness in the joints,
spondyloarthropathy. and may cause severe joint damage, loss of function, and disability. The disease
Pre-Columbian North Analysis of skeletal remains consistent with current criteria may last from months to a lifetime, and symptoms may improve and worsen
America for establishing the presence of RA. overDEFINITION
time”.1 RA can appear in the upper extremities, lower extremities, and
15th to 17th century Hands of models by painters of the Flemish school suggest spine and axial joints, with characteristics including:2
presence of RA-type lesions. • Inflammation (joint swelling with characteristic soft tissue involvement)
• Polyarthritis (involvement of >5 joints)
1800 Dissertation of AJ Landré-Beauvais separates RA from gout
as a unique disease. • Symmetry (same joint regions of both upper and lower extremities)
• Chronicity (duration of >6 weeks)
1875 Sir Alfred Baring proposes the term rheumatoid arthritis.
• Autoantibodies (RF, anti-CCP, anti-RA33)
1907 Sir Archibald Baring distinguishes osteoarthritis from RA.
• Erosions (bony destruction seen on conventional x-ray)
1922 British Ministry of Health officially adopts the designation • Absence of recent infections or comorbid conditions associated with
of RA. arthritides
1940 onward Science of immunology introduced to the study of RA. • Painful metacarpophalangeal (MCP) or metatarsophalangeal (MTP)
Discovery of rheumatoid factors. compression
1941 American Rheumatism Association (now the American • Morning stiffness (lasting more than a few minutes)
College of Rheumatology) officially adopts the designation • Genetics
of RA.
The disease process may be characterized as having four distinct phases: an ini-
1960–1970 onward Reports of highly specific antibodies for RA appear. tial phase in which there is no clinical evidence of the disease but some patients
Research focuses on anti-citrullinated peptide antibodies may have markers in the blood that denote autoimmunity; an early inflammatory
(ACPAs). phase that includes clinical manifestations that may or may not be accompa-
Early 1970s Rheumatoid arthritis and rheumatoid spondylitis, previously nied by a confirmed diagnosis of RA; a destructive phase that includes erosions
thought to be an arthritis of the spine, distinguished as and disease progression; and an ongoing phase accompanied by irreversible
separate diseases. RA antibodies were not present in joint destruction.3 Simultaneously, there are two overlapping subpopulations
patients with spondylitis. of patients with RA: individuals who are positive for the presence of rheuma-
Late 1970s onward Possible role of genetic factors explored. HLA-DRB1 toid factor (RF), and individuals who are positive for the presence of antibodies
associated with disease onset and severity. that can bind cyclic citrullinated peptides (CCP).4 Patients with either of these
2000 and beyond Research focused on gene–environment interactions. biomarkers tend to have a more severe course ofMichael RA,H Wisman,
with Rheumatic
anti-CCP
Arthritis,antibod-
OARL, 2011
4
 INTRODUCTION
1. Women
2. Autoimmune
3. Genetic
4. Environment
5. Systemic symptoms
6. High grade
inflammation
7. Polyarthritis
(PIP,MCP)
8. Specific deformities
A RA Mechanisms

B
 HOST AND MICROBIOME CROSS-TALK IN HEALTHY STATE AND AUTOIMMUNE ARTHRITIS

Host genetics Diet Antibiotics

Homeostasis Dysbiosis

Gut lumen

Mucus layer

Epithelial cells

SAA
PSA ATP
Th17 Th1 CCL5?

Lamina propria Dendritic Treg

cell

Plasma
cell
Macrophage

Blood
Circulation
vessel

Lymph node Spleen

Peripheral
immune
system
B cell

Bone
Ligament Autoreactive Th1 and Th17
Cartilage Pannus → proinflammatory cytokines
Synovial fluid formation (IL-17, IFN-γ, TNF, etc.)
Synovial membrane Immune-complex deposition
Macrophage, fibroblast, and
osteoclast activation
Bone → cartilage and bone degradation

Healthy Inflammatory
Joint Arthritis The microbiome and rheumatoid arthritis. Nat Rev Rheumatol 2011;7:569-78.)
Key pathogenetic
Table concepts
1.1 Key pathogenetic in RA
concepts in RA
Pathogenetic concept Consequences
Autoimmunity Citrullination of self-proteins in the lung generates neoepitopes,
Mucosal initiation which are presented by the shared epitope to cognate T-cells. Then,
Self-protein modifications the activated T-cell provide help to B-cell, which finally differentiate
Ag presentation by the SE to ACPA-producing plasma cells
Ab production
Gene-environment Smoking induces citrullination and inflammation in the lung and
interaction triggers ACPA production in carriers of SE or PTPN22 variants
Epigenetic imprinting RA FLS possess epigenetic modifications inducing long-lasting
changes in the expression of pathogenic genes even in the absence
of external stimulation.
Imprinted FLS may drive the residual inflammation observed in RA
despite aggressive immunosuppression with DMARDs
Cytokine hierarchy TNF and IL-6 are the dominant upstream inducers of the cascade of
mediators that drive synovitis
Inflammatory bone loss Inflammatory cytokines and autoantibodies induce activation of OC
Cytokine-driven bone loss and inhibition of OB, promoting systemic and local bone loss.
ACPA-driven bone loss ACPA may drive systemic bone loss in the absence of synovitis
Ag antigen, SE shared epitope, Ab antibody, ACPA anti-citrullinated peptide antibody, FLS
fibroblast-like synoviocytes, OC osteoclasts, OB osteoblasts
Diagnosis of RA
Development Diseases RA
Clinical Manifestation

2010 ACR/EULAR
classification
criteria for RA
wing erosions at the
alangeal joints
und of small joints, relatively
tection of synovitis and joint
eumatologists to confirm the
ess. Ultrasound and MRI are
e detection of joint inflamma-
more accurate assessment of
s diagnostic doubt.
aphy is the modality of choice
pulmonary fibrosis and should
mal lung function.
diagnosis in a typical presen-
Box 12.2 2010 ACR/EULAR classification criteria for RA
Target population: Patients who (i) have at least one joint with
clinical synovitis, and (ii) with the synovitis not better explained by
another disease
Add score of categories A–D; score of 6/10 or more is needed to
classify patient as having definite RA
A. Joint involvement (tender/swollen)
1 large joint 0
2–10 large joints 1
1–3 small joints (with or without involvement of large joints) 2
4–10 small joints (with or without involvement of large joints) 3
>10 joints (at least 1 small joint) 5
B. Serology
Negative RF and anti‐CCP 0
Low positive RF/low positive anti‐CCP 2
High positive RF/high positive anti‐CCP 3
C. Acute‐phase reactants
Normal CRP and ESR 0
Abnormal CRP and ESR 1
D. Duration of symptoms
Less than 6 weeks 0
6 weeks or more 1
 Clinical Presentation
and
Radiographic Features
Table 5.1 Upper and Lower Extremity Articular and Periarticular Manifestations of Rheumatoid Arthritis (RA)
Location Percent of Patients Affected
Upper Extremity
Hand • 55% of RA patients experience
tenderness, warmth, and
swelling along the flexor or
extensor digital tendons.
• MCP joints are usually the
“calling card” of patients with
RA and distinguish this disease
clinically from osteoarthritis
even in its inflammatory forms.
Wrist • Up to 50% of patients
experience wrist involvement
in the first two years from
disease onset.11
• Up to 75% of patients will
experience wrist involvement
during the course of the
disease.12
Signs and Symptoms
• Pain and swelling of the MCP
and PIP joints, usually symmetric. • Soft tissue swelling around the MCP and
• Pain and stiffness worse in the
morning.
• Tendon ruptures presenting
as painless, sudden loss of
extension or flexion.
• With ongoing inflammation,
evidence of clinical hypertrophy
of the synovial lining and
inflammation of periarticular
structures.
• Pain, swelling, limited range of
motion, usually symmetric.
• Pain and stiffness worse in the
morning.
• Pain on the radial aspect of the
wrist that may radiate proximally • Ongoing inflammation can lead to
caused by tenosynovitis.
• Loss of wrist extension.
• Decreased sensation with
numbness and tingling especially
in the night-time hours.
Clinical Exam
• Warm, erythematous joints with effusions.
PIP joints.
• Decreased grip strength.
• Synovial thickening can be detected on
physical exam by feeling a bogginess of the
joint on palpation.
• In later stages of RA, there are anatomic
disruptions of the integrity of the joint
surfaces, ligaments, and tendons that
cause visible joint deformities such as the
boutonniere and swan neck deformities.
• Swelling is most prominent dorsally as
well as over the ulnar styloid, and a typical
feature is often visible swelling and rope-
like thickening of the extensor carpi ulnaris
tendon sheath.
erosions, tenosynovitis, and nerve
compression.
• Chronic infl ammation at the wrist leads
to deformities, loss of function, and bony
attrition, affecting adjacent tendons that
may result in tendon rupture.
Radiographic Findings
• Joint space narrowing of MCP
and PIP joints.
• Soft tissue swelling related to
joint effusion, synovitis, and
periarticular edema.
• Progression of carpal
involvement measured by
cartilage loss and bone
compaction at the radial to
lunate, lunate to capitate, and
capitate to third metacarpal
articulations.
• Radial deviation at the wrist
can be readily seen on a PA
radiograph when more than half
of the lunate articular surface is no
longer articulating with the radius.
(continued)
Table 5.1 Continued
Location Percent of Patients Affected
Elbow • Incidence of mild erosions:
33%.
• Incidence of severe erosions:
18%.
Shoulder • Incidence of mild erosions: 27%. • Shoulder pain and stiffness.
• Incidence of severe erosions:
21%.
• 55% of seropositive RA patients
develop erosions of the
glenohumeral joints within 15
years of disease onset.
Signs and Symptoms
• Loss of full extension at the
elbow, of which patients may be
unaware due to compensatory
function by wrists and shoulders.
• Decreased range of motion.
• Difficulty sleeping.
Clinical Exam
• Mild flexion contractures and nodule
formation on the extensor surface of
the elbow that may lead to cortical bone
erosions in the underlying ulna and radius
and appear like scalloped defects.
• With continued inflammation, the valgus
angulation can become three times
greater than normal with severe flexion
contractures leading to functional disability.
• Erosions are most observed on the
capitellum, the lateral epicondyle, and the
olecranon.
• Limited abduction and external rotation of • Radiographic findings are
the affected arm.
• Shoulder joint, rotator cuff muscles, and
shoulder bursa may be affected.
• Synovitis may present with an anterior
effusion resembling a mass.
• Inflammation can progress to destruction of
the rotator cuff muscles, superior subluxation
of the humeral head, and extension of the
pannus into the glenohumeral joint.
Radiographic Findings
• Soft tissue changes are seen with
joint effusions displacing the
anterior and posterior fat pads.
• Initial positional changes include
an anterior, anterolateral, or
ventral subluxation of the
radial head in relation to the
capitellum of the humerus.
• Late radiographic changes
of joint destruction of the
elbow are narrowing of the
humeroradial and humeroulnar
joint spaces, and marked bone
destruction of both the humerus
and the olecranon bones at their
articulating surfaces.
typically absent in early RA
shoulder involvement in spite of
a great deal of pain and limited
mobility of the joint.
• A late finding on radiography
is glenohumeral joint space
narrowing, indicating more
marked erosive destruction.

Lower Extremity
Foot and • 90% of RA patients will
Ankle experience foot and ankle
manifestations during the
course of their disease.
• Pain on weight-bearing
movement and walking.
• Swelling of the feet may
necessitate an increase in shoe
size.
• Forefoot is the most common
painful area.
• Heel pain is uncommon.
• Patients may complain of
paresthesias if synovitis
compresses the tarsal tunnel
where the posterior tibial nerve
runs.
• With continued chronic inflammation,
weakening of the rotator cuff muscles will
cause superior subluxation of the humeral
head.
• Acromioclavicular joint damage is
commonly seen and correlates well with
glenohumeral joint destruction.
• Swelling in the synovium and soft tissues of • Early radiograph changes include
the metatarsal-phalangeal joints may cause
the metatarsal heads to splay laterally so
that a light shining between the toes can
be seen.
• A slight squeeze across the MTP joints may
prove very tender.
• Hallux valgus is present when the first
metatarsal and the base of the first
phalange are at an angle greater than 20
degrees.
• The hind foot structures (ankle and
subtalar joints) are typically affected;
grasping the hind foot and inverting it at
the level of the ankle will cause stress pain
across the subtalar joint.
• A very late and uncommon
finding is rupture of the long
head of the biceps tendon
presenting as a soft tissue mass
in the upper arm.
periarticular osteopenia and soft
tissue swelling.
• The forefoot usually displays
the earliest changes with the
lateral fifth metatarsal head first
to show an erosion as well as
the medial side of the proximal
interphalangeal joint of the
great toe.
• Diffuse joint space narrowing of
the ankle and tarsal articulations
may also be observed.
• With continued inflammation,
the AP radiography may show
proximal phalanges end-on, or
the “gun-barrel sign.”
(continued)

Table 5.1 Continued
Location Percent of Patients Affected
Knee • 70% to 80% of RA patients will
experience knee involvement
(4).
Hip • 10% in patients with disease
duration less than 10 years.
• 40% in patients with disease
duration more than 10 years.
Signs and Symptoms
• Pain associated with weight
bearing and restriction of
movement of the knee.
• Weakness, contractures, and
difficulty walking occur with
persistent inflammation.
• Stiffness.
• Groin pain or medial knee pain
that is referred from the hip.
28 CHAPTER 5
Clinical Exam
• Synovial hypertrophy can be palpated in
the supra-patellar pouch and alongside the
inferior margins of the patella.
• Effusions may be observed by patellar tap
(“ballottement”) or the bulge sign.
• Limited range of motion (by pain) may be
demonstrated in all directions but with
rotation primarily affected in the early
stages.
Clinical Signs and Symptoms
Radiographic Findings
• Joint effusion with enlargement
of the suprapatellar bursa on
lateral films.
• Narrowing of medial and lateral
knee compartments on weight
bearing films as well as bare area
erosions, and valgus or varus
deformities may occur as the
disease progresses.
• Popliteal or Baker’s cysts.
• Diffuse joint space narrowing
with erosions of the femoral
head and neck.
• Osteonecrosis or avascular
necrosis.
• Protrusio deformities can take
place in very late stage RA hip
involvement.
patients.16
Extra-articular RA Manifestations by Organ System 1

Clinical Signs and Symptoms

Table 5.2
Table 5.2 Extra-articular RA Manifestations by Organ System 1 Continued
Constitutional symptoms Neurologic
Fever Compression neuropathy (such as carpal tunnel syndrome)

29
Asthenia Mononeuritis multiplex
Weight loss Cervical myelopathy
Malaise Central nervous system disease (stroke, seizure, hemorrhage,
Anorexia encephalopathy, meningitis)
Rheumatoid nodules Skin
Subcutaneous Distal leg ulcers
Lung parenchymal Palmar erythema
Cutaneous vasculitis
Cardiovascular

CHAPTER 5
Vasculitis (coronary arteritis) Hematologic
Pericardial inflammation and effusion
74 ABC of Rheumatology
Anemia
Myocarditis Thrombocytosis
Mitral valve disease Granulocytopenia
Conduction defects Eosynophilia
Pulmonary Cryoglobulinemia
Pleural effusions Hyperviscosity
Pulmonary nodules Renal
Interstitial fibrosis Glomerulonephritis
Pneumonitis
Figure 12.1 Typical changes in the hands in rheumatoid arthritis
Vasculitis
Arteritis Figure 12.3 Magnetic resonance image of the cervical spine showing Secondary amyloidosis
atlantoaxial involvement in rheumatoid arthritis

Ocular Hepatic
30

Keratoconjunctivitis sicca Elevated liver enzymes

Episcleritis
Scleritis 1 Reprinted from European Journal of Radiology Vol 27, Grassi W, DeAngelis R, Lamanna G,
Cervini C. The clinical features of rheumatoid arthritis, S18-S24, 1998 with permission from Elsevier.
Conjunctivits Figure 12.4 Scleritis in rheumatoid arthritis
 as initially reported in patients receiving perforation. Histopathologic examination shows granulomatous inflammation
ammatory arthritis.21 It is characterized in the presence or absence of leukocytoclastic vasculitis. In some of the
les mainly on the hands of RA patients
nce of similar nodules has been observed
PsA. Accelerated rheumatoid nodulosis NONSPECIFIC SKIN MANIFESTATIONS AND ASSOCIATED
BOX 35.4 NONSPECIFIC SKIN MANIFESTATIONS AND ASSOCIATED
eceiving etanercept,22 as well as in one SKIN DISORDERS IN RHEUMATOID
SKIN DISORDERS ARTHRITIS
IN RHEUMATOID ARTHRITIS
bitor,23 thus indicating that MTX is not
manifestations of RA. Like other granu- Pyoderma gangrenosum
A (see later), infections by typical and Palisaded neutrophilic and granulomatous dermatitis
opportunistic or endemic bacteria, have Interstitial granulomatous dermatitis
s taking immunosuppressants. Atrophic and fragile skin
mplication of RA that may involve the Pale and transparent skin
y affect vessels of any size. Accordingly, Palmar erythema
a variety of cutaneous skin signs (Box Livedoid (Raynaud-like) fingertips
inly male RA patients with long-standing Onychorrhexis and clubbing of the nails
lly represents palpable and nonpalpable Onycholysis
ter hemorrhages, nail-fold infarctions Periungual erythema
neuropathy. In medium-vessel disease, Yellow nail syndrome
ulcerations, livedo reticularis, and digital Splinter hemorrhages and nail-fold thromboses
matoid vasculitis is associated with high Pressure ulcers
ntensive immunosuppressive therapy is Hyperpigmentation
s, preferentially nodules, and immuno- Transient macular erythema
n helpful in establishing the diagnosis. Erythromelalgia
requently observed in cases in which Noninflammatory purpura
e conduction studies and sural nerve or Erythema multiforme
he differential diagnosis of rheumatoid Urticaria
osa, pyoderma gangrenosum (PG), SLE, Erythema nodosum
y (ANCA)–associated granulomatous Vitiligo
iutinum. Alopecia areata
ntioned specific skin manifestations of Nonmelanoma skin cancer
n signs and associated dermatoses have Intralymphatic histiocytosis of the skin
associated with both seronegative and
Markus Böhm, The skin in rheumatic disease, Marc Hochberg, Rheumatology 2018
310 SECTION 3 Approach to the Patient
Table 40.3
Principal types of renal pathologies in the rheumatic diseases
Systemic lupus erythematosus
Mixed connective tissue disease
Rheumatoid arthritis
Sjögren syndrome
Relapsing polychondritis
Behçet disease
Polyarteritis nodosa (classic)
Microscopic polyarteritis
Glomerular diseases
Mesangial GN (WHO class II)
Focal proliferative GN (WHO class III)
Diffuse proliferative GN (WHO class IV),
including membranoproliferative GN
(mesangiocapillary GN) and crescentic and
necrotizing GN (WHO class V)
Membranous GN
Mesangial GN
Focal proliferative GN
Crescentic necrotizing GN (with vasculitis)
Membranous GN (gold, penicillamine)
Renal amyloidosis (see later)
Membranoproliferative GN (mesangiocapillary
GN) (with cryoglobulinemia)
Mild mesangial GN
Focal sclerosing GN
Crescentic GN or milder proliferative GN
Renal amyloidosis (see later)
Ischemic sclerosis of glomeruli
Focal necrotizing and crescentic GN
Renal vascular diseases Tubulointerstitial diseases
Vasculitis of the kidney Lupus tubulointerstitial nephritis
Thrombotic microangiopathy (with Drug induced (e.g., NSAIDs,
thrombotic thrombocytopenic cyclosporine)
purpura or anticardiolipin syndrome) Membranous GN
“Lupus vasculopathy” (see text)
Renal vein thrombosis
“Scleroderma kidney” (see later)
Vasculitis (rheumatoid) of the kidney Analgesic nephropathy (NSAIDs)
Other drug induced (e.g., NSAIDs,
methotrexate, cyclosporine)
Lymphocytic tubulointerstitial
nephritis (with hypokalemic RTA)
Tubulointerstitial nephritis
Renal artery aneurysms and intrarenal
microaneurysms
Arteritis and aneurysms of medium-
sized vessels Beje Thomas, The kidneys and rheumatic diseases, Marc Hochberg, Rheumatology 2018
Vasculitis of small vessels (arterioles,
Laboratory Test
 “First hit” “Second hit”
e.g., smoking e.g., trauma, infection, dysbiosis

Mucosal surfaces Synovium, Bone,

Synovium
(e.g., Lung) Cardiovascular system

Individuals at-risk Pre-clinical RA Early RA Established RA

Erosive Arthritis
RA-associated genetic variations Auto-Abs (ACPA, RF, anti-CarP) Arthralgia/Arthritis
Comorbidities
Epigenetic modifications Osteopenia

Key events: Key events: Key events:

Citrullination of lung proteins Epitope spreading Citrullination of synovial proteins
Activation of adaptive immunity Isotype class switch Local production of autoantibodies
Break of immune tolerance to modified proteins Cytokine/chemokine production Local production of complement
Production of autoantibodies Activation of synovial endothelium Immune complex deposition
Synovial infiltration by mononuclear cells Complement activation
Activation of resident synovial cells Cytokine networks
Osteoclast activation
Bone erosions and systemic bone loss
“Imprinting” of FLS
Pannus
Cartilage degradation

Fig. 1.1 The road map of RA pathogenesis

 Key1.2differences
Table Key differencesbetween seropositive-
between seropositive- and seronegative-RA
and seronegative-RA
Seropositive
RA Seronegative RA Comments
Serology Positive Negative In seropositive-RA, positivity for
ACPA, RF, and anti-CarP exists in
various combinations (e.g., single,
double, or triple)
Genetics Shared PRL Distinct and overlapping genetics
epitope NFIA suggest differences and similarities in
PTPN22 pathogenesis.
Ag-driven activation of T-cells is more
critical in ACPA-positive RA
Environment Smoking Unknown Environmental factors are critical for
both serotypes.
Lung irritation triggers ACPA
production
Joint damage Destructive Less destructive Bone erosions may occur via cytokine-
arthritis mediated effects on OC and OB in both
serotypes.
In ACPA-positive RA, there is an
additional ACPA-driven impact
Extra-articular Variable Less frequent Nodules, vasculitis, and serositis are
manifestations more frequent in seropositive RA
Treatment Variable Less responsive to Cytokine networks involved in both
responses rituximab and serotypes.
abatacept B-cells and T-cell co-stimulation less
critical in seronegative RA
ACPA anti-citrullinated peptide antibody, RF rheumatoid factor, CarP carbamylated proteins, OC
osteoclasts, OB osteoblasts

studies in ACPA-positive subjects revealing (a) radiographic signs of parenchymal George D. Kalliolias Absolute Rheumatology Review, 2019
 Table 12.1 Specificity and sensitivity
Specificity and sensitivity of RFofand anti‐CCP
RF and anti-CCP

RF Anti‐CCP

Specificity Fair (80%) Excellent (95%)

diagnostic Sensitivity Fair (78%) Fair (78%)
ositive and Frequency in healthy 10–15% 1–2%
2010 ACR/ individuals
Effect of age Increased levels None
Presence in other Infection, other autoimmune Very rare
diseases diseases, e.g. Sjogren’s
syndrome, cryoglobulinaemia,
n with time, lymphoproliferative disorders
the symp- Association with Positive Positive
X‐ray damage
ive pattern
a period of
lammatory
an raise the leucocyte response is uncommon and usually indicative of an infec- Mohammed Akil , ABC of Rheumatology, 2019

tion, which should be excluded in such situations. Acute‐phase

 Clue of Diagnosis RA

Poly artritis simetric

Small joint arthritis

Fever & fatigue

Radiographic Features
Fig.
Plain2.5
x-rayPlain x-ray
showing showing
changes changes
of early RA of early
– periarticular RA –with
osteopenia Fig. 2.6
periarticular osteopenia
reduced with reduced
joint space particularly joint
around the space
MCPs with established
particularly around the MCPs. of the MTP joint
and joint erosion
 Fig. 2.7 Plain x-ray of hands in long-standing Fig.
Plain x-ray of hands in long-standing destructive RA – generalized osteopenia, fusion
2.8 Ultrasoun
of both wrists with obliteration of joint spaces, erosive changes at MCPs and PIPs
both wrists
with destruction of thewith obliteration
metacarpal heads andofassociated
joint spaces, erosive
subluxation of the MCPs. hypertrophy
and
changes at MCPs and PIPs with destruction of the with active synov
Bilateral posteroanterior hand
radiographs demonstrate multiple
erosions (arrows) involving
predominantly the proximal
interphalangeal and
metacarpophalangeal joints.
Assessment of bilateral involvement
and symmetry is helpful in narrowing
the differential diagnosis.
 Fig. 6.3 Classic findings
on hand XRs in RA
include periarticular
osteoporosis, joint space
narrowing in 2nd and 3rd
MCPs and carpal joints
which has resulted in
carpal fusion. Marginal
erosions can be seen such
Classic findings on4th
as in the hand XRs in
and 5th
RA include periarticular
MCPs. Boutonniere
deformity can be seen in
osteoporosis, joint space
the 4th digit
narrowing in 2nd and 3rd
MCPs and carpal joints which
has resulted in carpal fusion.
Marginal erosions can be seen
such as in the 4th and 5th
MCPs. Boutonniere deformity
can be seen in the 4th digit
Differential Diagnosis
 216 is suggested by loca
and may be confirm
taining the wrist in
the digits distal to t
sor tendon sheaths.
DIP: OA, Focal wrist pain
psoriatic,
reactive
caused by De Qu
inflammation of the
PIP: OA, SLE, tor pollicis longus o
RA, psoriatic This commonly resu
and may be diagno
MCP: RA,
pseudogout,
result is present whe
hemochromatosis thumb is flexed and
1st CMC: OA
patient actively dev
deviation at the wri
Wrist: RA,
common disorder o
De Quervain's pseudogout, compression of the
SECTION II

tenosynovitis gonococcal arthritis, nel. Manifestations i

juvenile arthritis, ond and third finge
carpal tunnel syndrome
and, at times, atroph
John J Crush et al, Herrison Rheumatology 4th Ed; 2017
 Plate 4-12 Hand and Finger

ULNAR NERVE
Anterior (palmar) view

Palmar
digital
branches Median nerve
Palmar
branch
Palmar
digital
branches

Ulnar nerve

Palmar Superficial Radial nerve

branch branch

Lateral
antebrachial Musculocutaneous nerve
Medial antebrachial cutaneous
cutaneous nerve nerve

INNERVATION OF THE HAND

Plate 4-13 Musculoskeletal System: PART I
Nerve branches from the ulnar, median, and radial
nerve supply motor, sensory, and autonomic vasomotor Flexor pollicis brevis Palmar cutaneous branch
function in the hand. muscle (deep head only; MEDIAN NERVE
superficial head and other Palmar carpal ligament
thenar muscles supplied Posterior (dorsal) view
ULNAR NERVE
by median nerve)
Superficial branch
The ulnar nerve (C[7], 8; T1) is the main continuation Palmar
of the medial cord of the brachial plexus. In the forearm
and hand, the ulnar nerve gives off articular, muscular,
Deepdigital
branch
Adductor Palmar branches
palmar, dorsal, superficial and deep terminal, and vas- pollicis Median nerve digital
cular branches. It divides into branches for the areas of muscle branches Palmaris brevis
skin on the medial side of the back of the hand and Ulnar nerve
Abductor digiti minimi
fingers (see Plate 4-12). The ulnar nerve enters the hand Dorsal
to the radial side of the pisiform between the palmar Superficial Flexor digiti minimi brevis Hypothenar
branch muscles
carpal ligament and the flexor retinaculum. Just distal branch Opponensand digiti minimi
to the pisiform, the ulnar nerve divides into superficial and dorsal
and deep branches. dorsal digital digital nerve
Common palmar
The superficial terminal branch supplies the palmaris digital branches
brevis muscle, innervates the skin on the medial side of Radial nerve branches Communicating branch between
of medianulnar
nerve
the palm, and gives off two palmar digital nerves. The Division
with ulnar nerve
first is the proper palmar digital nerve for the medial side and radial nerve innervation
of the small finger; the second, the common palmar Posterior on interosseous
dorsum of hand is variable.
Palmar and dorsal muscles
digital nerve, communicates with the adjoining common antebrachial
palmar digital branch of the median nerve before divid- cutaneous 3rd and 4th lumbrical muscles (turned down)
ing into the two proper palmar digital nerves for the nerve (variable) Medial antebrachial
adjacent sides of the small and ring fingers. Rarely, cutaneous nerve
Palmar digital nerves
INNERVATION
the ulnar nerve supplies OF twoTHEand H one-half
AND rather than
one and one-half digits, and the areas supplied by
Lateral (dorsal digital nerves are from dorsal branch)
Musculocutaneous nerve antebrachial
(Continued)
the median and radial nerves are reciprocally reduced. cutaneous Dorsal branches to dorsum of middle
The deep terminal branch of the ulnar nerve, with the nerve (variable) and distal phalanges
deep branch of the ulnar artery, sinks between the
The firstofbranch
origins coursesdigiti
the abductor alongminimi
the ulnar
andside
theofflexor
the
dorsum
digiti of the hand
minimi brevisand supplies
muscles andthe ulnar side
perforates theof the
origin Palmar cutaneous branch of median nerve
of the
small opponens
finger as far digiti
as theminimi
root ofmuscle. It supplies
the nail. these
The second send a terminal branch into the deep head of the flexor from beneath the flexor carpi ulnaris tendon, and then
 they pronate and supinate the hand? Can they get
either secondary to RA, or as part of a primary then for swelling. Swelling can be bony, either from
theircan
vasculitis. Discoid lupus (1.13) palms and
affect the fingers
hands. flat together
osteoarthritic changewith their
or from wrists
‘burnt out’ arthritis
Tightness of the skin and atdistal
90° spindling
of dorsal of and
the palmar flexion?
with secondary damage, or ‘boggy’, due to ongoing
fingers is a feature of systemic sclerosis (1.14). The synovitis. Some swelling can be due to disease in
skin may also provide insights into previous therapy the overlying tendon sheath (1.16, in this case due
– for instance the thinning and easy bruising seen to overuse). Be careful when squeezing an actively
with long-term corticosteroid use (1.15). inflamed joint. It can be very painful. Blanching of
As can also be seen in Figure 1.15, loss of general your nail is a good guide as to the degree of pressure
muscle bulk may be indicative of disuse, secondary to apply. Rheumatoid arthritis classically affects the
to pain from arthritis, or due to drugs, particularly wrist, MCP and proximal interphalangeal (PIP)
corticosteroids. More specifically, wasting of joints and is symmetrical. In the longer term it can
the thenar eminence results from median nerve cause some characteristic deformities – swan neck
compression, or carpal tunnel syndrome, which is a (reversible or fixed hyperextension at the PIP and
complication of arthritis affecting the wrist and of flexion at the distal interphalangeal [DIP] joint),
flexor tenosynovitis, and can be a complication of boutonnière (flexion at the PIP and hyperextension
inflammatory arthritis.
Fig. 1.6 Dilated nail fold capillary loops and irregular,
at the DIP) (1.17) and subluxation or ulnar drift at
Inspect the joints, starting at the wrist and moving the MCPs (1.18).
distally. Look for swelling, redness and deformity.
dermatomyositis.
Fig. 1.1 Diffuse, symmetrical swelling of MCP and PIP
joints in a 23-year-old woman with early RA.
Diffuse, symmetrical swelling of Dilated nail fold capillary loops and 3
MCP and PIP joints in a 23-year- irregular,1 thickened cuticles in a 67-year-
old woman with early RA. old woman with dermatomyositis.
K21979 Manson vfi.indd 3 10/6/14 11:47 AM
9 Manson vfi.indd 1 10/6/14 11:47 AM

Healing discoid lupus on the hands of

a 19-year-old woman with SLE.

Fig. 1.13 Manson Jessica et al, Musculoscletal Examination, Rapid Review of Rheumatology and Musculoscletal Disorder, 2014
 Pattern Joint Arthritis

Rheumatoid Arthritis Psoriatic arthritis Ankylosing spondylitis Osteoarthritis

 evidence of digital infarcts.

e extensor
woman with
proximal nodule
oblem. Fig. 1.16 Swelling over the dorsum of the wrist due Fig. 1.17
to a mechanical tenosynovitis of the extensor tendon
Swelling over the dorsum of the wrist due to a
sheath in a 43-year-old man who was a martial arts
mechanical tenosynovitis of the extensor
enthusiast. RA. tendon sheath
in a 43-year-old man who was a martial arts enthusiast.
Fig. 1.12 A gouty tophus overlying

A gouty tophus overlying the

PIP joint gout.
tophaceous of the right index
finger of a 70-year-old man
with chronic tophaceous gout
bows. (Courtesy

5
Fig. 1.18
showing ulnar drift and subluxation of the MCP
10/6/14
joints.
11:47 AM

Manson Jessica et al, Musculoscletal Examination, Rapid Review of Rheumatology and Musculoscletal Disorder, 2014
 a b

Fig. 1.23 1.23a 1.23b

Jaccoud’s arthropathy at rest (a) and when fingers fully

extended
10 Rheumatological Disease(b) showing that changes are not fixed.
Categories

A 62-year-old woman with long-standing RA

Fig. 1.24
showing fixed
Fig. 1.25 Mechanical olecranon bursitis.
deformities at the wrists,
in a patient with oligoarticular juvenile idiopathic
arthritis.
subluxation of the MCPs and swan necking,
particularly of the right 9
little finger

K21979 Manson vfi.indd 9 10/6/14 11:47 AM

an with early RA. This Fig. 2.2

Manson Jessica et al, Musculoscletal Examination, Rapid Review of Rheumatology and Musculoscletal Disorder, 2014
 Fig.man
Fig. 1.19 A 33-year-old 1.21with psoriatic arthritis Fig. 1.22
Fig. 1.20 Dactylitis affecting the middle toe in a
A 33-year-old man with psoriatic
Fig. 1.19 ADIP
causing 33-year-old man
arthritis,with
with with psoriatic
psoriatic arthritis.
noticeable plaquesarthritis
of Fig. 1.20 Dactylitis affecting the middle toe in a
causing DIP arthritis, with noticeable plaques of Heberden’s (DIP) and Bouchard’s
arthritis causing DIP arthritis,
(PIP) nodes in a 75-year-old
with noticeable
8 plaques of
woman with osteoarthritis.
psoriasis on his knuckles. www.ebook3000.com
K21979 Manson vfi.indd 8 10/6/14 11:47 AM

Arthritis mutilans in a 57-year-old

woman with psoriatic arthritis.

Fig. 1.21 Fig. 1.22

with psoriatic arthritis.
Fig. 1.21 Fig. 1.22 Manson Jessica et al, Musculoscletal Examination, Rapid Review of Rheumatology and Musculoscletal Disorder, 2014
Ttttttttt
 Fig. 2.32 Fig. 2.31 Fig. 2.32
the right hand, and nodes, especially affecting the right hand, and
Bouchard’s nodes affecting Nodal OA hands, showing Heberden’s
middle and index finger of the nodes, especially affecting the right hand,
right hand. and Bouchard’s nodes affecting both
www.ebook3000.com
index fingers, and the right www.ebook3000.com
ring finger.
10/6/14 11:47 K21979
AM Manson vfi.indd 30

Manson Jessica et al, Musculoscletal Examination, Rapid Review of Rheumatology and Musculoscletal Disorder, 2014
Fig.
Plain2.5
x-rayPlain x-ray
showing showing
changes changes
of early RA of early
– periarticular RA –with
osteopenia Fig. 2.6
periarticular osteopenia
reduced with reduced
joint space particularly joint
around the space
MCPs with established
particularly around the MCPs. of the MTP joint
and joint erosion
 Fig. 2.7 Plain x-ray of hands in long-standing Fig.
Plain x-ray of hands in long-standing destructive RA – generalized osteopenia, fusion
2.8 Ultrasoun
of both wrists with obliteration of joint spaces, erosive changes at MCPs and PIPs
both wrists
with destruction of thewith obliteration
metacarpal heads andofassociated
joint spaces, erosive
subluxation of the MCPs. hypertrophy
and
changes at MCPs and PIPs with destruction of the with active synov
 7

Case 4

The patient is a 50-year-old

woman with polyarthralgias

A B

■ Clinical Presentation

The patient is a 50-year-old woman with polyarthralgias.

Fig. 2.23 Fig. 2.24
Calcification of the triangular cartilage
shown on x-rayshown on x-ray
of an elderly of an
woman elderly woman
presenting
presenting
presence of calcium pyrophosphate with an acutelywith
crystals. swollen wrist
an acutely with wrist
swollen aspirate provenproven
with aspirate pseudogout.
Also note the changes of first CMC OA st CMC OA.

25
 Fig. 1.9 Rheumatoid nodules over the extensor
Rheumatoid
surfaceFig. nodules
1.24elbow
of the over the
of a 58-year-old womanextensor
with Fig. 1.25 Mechanical olecranon bursitis.
surface in a patient
seropositive withelbow
ofRA.the
Note oligoarticular
that the more juvenile
of aproximal idiopathic
nodule
58-year-old
arthritis.
Mechanical olecranon bursitis
returned after surgery, a common problem.
woman with seropositive RA. Note that the
more proximal nodule returned after 9
surgery, a common problem.
K21979 Manson vfi.indd 9 10/6/14 11:47 AM
Fig. 1.12 A gouty tophus overlying

tophaceous gout.

Fig. 1.10 Plaque psoriasis over the elbows. (Courtesy

Manson Jessica et al, Musculoscletal Examination, Rapid Review of Rheumatology and Musculoscletal Disorder, 2014
Psoriasis

Fig. 1.7
An effusion affecting the left knee
of a 20-year-old woman with RA.
Fig. 1.26 Florid livedo reticularis is a patient with SLE
and anti-phospholipid syndrome.
any abnormal curvature of the spine – exaggerated
kyphosis or lordosis, or scoliosis. The ‘four point
test’ is a quick and easy way of assessing spinal
alignment. Ask the patient to stand against a wall;
with a normal spine, there should be four points
of contact: the heels, buttocks, shoulder blades and
occiput, with a normal lumbar lordosis.
Next, ask the patient to bend forward and
attempt to touch their toes, while keeping their knees
extended. Normal flexion should be sufficient to
separate fingers placed on adjacent lumbar vertebrae
(the modified Schober’s test). Check the spinous
processes for bony tenderness (rare) or pain on
percussion and the paraspinal muscles for tender
muscle spasm (much more common). Similarly,
assess cervical spine movements with lateral flexion
of the neck, a sensitive testValgus
Fig. 1.27 for pathology in this
deformity andarea.
effusion of the left
Valgus deformity and effusion of the
idiopathic arthritis.
left knee in a 19-year-old with
polyarticular juvenile idiopathic arthritis

www.ebook3000.com
K21979 Manson vfi.indd 10 10/6/14 11:47 AM

Fig. 1.8
involving the feet. Bilateral hallux valgus with over-
riding of the second toes.

4
Manson Jessica et al, Musculoscletal Examination, Rapid Review of Rheumatology and Musculoscletal Disorder, 2014
Shoulder Osteoarthritis
 a b

(a) Frontal radiograph of the shoulderweeks later, shows that the calcification now lies within the subacromial-
Fig. 5 (a) Frontal radiograph of the shoulder showing dense calcification
showing dense calcification (arrow) in the region of
subdeltoid bursa as well as within the superficial fibres of the tendon
(arrow) in the region of the supraspinatus tendon superficial to greater
the supraspinatus tendon superficial to greater trochanter.
(arrows). There is marked surrounding soft tissue oedema with ascites
trochanter. (b) T2-weighted gradient-echo oblique coronal image three

(b) T2-weighted gradient-echo oblique coronal image three weeks later, shows that the
calcification now lies within the subacromial- subdeltoid bursa as well as within the
superficial fibres of the tendon (arrows). There is marked surrounding soft tissue
oedema with ascites
Griffith JF, Musculocletal manifestation of Endocrine disease , Musculoscletal Disease 2017 - 2020 Imaging Diagnostic, 2017
MR Imaging of the Rotator Cuff and Rotator Interval

Anterosuperior impingement is much le

posterosuperior impingement and occurs
scapularis tendon is trapped between the
head and the anterosuperior glenoid and la
ward flexion of the arm.

Tendinosis (Tendinopathy)

Tendinosis histopathologically refers to ten

with collagen fiber disorientation, increase
deposition of mucoid, and absence of in
(thus the term tendinitis is inappropriate).
appearance of tendinosis is abnormal sign
Fig. 1 Coronal oblique T1-weighted image showing acromioclavicu-
ciated with morphology changes (Figs. 2
lar joint degenerative
Coronal changes with
oblique T1-weighted inferior
image osteophytes
showing causing supra- joint degenerative
acromioclavicular
spinatus impingement nal changes of tendinopathy typically are
changes with inferior osteophytes causing supra- spinatus impingement

a c

Abreou Marcelo R, MR Imaging of Rotator Cuff , Musculoscletal Disease 2017 - 2020 Imaging Diagnostic, 2017
 a c

Fig. 2 Coronal oblique T2-weighted fat suppressed images showing subacromial bursitis and tendinosis of supraspinatus (a), infraspinatus (b) and
intra-articular portion of long head of biceps tendon (c)

Coronal oblique T2-weighted fat suppressed images showing subacromial bursitis and
tendinosis of supraspinatus (a), infraspinatus (b) and intra-articular portion of long head of
biceps tendon (c)
Abreou Marcelo R, MR Imaging of Rotator Cuff , Musculoscletal Disease 2017 - 2020 Imaging Diagnostic, 2017
 Bilateral Hip Osteoarthritis

Joint space
Osteophyte of head narrowing
of Femoral
Joint space
narrowing
Subcondral
Acetabular margin
Sclerosis

Osteophyte of head
of Femoral
 SPINE INVOLVEMENT IN OSTEOARTHRITIS

Atlas (C1)

Axis (C2)

C7

Extensive thinning of cervical discs and hyperextension deformity with narrowing of intervertebral
foramina. Lateral radiograph reveals similar changes.

OSTEOARTHRITIS (Continued)

Topical NSAIDs or chili pepper–derived capsaicin

administered locally are helpful in many patients with
osteoarthritis and have the advantage of limited poten-
tial for toxicity.
Intra-articular corticosteroid administration is
extremely helpful for local flares for relief of pain and
inflammatory swelling. Too-frequent use should be
avoided owing to concerns regarding joint overuse and
aggravation of joint breakdown; repeated use more than
four times a year is generally to be avoided. Intra-
articular hyaluronan injections, approved for injection
into the knee, may improve pain and function; these
agents are slower than intra-articular corticosteroids
with respect to clinical response but may provide a
more prolonged duration of effect.
Glucosamine and chondroitin sulfate, available
without prescription, have been described as being
clinically beneficial, particularly on the basis of studies
in osteoarthritis of the knee. Several agents such as Degeneration of lumbar intervertebral discs and hypertrophic
diacerein and doxycycline, as well as glucosamine, Radiograph of thoracic spine shows changes at vertebral margins with spur formation.
chondroitin sulfate, avocado-soybean unsaponifiables, narrowing of intervertebral spaces and Osteophytic encroachment on intervertebral foramina
and intra-articular hyaluronans, have been described as spur formation. compresses spinal nerves.
being disease modifying; additional studies are required
before such agents can be definitively identified as
having an effect on the disease process. Structure-
 On MR imaging (Fig. 2), ARCO stage 1 is characterized
by the presence of a subchondral area of signal loss (“band
lesion”), which in stage 2 is separated from normal bone
marrow by an interface consisting of two parallel lines
(“double-line sign”). This sign can be seen on images with
T2 contrast and on gadolinium-enhanced T1-weighted
images and describes the presence of an inner hyperintense
line (fibrovascular tissue) and an outer hypointense line
(osteosclerosis) bordering the avascular bone segment. In
stage 3, a fracture line might become visible within the area
of necrosis which typically runs parallel to the surface of the
femoral head. Similar to radiographs and CT, femoral head
AVN
collapse (avascular
and OA arenecrosis) features indicative of the of stages 3 and 4 [1,
femoral
3, 6, 7]. Bone head marrow (ARCO edema stagecan be 3).associated with AVN of
Frog-leg
the femorallateral head butview doesshows not occur before the demarcation
of necrosis line
sclerotic and (blackthus, does not represent an early sign of
arrowheads)
ischemia
of reactive as previously
interfacebelieved between [2, 3, 7]. In patients with
AVN, bone marrow edema has been shown to be associated
necrotic segment and normal
with pain, femoral head collapse and a poor prognosis [8–
bone.
10]. A recent study demonstrated that bone marrow edema
adjacent
The curved to thesubchondral
demarcated necrotic fragment represents a
secondary sign of subchondral fracture and therefore indi-
radiolucent line (white arrows)
cates ARCO stage 3, even if the fracture line is not visible
indicates
on MR imaging fracture [3]. of the femoral
head The (“crescent
most important sign”)
tasks of imaging in patient with sus-
pected AVN of the femoral head are the verification of the diag-
nosis
Fig. 1 AVN of the femoral head (ARCO stage 3). Frog-leg lateral view Pathria Mini N, and the differentiation
Hip, Musculoscletal Disease 2017 - 2020 of AVN
Imaging from
Diagnostic, 2017 other causes of hip

is Fig. 2.2
man with psoriatic arthritis
h noticeable plaques of
Fig. 1.8
involving the feet. Bilateral hallux
riding of the second toes.
Fig. 1.20 Dactylitis affecting the middle toe in a
4
Dactylitis affecting the middle toe A 73-year-old woman with longstanding RA
www.ebook3000.com
in a 30-year-old man with new involving the feet. Bilateral hallux valgus
onset psoriatic arthritis. with over-riding of the second toes.
K21979 Manson vfi.indd 4

Fig. 2.4
valgus and
corn formation
over metatarsal
dislocation in

woman with RA.

Hallux valgus and corn formation over metatarsal
dislocation in a 70-year-old woman with RA

Fig. 1.22

Manson Jessica et al, Musculoscletal Examination, Rapid Review of Rheumatology and Musculoscletal Disorder, 2014
 sudden attacks of neuralgic pain (burning) or paraesthesia during
walking, often in the third and fourth toes. Examination may show
lesser toe deformities, slight splaying of the forefoot, abnormal
pronation and hallux valgus. These often occur in people who wear
footwear with a narrow toe box or those who undertake sporting
activities with increased movement in the forefoot. Compression of
Clinical features – Patients will often report an increase in the fre-
quency, duration or intensity of activity or exercise they undertake,
which may coincide with a change in occupation or footwear. The
symptom is a dull ache along the affected metatarsal shaft, which
changes to a sharp ache just behind the metatarsal head. The pain is

Abnormally pronated left foot demonstrating a

significantly everted heel position

Figure 7.3 Tarsal coalition. Magnetic resonance image in a patient with

Figure 7.1 Abnormally pronated left foot demonstrating a significantly calcaneonavicular coalition. Note synostosis between
Figure 7.3 the calcaneus
Tarsal coalition. Magneticand
resonance image in a patient with
everted heel position navicular
Figure 7.1 Abnormally pronated left bones (arrows)
foot demonstrating a significantly calcaneonavicular coalition. Note synostosis between the calcaneus and
everted heel position navicular bones (arrows)

Abnormally supinated foot with a high arch

profile and non-weight-bearing toes

Figure 7.2 Abnormally supinated foot with a high arch profile and non‐weight‐bearing toes
 Figure 7.8 Extensive forefoot deformity in a patient with rheumatoid
Extensive
arthritis; hallux forefoot
valgus withdeformity inthe
subluxation of a patient
lesser MTPwith
joints and Figure 7.9 Dactylitis of the fourth toe and nail dystrophy in a patient with
rheumatoid
retracted,
Figure 7.8 arthritis;
non‐weight‐bearing
Extensive hallux
toes invalgus
forefoot deformity a patientwith subluxation of
with rheumatoid psoriatic arthritis
arthritis;
thehallux
lesser valgus
MTP withjoints
subluxation
andofretracted,
the lesser MTPnon-weight-
joints and Figure 7.9 Dactylitis of the fourth toe and nail dystrophy in a patient with
retracted, non‐weight‐bearing toes psoriatic arthritis
bearing toes Dactylitis of the fourth toe and nail dystrophy in a
patient with psoriatic arthritis
Therapeutic Goal
OUTCOME
of RA
• Need early diagnosis
• Need early therapy

Early referral
OUTCOME of RA
Summary of Disease Activity Measure Recommended for Point of Care Clinical Use

ACR RA Disease Activity Measures Recommendations

Table 1. Summary of RA disease activity measures recommended for point-of-care clinical use*

Psychometric properties†
No. of Method of Time for Validated
Measure/scale Measure outputs items Response format administration administration in RA Reliability Validity Responsiveness

Patient-driven
composite tools
PAS A single score on 3 HAQ: 0–3 Patient Patient: !3.5 Yes Acceptable; Acceptable Acceptable for
a continuous Pain VAS: 0–10 questionnaire minutes test–retest individual
scale (0–10) Pt Global VAS: 0–10 Provider: !1 reliability for components
minute composite has
Lab: N/A not been
evaluated
PAS-II A single score on 3 HAQ-II: 0–3 Patient Patient: !1.5 Yes Acceptable; Acceptable Acceptable for
a continuous Pain VAS: 0–10 questionnaire minutes test–retest individual
scale (0–10) Pt Global VAS: 0–10 Provider: !30 reliability for components
seconds composite has
Lab: N/A not been
evaluated
RAPID-3 A single score on 3 MDHAQ: 0–3 Patient Patient: !1.5 Yes Acceptable; Good Acceptable for
a continuous Pain VAS: 0–10 questionnaire minutes test–retest individual
scale (0–10) Pt Global VAS: 0–10 Provider: !30 reliability for components
seconds composite has
Lab: N/A not been
evaluated
Patient and provider
composite tool
CDAI A single score on 4 28TJC: 0–28 Provider item; Patient: !10 Yes Good; test–retest Excellent Excellent
a continuous 28SJC: 0–28 patient item seconds reliability for
scale (0–76) Pt Global VAS: 0–10 Provider: !2 composite has
Pr Global VAS: 0–10 minutes not been
Lab: N/A evaluated
Patient, provider,
and laboratory
composite tools
DAS28 (ESR or A single score on 4, or 3 28TJC: 0–28 Provider Patient: !10 Yes Excellent Excellent Excellent
CRP) a continuous when 28SJC: 0–28 assessment; seconds
scale (0–9.4) general ESR: 0–100 or CRP patient item; Provider: 3–5
health is with lower lab minutes
omitted detection level of Lab: 1 hour
1.0 mg/liter waiting time
Pt Global VAS: 0–100 for ESR
SDAI A single score on 5 28TJC: 0–28 Provider item; Patient: !10 Yes Good; test–retest Excellent Excellent
a continuous 28SJC: 0–28 patient item; seconds reliability for
scale (0–86) Pt Global VAS: 0–10 lab Provider: !2 composite has
CRP: 0–10 minutes not been
Lab: waiting evaluated
time for CRP
varies by lab

* Measures are not shown in order of preference. RA " rheumatoid arthritis; PAS " Patient Activity Scale; HAQ " Health Assessment Questionnaire; VAS " visual analog scale; Pt Global VAS " patient
global assessment of disease activity VAS; Lab " laboratory value required; N/A " not applicable; RAPID-3 " Routine Assessment of Patient Index Data with 3 measures; MDHAQ " Multidimensional RA Disease Activity Measures:
HAQ; CDAI " Clinical Disease Activity Index; 28TJC " 28 tender joint count; 28SJC " 28 swollen joint count; Pr Global VAS " provider global assessment of disease activity VAS; DAS28 " Disease
Activity Score with 28-joint counts; ESR " erythrocyte sedimentation rate; CRP " C-reactive protein; SDAI " Simplified Disease Activity Index. ACR Recommendations for Use in

643
† Psychometric properties were subjectively ranked using an ordered category scale (excellent, good, acceptable, poor, and unacceptable) based on currently published literature. Clinical Practice 2012
 Patient Activity Scale II (PAS II) for RA

Without any difficulty With some difficulty With much difficulty Unable Quantifies severity of
Stand up from a straight chair RA using patient-
Walk outdoors on flat ground
reported symptoms.
Get on and off the toilet

Reach and get down a 5-pound object (such

as a bag of sugar) from just above the head

Open car doors

Do outside work (such as yard work)
Wait in a line for 15 minutes
Lift heavy objects

Move heavy objects

Go up 2 or more flights of stairs
Ask patient to rate pain on a scale of 0-10,
Pain Visual Analogue Scale: 1 - 10
where 10 is the worst pain imaginable
Ask patient to rate how well they are doing in
the past week considering all the ways their
Patient Global Assessment of Disease Activity. 1 - 10
disease affects them on a scale of 0-10,
where 10 is the worst

Dr. Frederick Wolfe, Pubmed

 rapid3
routine assessment of patient index data
RAPID3 (Routine Assessment of Patient Index Data 3),
The RAPID3 includes a subset of core variables found in the Multi-dimensional HAQ (MD-HAQ). Page 1 of the MD-HAQ, shown here, includes
an assessment of physical function (section 1), a patient global assessment (PGA) for pain (section 2), and a PGA for global health (section 3).
a Rheumatoid Arthritis Index Without Formal Joint Counts for Routine Care
RAPID3 scores are quickly tallied by adding subsets of the MD-HAQ as follows:

1. please check the ONE best answer for your abilities at this time: 1. a-j FN (0-10):

without ANY with SOME with MUCH UNABLE

OVER THE LAST WEEK, were you able to:
difficulty difficulty difficulty to do 1=0.3 16=5.3
2=0.7 17=5.7
a. Dress yourself, including tying shoelaces and
doing buttons? ___ 0 ___ 1 ___ 2 ___ 3 3=1.0 18=6.0
4=1.3 19=6.3
b. Get in and out of bed? ___ 0 ___ 1 ___ 2 ___ 3 5=1.7 20=6.7 RAPID3 scores are designed for usual
6=2.0 21=7.0
c. Lift a full cup or glass to your mouth? ___ 0 ___ 1 ___ 2 ___ 3 7=2.3 22=7.3 clinical care.. The 3 Core Data Set
d. Walk outdoors on flat ground? ___ 0 ___ 1 ___ 2 ___ 3
8=2.7
9=3.0
23=7.7
24=8.0
measures on the Multidimensional Health
e. Wash and dry your entire body? ___ 0 ___ 1 ___ 2 ___ 3
10=3.3 25=8.3 Assessment Questionnaire (MDHA, for
11=3.7 26=8.7
f. Bend down to pick up clothing from the floor? ___ 0 ___ 1 ___ 2 ___ 3 12=4.0 27=9.0 function (FN), pain (PN), and patient global
13=4.3 28=9.3
g. Turn regular faucets on and off? ___ 0 ___ 1 ___ 2 ___ 3 14=4.7 29=9.7
estimate (PTGL), are each scored 0–10
15=5.0 30=10 and recorded on the MDHAQ
h. Get in and out of a car, bus, train, or airplane? ___ 0 ___ 1 ___ 2 ___ 3
2. PN (0-10):
i. Walk two miles or three kilometers, if you wish? ___ 0 ___ 1 ___ 2 ___ 3
j. Participate in recreational activities and sports
as you would like, if you wish? ___ 0 ___ 1 ___ 2 ___ 3 3. PTGE (0-10):

k. Get a good night’s sleep? ___ 0 ___ 1.1 ___ 2.2 ___ 3.3
RAPID3 (0-30)
l. Deal with feelings of anxiety or being nervous? ___ 0 ___ 1.1 ___ 2.2 ___ 3.3
m. Deal with feelings of depression or feeling blue? ___ 0 ___ 1.1 ___ 2.2 ___ 3.3

2. how much pain have you had because of your condition OVER THE PAST WEEK?
Please indicate below how severe your pain has been:
NO PAIN PAIN AS BAD AS IT COULD BE
! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10

3. considering all the ways in which illness and health conditions may affect you
at this time, please indicate below how you are doing:
VERY WELL VERY POORLY
! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10
conversion table
Near Remission (NR): 1=0.3; 2=0.7; 3=1.0 High Severity (HS): 13=4.3; 14=4.7; 15=5.0; 16=5.3; 17=5.7; 18=6.0; 19=6.3; 20=6.7;
Low Severity (LS): 4=1.3; 5=1.7; 6=2.0 21=7.0; 22=7.3; 23=7.7; 24=8.0; 25=8.3; 26=8.7; 27=9.0; 28=9.3; 29=9.7; 30=10.0
Moderate Severity (MS): 7=2.3; 8=2.7; 9=3.0; 10=3.3; 11=3.7; 12=4.0
Pincus Theodore, The Journal of Rheumatology 2008
 PIP 2 PIP 4
PIP 3
PIP 3 PIP 5
PIP 4
PIP 4 Knee
PIP 5
PIP 5 Clinical Disease Activity Index (CDAI)
Total
Knee
calClinical
DiseaseDisease Activity
Activity Index Index
Knee (CDAI)(CDAI) Total

Total Patient Global Assessment of Disease Activity

Joint Left Right Patient Global Assessment of Disease Activity
Left Right Considering all the ways your arthritis affects you, rate how well you are doing on the following scale:
Tender Swollen Tender Swollen
Tender Swollen Tender
Patient Global Swollen
Assessment of Disease Activity Considering all the ways your arthritis affects you, rate how well you are doing on the following scale:
Shoulder
derElbow
Wrist Considering all the ways your arthritis affects you, rate how wellYour
you are doing on the following scale: Date of Birth ____________ Today’s Date ______________
Name_____________________________________
MCP 1 Your Name_____________________________________ Date of Birth ____________ Today’s Date ______________
MCP 2 Provider Global Assessment of Disease Activity
MCP 3 Provider Global Assessment of Disease Activity
MCP 4 Your Name_____________________________________ Date of Birth ____________ Today’s Date ______________
MCP 5
PIP 1 How to Score the CDAI

PIP 2 Provider Global Assessment of Disease Activity How to Score the CDAI
Variable Range Value CDAI Score Interpretation
PIP 3
Variable Range Value CDAI Score Interpretation
PIP 4
PIP 5
Knee Add the above values to (0-76)
How to Score the CDAI calculate the CDAI score
Total Add the above values to (0-76)
calculate the CDAI score
Variable Range Value CDAI Score Interpretation
Patient Global Assessment of Disease Activity
nt Global Determines
Assessment of severity
Disease of rheumatoid
Activity
Considering all the ways your arthritis affects you, rate how well you are doing on the following scale:
arthritis using only clinical data.
ering all the ways your Add the above
arthritis affectsvalues to how
you, rate (0-76)
well you are doing on the following scale:
calculate the CDAI score
Simplified Disease Activity Index (SDAI)

Tender joint count of 28 joints

Swollen joint count of 28 joints
C-reactive protein
Patient global assessment of disease activity on visual analogue scale (0–10)
Physician global assessment of disease activity on visual analogue scale (0–10)
SDAI is the numerical sum of the above components (range 0–86)
Categories:
– Remission≤3.3
– Low disease activity >3.3 and <20
– Moderate disease activity > 20 and ≤ 40
– High disease activity >40

Marta Maria das Chagas Medeiros : rev bras reumatol. 2015;55(6):477–484

J. S. Smolen, Rheumatology (Oxford) 2003; 42:244–257,.

 Gold
Rheumatoid Arthritis Disease Activity Score DAS-28 : ESR or CRP n d a rd
Sta

Aletaha D,. Arthritis Rheum. 2005 Sep;52(9):2625-36. PubMed ID: 16142705

van der Heijde DM, J Rheumatol. 1993 Mar;20(3):579-81. PubMed ID: 8478878
Formulir DAS 28

Diagnosis dan Pengelolaan Artritis Reumatoid

Rekomendasi Perhimpunan Reumatologi Indonesia 2014
 644 Anderson et al

Required components of RA disease activity measures recommended for point-of-care clinical use
Table 2. Required components of rheumatoid arthritis disease activity measures recommended for point-of-care clinical use*

Defined
Physician Patient Provider HAQ remission
joint count global VAS global VAS version Pain criteria

Patient-driven composite tools

PAS ● HAQ ● ●
PAS-II ● HAQ-II ● ●
RAPID-3 ● MDHAQ ● ●
Patient and provider composite tool
CDAI ● ● ● N/A ●
Patient, provider, and laboratory
composite tools
DAS28 (ESR or CRP) ● ● N/A ●
SDAI ● ● ● N/A ●

* Measures are not shown in order of preference. VAS ! visual analog scale; HAQ ! Health Assessment Questionnaire; PAS ! Patient Activity Scale;
RAPID-3 ! Routine Assessment of Patient Index Data with 3 measures; MDHAQ ! Multidimensional HAQ; CDAI ! Clinical Disease Activity Index;
N/A ! not applicable; DAS28 ! Disease Activity Score with 28-joint counts; ESR ! erythrocyte sedimentation rate; CRP ! C-reactive protein; SDAI !
Simplified Disease Activity Index.

measurement: the CDAI, DAS28 (erythrocyte sedimenta- (SDAI and DAS28). Below we summarize the key features
tion rate [ESR] or C-reactive protein [CRP]), PAS, PAS-II, of each measure to allow those caring for patients with RA
A S 28
RAPID-3,D and SDAI (Table 2). to select the one best suited to their clinical practice.
old
G
d a rd?? Patient-driven composite tools (PAS [10], PAS-II [10],
Stan
Discussion and RAPID-3 [11]) have the advantage of being relatively
RA Disease Activity Measures:

Since the 1950s, when the first composite disease activity easy to use in clinical practice because they do not require
ACR Recommendations for Use in Clinical Practice 2012
Instruments
Table 2.toInstruments
measure RA disease
to measure activity
rheumatoid and
arthritis to activity
disease defineand
remission
to
define remission*

Instrument (reference) Thresholds of disease activity

Patient Activity Scale (PAS) or PASII Remission: 0–0.25

(range 0–10) (149) Low activity: .0.25–3.7
Moderate activity: .3.7 to ,8.0
High activity: $8.0
Routine Assessment of Patient Index Data 3 Remission: 0–1.0
(RAPID3) (range 0–10) (155) Low activity: .1.0–2.0
Moderate activity: .2.0–4.0
High activity: .4.0–10
Clinical Disease Activity Index (CDAI) Remission: #2.8
(range 0–76.0) (156) Low activity: .2.8–10.0
Moderate activity: .10.0–22.0
High activity: .22
Disease Activity Score (DAS) 28 Remission: ,2.6
erythrocyte sedimentation rate (ESR) Low activity: $2.6 to ,3.2
(range 0–9.4) (157) Moderate activity: $3.2 to #5.1
High activity: .5.1
Simplified Disease Activity Index (SDAI) Remission: #3.3
(range 0–86.0) (158) Low activity: .3.3 to #11.0
Moderate activity: .11.0 to #26
High activity: .26

2015
* These 6 measures were endorsed by the American College of American College of Rheumatology
Rheumatology in 2012 (16).Guideline for the Treatment of Rheumatoid Arthritis
Other
Recommended
Table composite
3 Recommended disease
composite activity
disease activity assessments
assessments and prognostic
and prognostic assessment assessment to guide treatment
to guide treatment
Guideline Composite Disease Activity Assessments Prognostic Assessments
PAS RAPID3 CDAI SDAI DAS28 RF ACPA X-ray Poor Extra-Articular
Erosions Function Disease
1. American [14] Yes Yes Yes Yes Yes
2. APLAR [15] – – Yes Yes Yes Yes Yes Yes
3. Australian [16] – – – – – Yes Yes Yes
4. Brazilian [17] – – Yes Yes Yes Yes Yes Yes
5. British Columbia [18] – – – – – Yes Yes
6. British Society For Rheumatology: Established [19] – – – – –
7. British Society For Rheumatology: Early [20] – – – – –
8. Canadian [21] Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
9. EULAR [22] Yes Yes Yes Yes Yes Yes
10. French [23] Yes Yes Yes Yes Yes Yes
11. German [24] – – – – Yes Yes Yes Yes
12. Hong Kong [25] – – Yes Yes Yes Yes Yes Yes Yes Yes
13. Indian [26] – – Yes Yes Yes Yes Yes Yes Yes
14. Latin American [27] – – – – Yes Yes Yes Yes Yes Yes
15. Mexican [28] Yes Yes Yes Yes Yes Yes
16. England [29] – – – – Yes
17. Scotland [30] – – Yes Yes Yes
18. South African [31] – – – Yes Yes Yes Yes Yes Yes Yes
19. Spanish [32] – – Yes Yes Yes Yes Yes Yes Yes Yes
20. Swedish [33] – – Yes Yes Yes Yes Yes Yes Yes Yes
21. Treat to Target [34] – – Yes Yes Yes
22. Turkish [35] – – – – Yes Yes Yes Yes
Mian et al. BMC Rheumatology (2019) 3:42
RF Rheumatoid factor, ACPA Anti-citrullinated protein antibody
American College of Rheumatology disease activity measures for rheumatoid arthritis clinical trials: Core Set

ACR response is scored as a percentage improvement, comparing disease activity at

two discrete time points (usually baseline and post-baseline comparison).

• ACR20 is ≥ 20% improvement

• ACR50 is ≥ 50% improvement
• ACR50 responders include ACR20 responders
• ACR70 is ≥ 70% improvement
• ACR70 responders include ACR20 & ACR50 responders

It is worth noting that the ACR response criteria is a dichotomous variable with a positive
(=responder) or negative (=non-responder) outcome.

David T Felson, Felson and LaValley Arthritis Research & Therapy 2014, 16:101
Management of RA with systemic
and biological disease modifying
antirheumatic drugs
Screening RA
2015 American College of
Rheumatology
recommendations for the
treatment of Early
rheumatoid arthritis (RA),
defined as disease duration ACR RA Treatment Recommendations 9

6 months

Figure 3. 2015 American College of Rheumatology recommendations for the treatment of Early rheumatoid arthritis (RA), defined as disease
duration ,6 months. * 5 consider adding low-dose glucocorticoids (#10 mg/day of prednisone or equivalent) in patients with moderate or
high RA disease activity when starting disease-modifying antirheumatic drugs (DMARDs) and in patients with DMARD failure or biologic
failure. † 5 also consider using short-term glucocorticoids (defined as ,3 months treatment) for RA disease flares. Glucocorticoids should be
used at the lowest possible dose and for the shortest possible duration to provide the best benefit-risk ratio for the patient. # 5 treatment target
should ideally be low disease activity or remission. For the level of evidence supporting each recommendation, see the related section in the
Arthritis
Results. This figure is derived from recommendations based on PICO (population, Care &
intervention, Research
comparator, and outcomes) questions A.1 to
DOI 10.1002/acr.22783
A.12. For definitions of disease activity (categorized as low, moderate, or high) and descriptions, see Tables 1 and 2. MTX 5 methotrexate.

VC 2015, American College of Rheumatology

 2015 American College of
12
Rheumatology (ACR) Singh et al

recommendations for the

treatment of Established Singh et al

rheumatoid arthritis (RA)

Figure 5. 2015 American College of Rheumatology (ACR) recommendations for the treatment of Established rheumatoid arthritis (RA),
defined as disease duration $6 months, or meeting the 1987 ACR classification criteria (81). Due to complexity of management of
established RA, not all clinical situations and choices could be depicted in this flow chart, and therefore we show the key recommen-
dations. For a complete list of recommendations, please refer to the Results. * 5 consider adding low-dose glucocorticoids (#10 mg/day
of prednisone
r the treatment or equivalent)
of Established in patients
rheumatoid with
arthritis moderate or high RA disease activity when starting traditional disease-modifying antirheu-
(RA), Arthritis Care & Research
matic (81).
tion criteria drugsDue (DMARDs) and in
to complexity patients withof DMARD failure or biologic failure. † 5 also consider using short-term glucocorticoids
of management DOI 10.1002/acr.22783
is flow(defined
chart, and ,3 months
as therefore we treatment)
show the key
for recommen-
RA disease flares. Glucocorticoids should be used at the lowest possible dose and for the shortest
VC 2015, American College of Rheumatology
5 consider adding low-dose glucocorticoids (#10 mg/day ratio for the patient. # 5 treatment target should ideally be low disease activity or remis-
possible duration to provide the best benefit-risk
vity when starting traditional disease-modifying antirheu-
sion. ** 5 tapering denotes scaling back therapy (reducing dose or dosing frequency), not discontinuing it and if done, must be conducted
 Algorithm based on the
2016 European League
Against Rheumatism
(EULAR) recommendations
on RA management.

Figure 1 Algorithm based on the 2016 European League Against Rheumatism (EULAR) recommendations on rheumatoid arthritis (
management. ACPA, anticitrullinated protein antibody; ACR, American College of Rheumatology; bDMARD, biological DMARD; bsDM
DMARDs; csDMARDs, conventional synthetic DMARDs; DMARDs, disease-modifying antirheumatic drugs; EMA, European Medicines
Food and Drug Administration; IL, interleukin; MTX, methotrexate; RF, rheumatoid factor; TNF, tumour necrosis factor; tsDMARDs, ta
DMARDs.

968 Smolen JS, et al. Ann Rheum Dis 2017;76:960–977. doi:10.1136/annrheu

Smolen JS, et al. Ann Rheum Dis 2017;76:960–977. doi:10.1136/

annrheumdis-2016-210715
 Recommendation Grade

1
2018 update of the
2
APLAR recommendations
for treatment of 3
rheumatoid arthritis
4

recommended.
7

9
10

11
12

13

14
15

16 Lau Chak Sing, International Journal of Rheumatic

Disease, 2019. DOI: 10.1111/1756-185X.13513
 nn Rheum Dis: first published as 10.1136/annrheumdis-2019-216655 on 22 January 2020. Downloaded from http://ard.bmj.com/ on August 18, 20
EULAR recommendations for
the management of RA with
synthetic and biological
DMARD: 2019 update

Figure 1 Presentation of the 2019 update of the EULAR RA management re

version aiming to provide a general overview, but it must be borne in mind th
the discussion of the individual recommendations in the paper which are part
antibody; ACR, American College of Rheumatology; bDMARDs, biological DMA
DMARDs; DMARDs, disease-modifying antirheumatic drugs; EMA, European M
Food and Drug
Figure 1 Presentation of the 2019 update of the EULAR RA management Administration;inIL-form
recommendations 6R, interleukin 6 receptor;
of an algorithm. This isJAK, Janus kinase
an abbreviated
TNF,intumour
version aiming to provide a general overview, but it must be borne necrosis
mind that factor; tsDMARDs,
the algorithm cannot betargeted
separatedsynthetic
from theDMARDs.
details presented
the discussion of the individual recommendations in the paper which are part and parcel of these recommendations. ACPA, anticitrullinated pr
Smolen JS,DMARDs;
antibody; ACR, American College of Rheumatology; bDMARDs, biological et al. Ann Rheum Dis 2020;79:685–699.
bsDMARD, doi:10.1136/annrheumdis-2019-2166
biosimilar DMARDs; csDMARDs, conventional s
DMARDs; DMARDs, disease-modifying antirheumatic drugs; EMA, European Medicines Agency; EULAR, European League Against Rheumatism
Food and Drug Administration; IL-6R, interleukin 6 receptor; JAK, Janus kinase; MTX, methotrexate; RA, rheumatoid arthritis; RF,rheumatoid fac
TNF, tumour necrosis factor; tsDMARDs, targeted synthetic DMARDs.

Smolen JS, et al. Ann Rheum Dis 2020;79:685–699. doi:10.1136/annrheumdis-2019-216655

Smolen JS, et al. Ann Rheum Dis 2020;79:685–699. doi:10.1136/

annrheumdis-2019-216655
 Drug treatment recommendations
Table 4 Drug treatment recommendations
Guideline DMARDs Biologics Symptomatic
Treatments
MTX Others Combinations JAK Glucocorticoids First Subsequent Tapering NSAIDs Pain
Inhibitors (steroids)
1. American [14] Yes Yes Yes Yes Yes Yes Yes Yes – –
2. APLAR [15] Yes Yes Yes Yes Yes Yes Yes Yes Yes –
3. Australian [16] Yes Yes Yes – Yes Only for specialists Yes Yes
4. Brazilian [17] Yes Yes Yes – Yes Yes Yes Yes Yes –
5. British Columbia [18] Yes Yes Yes – Yes Only for specialists Yes Yes
6. British Society For Rheumatology: Generic – – – Generic biologics Yes Yes
Established [19] DMARDs
7. British Society For Rheumatology: Early Generic Yes – Yes Generic biologics Implied Yes Yes
[20] DMARDs
8. Canadian [21] Yes Yes Yes – Yes Yes Yes Yes – –
9. EULAR [22] Yes Yes – Yes Yes Yes Yes Yes – –
10. French [23] Yes Yes Yes – Yes Yes Yes Yes – –
11. German [24] Yes Yes Yes – Yes Yes Yes – – –
12. Hong Kong [25] Yes Yes Yes – Yes Yes Yes – – –
13. Indian [26] Yes Yes Yes – Yes Yes Yes – Yes Yes
14. Latin American [27] Yes Yes Yes – Yes Yes Yes – Yes Yes
15. Mexican [28] Yes Yes Yes Yes Yes Yes Yes – Yes Yes
16. England [29] Yes Yes Yes – Yes Yes Yes – Yes Yes
17. Scotland [30] Yes Yes Yes – Yes Yes Yes – Yes Yes
18. South African [31] Yes Yes Yes – Yes Yes Yes – Yes Yes
19. Spanish [32] Yes Yes Yes – Yes Yes Yes – Yes Yes
20. Swedish [33] Yes Yes Yes – Yes Yes Yes Yes – –
21. Treat to Target [34] Generic DMARD treatments – Yes Generic biologics Implied – –
22. Turkish [35] Yes Yes Yes – Yes Yes Yes Yes – –
Mian et al. BMC Rheumatology (2019) 3:42
Table 64.2
Studies of oral glucocorticoids and radiographic progression in rheumatoid arthritis
Study type Effect on radiologic
Study (year) Experimental group Control group (subjects, n) progression Comments
MRC156 (1955) Cortisone (69 mg/day) ASA CT (100) No difference Trend toward protective effect
MRC157 (1959) Prednisolone (initial: 20 mg, 12 mg/day ASA CT (77) Reduction after 2 yr; Control patients offered
by yr 1, 10 mg/day by yr 2) less after 3 yr prednisolone in yr 3
Bernsten158 Various glucocorticoids, dose not IM gold, analgesics Retrospective Deterioration in all Many patients had already failed
(1961) reported (388) groups other drugs
Harris159 (1983) Prednisone (5 mg/day) and DMARD PBO and DMARD DB RCT (34) No significant difference Trend toward reduction
Million160 (1984) Prednisolone (10.3 mg/day) and No prednisolone RCT (103) Significant reduction 10-year study
DMARD
Kirwan47 (1995) Prednisolone (7.5 mg/day) and DMARD PBO and DMARD DB RCT (106) Significant reduction
Boers50 (1997) Prednisolone (60 mg/day with taper) PBO and SSZ DB RCT (102) Significant reduction
and MTX, SSZ
Hansen51 (1999) Prednisolone (6 mg/day) and DMARD DMARD RCT (102) No significant difference Trend toward reduction
Van Everdingen103 Prednisolone (10 mg/day) and SSZ as PBO and SSZ as DB RCT (81) Significant reduction Only study since the MRC to not
(2002) rescue rescue allow background DMARDs;
SSA allowed after 6 months
Capell102 (2004) Prednisolone (7 mg/day) and SSZ PBO and SSZ DB RCT (167) No significant difference Discordance in radiographic
interpretations among readers
Wassenberg53 Prednisolone (5 mg/day) and either AU PBO and either AU DB RCT (166) Significant reduction Relatively new-onset RA
(2005) or MTX or MTX One of the lowest doses to show
radiographic protection
Svensson52 (2005) Prednisolone (7.5 mg/day) and DMARD No prednisone and Open RT (225) Significant reduction Early RA
DMARD
Bakker54 (2012) Prednisone (10 mg/day) and MTX PBO and MTX DB RCT (236) Significant reduction Early RA; tight RA control sought
with monthly methotrexate dose
adjustments

ASA, High-dose aspirin; AU, auranofin; CT, controlled trial; DB, double blind; DMARD, disease modifying antirheumatic drug; IM, intramuscular; MRC, Medical Research Council; MTX, methotrexate; NA, not assessed;
NS, not significant; PBO, placebo; R, randomized; SSZ, sulfasalazine.
 Steroid Injection
CHAPTER 44 Aspiration and injection of joints and periarticular tissue and intralesional therapy 337.e1
(a) Injection of third
metacarpophalangeal joint in
a patient with rheumatoid
arthritis.
(b) The needle (red arrow)
enters the
metacarpophalangeal joint
space from the anterior
radial side of the joint capsule
through skin; the blue
indicates the injected dye
diffusion into the joint. 1,
Metacarpal bone; 2, extensor
a b mechanisms of the finger.
192
193 DMARD = Refers to any csDMARD, boDMARD or tsDMARD
194
195 DMARD Groups
DMARDs
196
csDMARDs boDMARDs tsDMARDs
Methotrexate (MTX) TNF Inhibitors JAK Inhibitors
Hydroxychloroquine (HCQ) Etanercept Tofacitinib
Sulfasalazine (SSZ) Adalimumab Baricitinib
Leflunomide (LEF) Certolizumab
Golimumab
Infliximab
Abatacept
Rituximab
IL-6 Receptor Inhibitors
Tocilizumab
Sarilumab
197 cs = conventional synthetic , bo = biosimilar, ts = targeted synthetic

198 GC = glucocorticoids / steroids (prednisone, or equivalent); PROM = patient reported outcome

199 measure American College Of Rheumatology
Updated Guideline for the Management of Rheumatoid Arthritis Project Plan 2018
200
Biologic Therapy
 which Table 66.1
ion of
rmine Methotrexate efficacy as monotherapy in studies of biologics
refore, Abatacept
these Tempo* Premier †
Aspire ‡
Comet §
Ambition study¶
matory ACR 20 (%) 75 63 54 67 52 Not reported
F) and ACR 50 (%) 43 46 32 49 34 43
in the ACR 70 (%) 19 28 21 28 28 27
wn to DAS remission 13 21 15 28 12 23
ltured (%)
gonize
TSP-1) *Study comparing methotrexate, etanercept, and the combination of both drugs.54
39
RP1). †

‡
Study comparing methotrexate, adalimumab, and the combination of both drugs.56
120
Study comparing methotrexate to methotrexate plus infliximab.
ormal §
Study comparing methotrexate to the combination of methotrexate and etanercept.55
ipants Study comparing methotrexate to tocilizumab.57
reased ¶
Study comparing methotrexate to the combination of methotrexate and abatacept.121
MTX ACR, American College of Rheumatology; DAS, disease activity score.
study
signal
 manyAmerica
North rheumatologists recommend stopping
registry (Consortium it 3 monthsresearchers
of rheumatology before attempting
of North BOX and RECOMMENDATIONS
66.1
illness, nonspecific centralFOR MONITORING
nervous systemFOR HEPATIC
effects (e.g., dizzin
conception.
America, There are few of
or CORRONA) data to determine
1953, whichtaking
RA patients recommendation
MTX, 22%is increased
correct. headache, mood SAFETY IN PATIENTS
alteration, memoryWITH RHEUMATOID
impairment). 99 ARTHRITIS
Fatigue is one of m
MTX should not be used during lactation because the drug can be excreted RECEIVING METHOTREXATE 112
their aspartate transaminase (AST) or alanine transaminase (ALT0 levels common reasons that patients stop MTX; folinic acid may reduce fatig
in breast milk. In men with psoriasis, a reversible decrease in sperm count
above the upper
was seen. The
limit of insert
package
normal, and 1% had
recommends that
amen
twofold
stop
increase
MTX 3
in these
months
An increased risk (standardized incidence ratio [SIR] 3.0) of melan
A. Baseline
88
enzymes. Independent
before attempting predictors
conception, but of abnormal
there are no AST values
firm data to were a lack
support this of has1. been
Tests observed in patients with RA receiving MTX compared w
for all patients
100
recommendation. normal population.
a. Liver blood tests (AST,Generally, an increase
ALT, alkaline in other
phosphatase, solid tumors is
albumin,
associated with MTX
bilirubin), useBbased
hepatitis and C on the experience
serology studies with high-dose MTX
Table 66.2 malignancy
b. Otherorstandard
low-dose MTX
tests, for psoriasis.
including CBC countHowever,
and serum MTX was associ
creatinine
FOLIC ACID SUPPLEMENTATION with
2. aPretreatment
higher riskliverof malignancy compared
biopsy (Menghini with needle)
suction-type other nonbiologic
only for DMA
Adverse effects of methotrexate in rheumatoid arthritis and TNF antagonists
patients with: in the CORRONA registry of 6806 RA patients, u
To reduce the adverse effects of MTX such as nausea, diarrhea, stomatitis,
hair thinning, fatigue, headaches, and hematologic toxicity, Estimatedfolic acid or
incidence in propensity
a. Prior scores to improve
excessive the balance among cohorts.101 A higher ra
alcohol consumption
folinic effect
Adverse acid (leucovorin) should be coadministered. rheumatoid
Folic acid arthritis
(5 mg or b. Persistently
lymphoma was notabnormal
observed baseline AST values
in patients with RA treated with MTX the
27.5 mg each week)
Gastrointestinal: hasnausea,
anorexia, been shown to diarrhea
vomiting, decrease MTX
10% toxicity
87 without alonec.compared
Chronic hepatitis B or C infection
with patients with RA never exposed to MTX therap
reducing the efficacy of MTX.106 Folic acid 1 mg/day or folinic acid 2.5 mg/ B. Monitor
There AST,
is an ALT, andrisk
increased albumin at Epstein-Barr
of rare 4- to 8-week intervals
virus–associated lymphom
Hematologic: leukopenia, anemia, thrombocytopenia 3%87,89
wk reduced the incidence of elevated liver enzyme levels89and decreased C. Perform
that liver biopsy if: regress upon discontinuation of MTX.104
may occasionally
Hepatic: elevated transaminases, cirrhosis, liver failure 15% 1. Five of 9 determinations of AST within a given 12-month interval (6 of
toxicity-related discontinuation but had no effect on gastrointestinal side
effects106 The mean doses of MTX at the end of this 0.1% 48-week 5-yrstudy
cumulative
were 12 if tests are performed monthly) are abnormal (defined as an
higher in the folic acid and folinic acid groups than the incidence
placebo
91

122
group, TERATOGENICITY
elevation above the upper limit of normal)
Pulmonary:
suggesting interstitial
that higherpneumonitis
doses of MTX might be necessary2.1%–8%
for the same clinical 2. There is a decrease in serum albumin below the normal range (in the
Epstein-Barr virus–associated Methotrexate is a known teratogen, leading to multiple congenital abnorm
effect.107 Folinic acid (up tolymphomas
30 mg/wk) compared with Unknown
placebo taken 24 setting of well-controlled RA)
Accelerated
hours after nodulosis
the MTX dose led to fewer adverse effects with 8%98 no difference in ties,
D. especially
If results of liverofbiopsy
the nervous
are: system, called the aminopterin syndrome,
Central
diseasenervous
activitysystem: dizziness,
compared headache,
with placebo. 108
mood
In contrast25% 99
in another placebo- higher dose MTX
1. Roenigk grade is used
I, II, IIIA,toresume
induce abortion.
MTX and Even
monitor as low-dose
in B, C1, MTX
and C2 can
105
alteration, trial
controlled memory impairment
in which leucovorin (15 mg) was given 2 hours after MTX, to fetal abnormalities.
above The sponsor package insert recommends that M
the clinical and laboratory indices of disease worsened in the leucovorin be2.stopped
Roenigkatgrade
leastIIIB
one or menstrual cycle
IV, discontinue MTXbefore attempting conception
group,109 suggesting that the timing of folinic acid administration is important. E. Discontinue MTX in patients with persistent liver test abnormalities, as
Folinic acid should be taken 8 to 24 hours after MTX so that it does not defined in C1 and C2 above, who refuse liver biopsy
block the efficacy of MTX but remains effective in reducing side effects.
ALT, Alanine aminotransferase; AST, aspartate aminotransferase; CBC, complete blood cell; MTX,
methotrexate; RA, rheumatoid arthritis.
PHARMACOGENOMICS From Kremer JM, Alarcon GS, Lightfoot RW Jr, et al. Methotrexate for rheumatoid arthritis. Suggested
guidelines for monitoring liver toxicity. American College of Rheumatology. Arthritis Rheum
Ideally, we would like to treat only patients who will safely tolerate MTX 1994;37:316-328.
and for whom MTX will provide benefit. Because the critical players in the
function and metabolism of MTX are known, it has been possible to study
polymorphisms in some of these proteins to determine if they influence the of arthritis 4 to 6 weeks after stopping the drug. At least 1 mg each day of
Cyclosporine and Parent compound and Calcineurin inhibitor half-life of 11 to 16 hours.41 Although 90% is renally excreted, there is an
other IL-2 up to 15 metabolites Suppresses IL-2, IL-4, and enterohepatic recirculation that will safely clear the drug in the setting of Table 67.5
inhibitors T-cell proliferation renal insufficiency.41 Toxicity of the disease-modifying antirheumatic drugs
Mycophenolate Mycophenolic acid Interferes with inosine The concentration of MPA correlates with serum bilirubin, creatinine,
mofetil monophosphate and albumin concentrations and thus is affected by both renal and liver
Dehydrogenase inhibits T-cell
AZA (%) CYC (%) CsA (%) MMF (%)* TAC (%)
disease.41 MPA pharmacokinetics was positively correlated with thera-
and endothelial function peutic responses of MMF in patients with biopsy-proven World Health Shared
Tacrolimus Tacrolimus (previously Calcineurin inhibitor Organization (WHO) class III or IV lupus nephritis.42 Monitoring inosine Dose-related marrow 4–27 6–32 2–6 — —
known as FK506) Suppresses T-lymphocyte monophosphate dehydrogenase (IMPDH) activity (which correlates with suppression
proliferation MPA activity) as a biomarker of MPA-induced immunosuppression is being Leukopenia or 0–5 0–4 ≤2 0–37 —
considered as a novel approach in pharmacokinetics- and pharmacodynamics-
IL, Interleukin. thrombocytopenia
guided therapy.43
Susceptibility to infection

Overall 0–9 0–22 0–6 0–68 75

Table 67.2
Herpes zoster 0–6 5–30 0–3 3–30 —
Pharmacokinetics of the disease-modifying antirheumatic drugs
Gastrointestinal intolerance
Clearance Serum elimination
Bioavailability (mL/min/kg) half-life (hr) Unbound fraction Routes of elimination Site of metabolism Nausea, vomiting 9–23 19–45 4–40 0–34 17–46
Azathioprine 0.8 (6-MP) 114 (6-MP) 1.2–1.5 (6-MP) 0.80 (6-MP) Renal (20%–45%) Liver, kidneys Diarrhea ≤1 3–18 2–18 0–30 22–72
Cyclophosphamide 0.97 1.2 2–8 0.87 Renal (cyclophosphamide, 50%; Liver Rash 1–6 — — 0–7 —
8.7 (mustard) 0.45 (mustard) metabolites, 8%–35%)
Cyclosporine 0.2–0.5 2–32 10–30 0.10 Renal (6%) Liver
Not shared
Bile (94%) Hair
Mycophenolic mofetil 94 1.0 11.6 3 GI Liver, GI tract
Tacrolimus 0.25 5.4–16.9 12 <0.01 GI Liver Alopecia — 7–80 — 0–16 —
(0.54 L/hr/kg) Hypertrichosis — — 7–49 — —
GI, Gastrointestinal; 6-MP, 6-methylmercaptopurine.
Stomatitis 0–5 — 0–8 5 —
Gum hyperplasia — — 4–12 — —
Hepatic

Abnormal liver function 0–5 — 0–8 — —

Fibrosis or cirrhosis — — — — —
Azoospermia or — 60–100 — — —
oligospermia
Amenorrhea — 0–53 — 0–15 —
Cystitis — 4–45 — — —
Teratogenesis ± — ± + —
Neoplasia — — — 0–7 —
Decreased GFR — — 50–87 — 5
Hypertension — — 33 — +
Neurotoxicity — — 10–40 0–19.7 50
Pneumonitis — — — — —
Diabetogenetic — — — — 53

*Data from Touma Z, Gladman DD, Urowitz MB, et al. Mycophenolate mofetil for induction treatment of
lupus nephritis: a systematic review and metaanalysis. J Rheumatol 2011;38:69-78; Hoeltzenbein M,
Elefant E, Vial T, et al. Teratogenicity of mycophenolate confirmed in a prospective study of the
 CHAPTER 72 Tumor necrosis factor inhibitors 555

Table 72.1
U.S. Food and Drug Administration–approved indications for tumor necrosis factor-α inhibitors
Indication Etanercept Infliximab Adalimumab Golimumab Certolizumab
Rheumatoid arthritis Yes* Yes† Yes* Yes† Yes
Early rheumatoid arthritis Yes Yes Yes — —
Polyarticular juvenile arthritis Yes‡ — Yes§ — —
Psoriatic arthritis Yes¶ Yes Yes Yes Yes
Ankylosing spondylitis Yes** Yes** Yes** Yes Yes
Psoriasis Yes†† Yes Yes‡‡ — —
Crohn disease — Yes§§ Yes§§ — Yes
Ulcerative colitis — Yes¶¶ Yes Yes —

*Indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis. It can be initiated alone or
in combination with methotrexate (MTX).
†
Infliximab and golimumab are approved for use in combination with MTX only.
‡
Indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile rheumatoid arthritis in patients (age ≥2 years) who have had an inadequate response to one or more disease-modifying
antirheumatic drugs.
§
Indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile rheumatoid arthritis in patients (age ≥2 years) with or without MTX.
¶
Only etanercept is indicated to inhibit the progression of structural damage and improve physical function in patients with moderately to severely active psoriatic arthritis (PsA). It can be used in combination with MTX in
patients who do not show adequate response to MTX alone.
Indicated for reducing signs and symptoms of active arthritis in patients with PsA.
**Indicated for reducing signs and symptoms in patients with active ankylosing spondylitis.
††
Indicated for the treatment of adult patients (older than 18 years of age) with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.
‡‡
Indicated for the treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate.
§§
Indicated for reducing signs and symptoms and inducing or maintaining clinical remission in patients with moderately to severely active Crohn disease who have had an inadequate response to conventional therapy. Also
 disease should undergo serologic testing to help
Common B and C testing is also recommended before
At each visit, the patient should be caref
ADVERSE EVENTS ■ Injection site reactions
presence of infection, malignancy, demyelinat
■ Infusion reactions
ASSOCIATED WITH USE ■ Upper respiratory tract infections onset or worsening CHF, and any other com
patient’s risk-to-benefit ratio. Physicians shou
OF TUMOR NECROSIS Uncommon and exercise caution when patients develop a
Serious infectious events
FACTOR INHIBITORS ■
■ Mycobacterial infection
■ Fungal infection CONCLUSION
■ Opportunistic infections
■ Viral infection (herpes zoster, hepatitis B) Although currently available TNF blockers und
■ Lymphoma and malignancy able advance in the management of RA, future c
■ Autoimmunity, autoantibodies, and lupus-like disease further research is necessary to identify ideal pat
■ Heart failure patients in whom TNF inhibition should be a
■ Interstitial lung disease the dosage of TNF inhibitor can be optimized e
■ Cytopenias when necessary based on trough levels of dr
■ Demyelinating disorders identification of demographic, clinical, labor
■ Hepatotoxicity would predict clinical response or toxicit
desirable.
Rare or uncertain relationship In all, anti-TNF therapy has given much ho
■ Accidental injury activity with reduction in disability in our pa
■ Weight gain of these agents is an evolving story.
■ Pulmonary fibrosis
■ Asthma
■ Adult respiratory distress syndrome
■ Granulomatous lung disease
■ Colonic perforations
■ Vesicocolic fistula
■ Paresthesia
■ Neuropathy
■ Seizures
■ Foot drop
■ Asthenozoospermia
■ Glomerulonephritis
■ Proliferative lupus nephritis
 JAKINIBS BLOCK MULTIPLE ASPECTS OF CYTOKINE SIGNALING

IL-2 IFN-!
I I
!c F F
N N
! !
" PIP3 R
PI3-K " R
JAK1 # JAK3 JAK1 #
P FIG. 68.2 Binding of a cytokine t
Cytoplasm P PKB JAK2
leads to phosphorylation of the i
receptor by specific Janus kinas
TSC2 TSC2 transducers and activators of tra
Tofacitinib Ruloxitinib
Dimerization VX-509 Dimerization Lestaurtinib then recruited, bind to the recep
Ruloxitinib
R348 Rheb Tofacitinib phosphorylated by JAKs. This re
Lestaurtinib
Tofacitinib Baracitinib dimerization, translocation, and
Baracitinib CYT387 transcription. Cytokines also acti
P P P
CYT387 P mTOR GLPG0634 mammalian target of rapamycin
GLPG0634 STAT5 STAT5 STAT1 STAT1 TG101348 carefully studied, it is highly like
AZD1480 AC-430 cytokine signals will disrupt all d
R723
IFN, Interferon; IL, interleukin. (
Initiation & maintenance BMS911543
AZD1480 Kotlyar A, Laurence A, et al. Jak
Translocation of translation
Translocation SB1518 kinase inhibitors in cancer and a
CEP33779 Opin Pharmacol 2012;12:464-7

P P P P
Nucleus STAT5 STAT5 STAT1 STAT1
2 mg/day, or baricitinib 4 mg/day.36 Clinical responses with the 4-mg dose
of active drug were significantly better than with placebo, including the
ACR20 response (55% vs 27%), improvement in Health Assessment Question-
naire Disability Index (HAQ-DI), and clinical remission by DAS28-
C-reactive protein (defined as a DAS28-CRP <2.6). For remission, according
to simple disease activity index (SDAI), statistical significance was not achieved.
24 patients were given GLPG0634 (half received 200 mg/day and half
200 mg twice daily), and 12 patients were given placebo. An ACR20
response was achieved by 83% of patients given GLPG0634 versus 33%
of those given placebo. In this very small study, no anemia, increases in
LDL level, elevated transaminase levels, or changes in creatinine level
were seen.

Table 68.3
JAK inhibitors in clinical development

Specific target(s) Being developed for use in Stage of clinical development

Tofacitinib JAK3, JAK1 (JAK2) RA, ankylosing spondylitis, psoriasis, ulcerative Approved by FDA and many other regulatory
colitis, transplantation agencies for RA
Baricitinib (INCB028050/LY3009104) JAK1, JAK2 RA, psoriasis Phase 3 program completed; under
regulatory review
Filgotinib (GLPG0634) JAK1 (JAK2, TYK) RA Phase 2
Decernotinib (VX-509) JAK3 RA Phase 2
Ruxolitinib JAK2 (JAK1) Myelofibrosis, polycythemia vera, essential Approved for myelofibrosis; phase 2/3 for
thrombocytosis other indications; unclear for RA
ABT-464 JAK1 RA Phase 2

FDA, Food and Drug Administration; JAK, Janus kinase; RA, rheumatoid arthritis.
 ■ Reduced confirmation
levels of serumthat
rheumatoid factor and
TNF blockade cyclicleukocyte
reduces citrullinated peptide
traffic to inflam
antibodieswas obtained in an open-label clinical trial demonstrating a 40
BOX 72.2 BIOLOGIC EFFECTS OF TUMOR NECROSIS FACTOR-α Decreaseddecrease
frequency
■ in of cardiovascular
retention events inindium-111–labeled
of autologous patients with RA granuloc
554 SECTION ■5 Adhesion
Principles of expression
molecule Management(E-selectin, ICAM-1) hands, wrists, and knees 2 weeks after infliximab treatment. 8 T
■ Synthesis of other proinflammatory cytokines (IL-1, IL-6, GM-CSF) reduction in the marginating granulocyte pool after infliximab
BOX 72.1 BENEFITS ■ Synthesis of chemokines (e.g., RANTES, IL-8, MIP-1)
OF TUMOR NECROSIS FACTOR BLOCKADE
BENEFITS OF TUMOR NECROSIS FACTOR BLOCKADE BIOLOGIC A majoran mechanism
EFFECTS
observation OFthatof action
TUMOR
would
BOX 72.2 BIOLOGIC EFFECTS OF TUMOR NECROSIS FACTOR-α
of TNF
NECROSIS
normally inhibitors
be is
FACTOR-α
associated likely
with a to
rise be
in
■ Activation of numerous cell types (T cells, B cells, macrophages) of inflammatory blood granulocyte cell traffic. counts.A9 However,
dose-dependent in contrast rise in peripb
to peripheral
■ Efficacy, safety, and ■approvalInhibitionfor of use in numerous
regulatory T cells inflammatory states: ■ Adhesion molecule expression (E-selectin, ICAM-1)
lymphocyte phocyte counts counts,is observed
the numbersafter infliximab
of peripheral bloodinfusion,
granulocytes withdec
MMP induction ■ Synthesis of other proinflammatory cytokines 6 (IL-1, IL-6,within
GM-CSF)
rheumatoid arthritis ■(RA), juvenile arthritis, psoriasis, psoriatic arthritis, rise withininfliximab
24 hours dosing
of with maximal
treatment. changes
This is mediated 24 by
hours. The
modula
■ Upregulation of RANK ligand expression ■ Synthesis this of chemokines
is that (e.g., cell
myeloid RANTES, IL-8, MIP-1)
production is reduced secondary to down
ankylosing spondylitis, Crohn disease, and ulcerative colitis ■ arms of the
Activation inflammatory cell(Trecruitment cascade. factor
Thereasisareduce
■ Induction of apoptosis ofof granulocyte-macrophage
numerous cell types cells, B cells, macrophages)
colony-stimulating conse
■ Increased odds of remission
■ Antiviral inand
both randomized
antitumor effects ofcontrolled
TNF trials and ■ expression
Inhibition TNF of blockade.
synovial
of regulatory cytokine–induced
T cells vascularhalf-life
adhesion mol
Because of the short circulating of the gr
clinical practice (in both early and established RA) ■ asMMP induction
E-selectin and VCAM-1,
of approximately 8 hours, after anti-TNFrate
a diminished treatment, 7
a signi
of cell production
■ Significant disease modification as assessed
GM-CSF, Granulocyte-macrophage by radiographic
colony-stimulating studies
factor; ICAM-1, ■ Upregulation
intercellular adhesion molecule 1; of RANK ligand expression
IL, interleukin; MIP-1, macrophage inhibitory protein 1; MMP, matrix metalloproteinase; RANK, receptordependent the reduction
peripheral in
blood soluble
picture. serum E-selectin and intercellu
■ Induction of apoptosis
■ Dramatic normalization of ofacute-phase
activator reactants
nuclear factor-κB; RANTES, molecule
regulated on activation, normal T cell expressed and secreted; 1 One factor contributing
concentrations, 6
and a to the rapid reduction
significantly diminished in joint immuswe
■ Antiviral and antitumor
anti-TNF effectsisoflikely
therapy TNF to be a reduction in tissue edema and
■ Reduced levels of serum rheumatoid factor and cyclic citrullinated peptide
TNF, tumor necrosis factor.
expression of the chemokines IL-8 and MCP-1, with a trend towaa
leak, mediated by vascular endothelial growth factor (VEGF),
antibodies in a Granulocyte-macrophage
GM-CSF, number of other chemokines.
colony-stimulating 8
factor; ICAM-1, intercellular adhesion molecule 1;
implicated in new blood vessel formation and found to be eleva
■ Decreased frequency of cardiovascular events in patients with RA IL, interleukin; MIP-1,
Infliximab
serum
macrophage
therapy
of
inhibitory
patients is protein
also
with
1;
RA.
MMP, matrix
associated
10
Serum
metalloproteinase;
with RANK,
a reductionreceptor
VEGF in
activator of nuclear factor-κB; RANTES, regulated on activation, normalconcentrations
T cell expressed and of
secreted; sho
SIMPLIFIED DIAGRAM OF THE MOLECULAR STRUCTURES OF FIVE synovial
TNF, tissue
factor. macrophages
dependent
tumor necrosis reduction afterand infliximab infusions 7,8
lymphocytes. butHowever,
without norm th
BIOLOGIC TNF INHIBITORS confirmation Therethat is alsoTNF reduction
blockade in synovial
reducesvascular leukocyte density
trafficandtoininflpa
reduction in angiogenesis, as assessed by diminished number
BOX 72.2 BIOLOGIC EFFECTS OF TUMOR NECROSIS FACTOR-α was obtained in an open-label clinical trial
expressing the αVβ3 integrin. The vascular signal on quantitat
11 demonstrating a 4
Chimeric Human Human Humanized
decrease in DIAGRAM
retention ofTHEautologous indium-111–labeled granulo
monoclonal monoclonal recombinant Fab′ SIMPLIFIED Doppler imaging OF is MOLECULAR
also significantly STRUCTURES
reduced afterOF FIVE
infliximab the
■ Adhesion molecule expression (E-selectin, ICAM-1) hands, wrists,
antibody antibody receptor/Fc fusion fragment marked and knees
BIOLOGIC
reduction 2 weeks
TNF INHIBITORS
in circulating after infliximab
concentrations of the treatment.
precursors o
■ Synthesis of other proinflammatory cytokines (IL-1, IL-6, GM-CSF) protein reduction in the marginating granulocyte
enzymes MMP-1 and MMP-3, 14
and a significantpool after
reductioninfliximab
in syno
= Murine = Human
■ Synthesis of chemokines (e.g., RANTES, IL-8, MIP-1) an Chimeric expression
observation that of MMPs was noted.
would normallyHuman
15
Cartilage
be associated damage by MMPs
with a riseis in
t
Human Humanized
■ Activation of numerous cell types (T cells, B cells, macrophages) p75 be one ofmonoclonal
SIMPLIFIED
monoclonal the main steps
DIAGRAM 9 OFin THEprogression
MOLECULAR
recombinant of joint damage.
Fab′ Serum
blood granulocyte
osteoprotegerin
counts.
(OPG)
However,
andreceptor/Fc
solubleTNF
in contrast
receptor
to
activator
peripheral
of nuclear
■ Inhibition of regulatory T cells receptor antibody
STRUCTURES antibody
OF FIVE BIOLOGIC fusion INHIBITORS fragment
phocyte counts, ligands the numbers
(sRANKL), both ofofperipheral
which are
protein
blood granulocytes
elevated in RA sera comp d
■ MMP induction = Murine = Human
Fc Fc infliximab dosing
normal sera,with maximal changes
are normalized after infliximab withintherapy
24 hours.without Thin
■ Upregulation of RANK ligand expression IgG1 IgG1 this is that themyeloid cell production
ratio.16 These is reduced
OPG-sRANKL observations p75secondary
predicted thetobenefi dow
■ Induction of apoptosis on radiographic erosions
of granulocyte-macrophage with anti-TNF receptor
colony-stimulating inhibitors.
factor as a con
■ Antiviral and antitumor effects of TNF One hypothesis for the failure of etanercept to work in Croh
Infliximab Adalimumab Etanercept TNF blockade. Because of the short circulating half-life of the
Certolizumab in contrast
Fc to the marked Fc benefits demonstrated with mAbs to
Golimumab pegolof approximatelythat IgG1
the 8 hours,may
antibodies a IgG1
diminished
cause an rate in
increase of apoptosis
cell productionof lamin
GM-CSF, Granulocyte-macrophage colony-stimulating factor; ICAM-1, intercellular adhesion molecule 1;
 Key terms
Adult RA patient
Health benefits and harms
Early RA
Established RA
Disease activity
RA remission
Optimal dosing of RA treatments
DMARD failure
Biologic failure
Secondary biologic failure
Active hepatitis B infection
Hepatitis C infection
NYHA class III and IV
Drug category
Methotrexate
DMARDs§
ACR RA Treatment Recommendations
DMARD monotherapy
Double DMARD therapy
Drug category
Triple DMARD therapy
DMARD combination therapy
Tofacitinib
Biologics
TNFi biologics
Non-TNF biologics
Low-dose glucocorticoid
High-dose glucocorticoid
Short-term glucocorticoid
Definitions
Adults, $18 years, meeting the ACR RA classification criteria (1987 or 2010 revised
criteria) (81,82).
Efficacy and safety of treatments including desirable and undesirable effects.
RA with duration of disease/symptoms of ,6 months, where “duration” denotes the
length of time the patient has had symptoms/disease, not the length of time since
RA diagnosis.
RA with duration of disease/symptoms of $6 months or meeting 1987 ACR RA classi-
fication criteria (81).‡
Categorized as low, moderate, or high as per validated scales (Table 2) (144–150). Mod-
erate and high disease activity categories were combined based on feedback from the
Content Panel, as used previously for the 2012 ACR RA treatment recommendations.
A joint ACR/EULAR task force defined remission as a tender joint count, swollen joint
count, C-reactive protein level (mg/dl), and patient global assessment of #1 each or
a Simplified DAS of #3.3 (151), 1 of 6 ACR-endorsed disease activity measures.†
1) Dosing to achieve a therapeutic target derived from mutual patient-clinician consid-
eration of patient priorities, and 2) given for at least 3 months before therapy escala-
tion or switching.
Failure of traditional/conventional DMARD(s) due to lack of efficacy/desired response
or side effects.
Failure of biologic(s) due to lack of efficacy/desired response or side effects.
Biologic was efficacious initially but subsequently became inefficacious.
Hepatitis B surface antigen positive, hepatitis B surface antibody negative, hepatitis B
core antibody total positive (less important), AST/ALT typically increased, HBV
DNA positive (if checked).
HCV antibody positive, HCV RNA positive, AST/ALT typically increased.
NYHA class III includes patients with cardiac disease resulting in marked limitation of
physical activity with less than ordinary physical activity causing fatigue, palpita-
tion, dyspnea, or angina, but no symptoms at rest. NYHA class IV includes patients
with cardiac disease resulting in inability to carry on any physical activity without
discomfort, symptoms of heart failure are present even at rest, and discomfort
increases if any physical activity is undertaken (152).
Descriptions
Used either oral or subcutaneous (a DMARD).
Traditional/conventional DMARDs including HCQ, LEF, MTX, or SSZ (excludes aza-
thioprine, cyclosporine, minocycline and gold), it does not include tofacitinib,
5
which is considered separately.¶
Most often defined as the use of MTX monotherapy, but may also be SSZ, HCQ, or
LEF.
Table 1. (Cont’d)
MTX1SSZ, MTX1HCQ, SSZ1HCQ, or combinations with LEF.
(continued)
Descriptions
MTX1SSZ1HCQ.
Double or triple traditional/conventional DMARD therapy.
Oral synthetic small molecule.
TNFi biologic or non-TNF biologic (excludes anakinra).§
Adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab.
Abatacept, rituximab, or tocilizumab (excludes anakinra).§
#10 mg/day of prednisone (or equivalent). Arthritis Care & Research
.10 mg/day of prednisone (or equivalent) and up to 60 mg/day with a rapid taper.# DOI 10.1002/acr.22783
VC 2015, American College of Rheumatology
,3 month treatment.
 Treatment of Rheumatoid Arthritis 79
Table 13.1 Biological properties

Biological properties
Table 13.1 Biological properties Infliximab Etanercept Adalimumab Certolizumab Golimu

Structure Monoclonal P75TNFR/Fc Monoclonal Pegylated Monoc

Infliximab Etanercept Adalimumab Certolizumab Golimumab Rituximab Tocilizumab Abatacept
antibody fusion antibody monoclonal antibod
Structure Monoclonal P75TNFR/Fc Monoclonal Pegylated Monoclonal Monoclonal antibody CFLA‐4/Fc
Monoclonal
antibody fusion antibodyDosing method
monoclonalIV antibodySC SC
antibody antibodySC SC
antibody 8 weeks
Dosing frequency Weekly 2 weeks 2 weeks Month
Dosing method IV SC SC SC SC IV IV or SC IV or SC
Dosing frequency 8 weeks Weekly 2 weeks Half‐life in 2 weeks 9.5 Monthly3 14
Dependent 14
4 weeks (IV), 12
4 weeks (IV),
humans (days) on response weekly (SC) weekly (SC)
Half‐life in 9.5 3 14 Target (s) 14 TNF 12 TNF and 22 TNF 12 TNF 13 TNF
humans (days) lymphotoxin

Target (s) TNF TNF and TNF IL, interleukin;

TNF IV, intravenous; SC,
TNFsubcutaneous;CD20
TNF, tumour necrosis factor.
IL‐6 receptor CD80 &
lymphotoxin CD86

IL, interleukin; IV, intravenous; SC, subcutaneous; TNF, tumour necrosis factor.Structural classification of biological therapies
Table 13.2 clinicians shoul
eases, such as pr
% Human by infection with
Table 13.2 Structural classification of biological therapies clinicians Suffix
Molecular structure should be alerted to reports
sequence of rare neurological dis-
Example
eases, such as progressive multifocal leucoencephalopathy caused
% Human Monoclonal antibodies ‐ximab 60–70 Infliximab Abatacept
by infection with the polyoma JC virus.
Molecular structure
Structural classification Suffix
of biologicalsequence
therapies Example ‐zumab 90+ Tocilizumab T‐lymphocyte ac
‐mumab 100 Adalimumab tory signal that i
Monoclonal antibodies ‐ximab 60–70 Infliximab Abatacept
Receptor fusion proteins ‐cept 100 Abatacept cell. Interruption
‐zumab 90+ Tocilizumab T‐lymphocyte activation and proliferation requires a dual
Etanercept stimula-
such as CTLA‐4
‐mumab 100 Adalimumab tory signal that involves both the T‐cell and the antigen presenting
Comorbidities and Prognosis
 Inflamed Synovium
Skeletal
Muscle

TNF-α,IL-1, IFN-γ, IL-6

Smoot
Mac
Insulin Fibrinogen CRP

Endothelial Act

rop
Resistance

h
PAI-1

Muscle

hag
eA
Adipose

Cell A
Intima

ctiv
Tissue Thrombosis

atio
Media

ctivati
ivation
Dy

n
slip

on
id e Lipid
mia
Core

Figure 6.1 Diagram

Diagram depicting depicting
the inflammatory the by
pathways inflwhich
ammatory
mediatorspathways by which
of synovitis, including tumormediators of (TNF)–D,
necrosis factor syno-
vitis, including
may alter arterial tumor necrosis
biology and factor
risk factors (TNF)–!, may
for atherosclerosis, alterinsulin
including arterial biology
resistance, and risk
dyslipidemia, factors
fibrinogen,
plasminogen activator inhibitor–1 (PAI-1), and heighten the production by the liver of the biomarker of inflammation C-
for atherosclerosis, including insulin resistance, dyslipidemia, fibrinogen, plasminogen
reactive protein (CRP). IFN = interferon; IL = interleukin
activator inhibitor–1 (PAI-1), and heighten the production by the liver of the biomarker
of inflammation C-reactive protein (CRP). IFN = interferon; IL = interleukin
 management of RA. The previous ver-
sion was published in 2012.
The new guidelines used the GRADE
(Grading of Recommendations Assess-
ment, Development, and Evaluation)
Management of RA
methodology to rate the quality of
evidence. A total of 74 recommenda-
in patients with
tions are included in the guidelines,
with 23% ranked as “strong” and the
established disease
remaining 77% ranked as “condi-
tional.” A summary of key guideline
and moderate or
updates are presented here. Clinicians
can access the full guidelines at www.
high disease activity
rheumatology.org.
and select high-risk
Treat-to-target approach
comorbidities
For all patients, such as those with early
RA (<6 mo) and established RA (≥6 mo),
a treat-to-target approach is strongly
recommended, compared with a non-
targeted approach. In general, ACR rec-
ommends that an ideal target should
be low disease activity or remission,
as determined by the clinician and the
patient. ACR did note, however, that
in some cases, another target may be
chosen because patient risk tolerance or
comorbidities may mitigate the usual
choices.
Early RA treatment
For patients with early RA who are
DMARD-naive, the guidelines strongly
recommend DMARD monotherapy
over double or triple DMARD therapy
in those with low disease activity.
or high disease activity and select high-risk comorbidities
Comorbid condition Recommendation (ranking)
■ Combination DMARD therapy, a non-TNF biologic, or
tofacitinib should be used rather than a TNF inhibitor
(conditional).
■ If treated with a TNF inhibitor and the heart failure
worsens while on therapy, switch to combination
DMARD therapy, a non-TNF biologic, or tofacitinib
Congestive heart failure rather than a different TNF inhibitor (conditional).
■ In those with active hepatitis B infection who
are receiving or have received effective antiviral
treatment, treatment should be the same as those
without this condition (strong).
■ For patients with chronic hepatitis B who are
untreated, referral for antiviral therapy first is
Hepatitis B
appropriate prior to starting immunosuppressive
therapy (conditional).
■ In those with chronic hepatitis C infection who
are receiving or have received effective antiviral
treatment, treatment should be the same as those
without this condition (conditional).
■ For patients who do not require or are receiving
antiviral treatment for hepatitis C, DMARD therapy
rather than a TNF inhibitor is recommended
Hepatitis C (conditional).
Previous melanoma and ■ Use of DMARD therapy over biologics or tofacitinib is
nonmelanoma skin cancer recommended (conditional).
■ Use of rituximab rather than a TNF inhibitor is
recommended (strong).
■ Combination DMARD therapy, abatacept, or
Previous lymphoproliferative tocilizumab rather than a TNF inhibitor is also
disorders recommended (conditional).
■ Treatment of RA should be just the same as in
patients without a history of solid organ cancer
Previous solid organ cancer (conditional).
■ DMARD therapy or abatacept rather than a TNF
Previous serious infections inhibitor is recommended (conditional).
Abbreviations used: DMARD, disease-modifying antirheumatic drugs; TNF, tumor necrosis factor; RA, rheumatoid arthritis. maria g. tanzi PharmacyToday • MARCH 2016
 , the guidelines strongly rec- Summary
using combination DMARDs The 2015 ACR guidelines for RA man- Maria G. Tanzi, PharmD,
g a TNF inhibitor or non-TNF agement are very comprehensive and contributing writer
or tofacitinib (Xeljanz—Pfizer)
an continuing DMARD mono- Recommended
Table useuse
2. Recommended of of
vaccines inpatients
vaccines in patientswithwith RA treatment
RA treatment 1
alone. Again, as with early RA,
ese choices are with or with- Vaccine
and in no particular order of
ce. Influenza
uidelines also include spe- RA Pneumo- (killed/ Human Herpes
treatment coccal inactivated) Hepatitis B papilloma zoster
mmendations for select clini-
Before initiating therapy
arios in established RA based
DMARD
onse to previous treatments. X X X X X
monotherapy
trong recommendations for
Combination
ed RA include continuing pre- DMARDs
therapies for those with low TNF
activity and not discontinuing X X X X X
inhibitors
pies in patients with estab- Non-TNF
A in disease remission. X X X X X
biologics
While taking therapy
ement of high-risk DMARD
X X X X X
ions monotherapy
ated guidelines also include Combination
X X X X X
ndations for patients with DMARDs
gh-risk comorbidities. A sum- TNF Not
X X X X
hese recommendations is listed inhibitors recommended
1. In addition, the guidelines Non-TNF Not
X X X X
pecific guidance on the use of biologics recommended
Abbreviations used: RA, rheumatoid arthritis; DMARD, disease-modifying antirheumatic drugs; TNF, tumor necrosis factor.
ccines in patients with RA. For
maria g. tanzi PharmacyToday • MARCH 2016
 COMORBIDITY AND MULTIMORBIDITY IN A PATIENT WITH RA

Comorbidity Multimorbidity

(a) For comorbidity, rheumatoid Peptic RA

ulcer
arthritis (RA) is the index
disease, and all FIG.
other 53.1 diseases
(a) For comorbidity,
are mainly regarded
rheumatoid as arthritis (RA) is the
index disease, and all other
consequential. (b) In the
diseases are mainly regarded
as consequential.
multimorbidity concept, the (b) In the Osteoporosis RA
Cardiovascular
Osteoporosis Patient
Cardiovascular
multimorbidity concept, the disease disease
patient is of central
patientconcern, and
is of central concern,
all diseases are andof all diseases are of equal
equal
importance with interactions
importance withamong interactions
each other. (c) In the
comorbidity concept, treatment
among each other. (c) In the
is primarily focused on the
comorbidity concept, treatment
index disease and the effect Diabetes Diabetes
quantified by evaluating RA mellitus mellitus
is primarily focused on the index
disease activity. (d) In the
a b

disease and themultimorbidity

effect quantified concept,
by evaluating RAtreatment
disease focuses on the
activity.
patient, and treatment
Comorbidity Multimorbidity
(d) In the multimorbidity
effectiveness concept,
is quantified by
Peptic
overall indicators such as RA
treatment focuses ulcer
qualityon theor physical
of life
Secondary
patient, and treatment
function. (From Radner H,
treatment
Yoshida K, Smolen JS, Primary Primary
effectiveness is Solomon
quantified by focus
DH. Multimorbidity treatment treatment
overall indicatorsandsuch
rheumatic as conditions—
quality focus focus
enhancing the concept of
of life or physicalcomorbidity.
function. Nat Rev Cardiovascular Cardiovascular
Rheumatol. 2014;10(4): Osteoporosis RA Osteoporosis Patient
disease disease
252-6.)
Assess Assess
effectiveness by effectiveness using
evaluating RA overall concepts
Secondary
disease activity such as quality of
treatment
life or function
focus
Diabetes Diabetes
c mellitus d mellitus Lyn M. March, Treatment recommendations and “treat
to target”, Marc Hochberg, Rheumatology 2018
428 SECTION 5 Principles of Management

ROLE OF PHYSICAL AND OCCUPATIONAL THERAPY IN RHEUMATIC DISEASE

Health condition
Rheumatic diseases commonly requiring rehabilitation
(e.g., osteoarthritis, rheumatoid arthritis, regional and
widespread pain, fibromyalgia)

Impairments in body structures or functions Activity limitations Participation restrictions

Pain Hand function (e.g., buttons, grasping, turning taps) Occupation
Altered sensation Gait and locomotion Sports and leisure pursuits
Inflammation Stair climbing Family responsibilities and roles
Decreased muscle strength and power Transfer ability (e.g., getting in/out of a chair, car) Socializing with family and friends
Altered muscle coordination Activities of daily living (e.g., bathing, driving) Community roles
Reduced joint range of motion Squatting and kneeling
Reduced muscle flexibility Sports-specific tasks (e.g., running, jumping, hopping)
Impaired balance and postural control
Reduced endurance and cardiovascular fitness
Fatigue

Environmental factors Personal factors

Access to rehabilitation services Age
Rehabilitation strategy Gender
Occupational demands Socioeconomic status
Carer responsibilities Weight and other comorbidities (e.g., depression,
Provision of adaptive equipment/aids anxiety)
Family and social supports Pain coping strategies and style
Culture Attitudes and beliefs
Adherence to rehabilitation recommendations

FIG. 55.1 Role of physical therapy and occupational therapy rehabilitation in rheumatic diseases, as illustrated by the International Classification of Functioning, Disability
and Health framework.5
Table 55.1
Table 55.2
Guidelines for prescription of structured exercise in people with arthritis33,34
Examples
Exercise typeof strategies
Goal that can be recommended Intensity
to increase general physical activity levels
Volume Frequency
Stretching
To increase amount ofMaintain
physical or increase muscle
activity Stretch to the intensity
To increase point of of
feeling tightness
physical activity or 3–5 stretches/key muscle
To monitor groups;
physical hold
activity Daily initially, building
flexibility slight discomfort, with the goal of position for 5–15 sec and build toward 3–5/week
Alter transport to more active options Walk at a to
stretching faster rate than
full range normal
of motion Use a pedometer
toward 20–30-sec holds or activity tracking device to record
Commence
Range a new activity,
of motion Maintainsport, or exercise
or increase jointclass
range Walk up
Respect theorphysiology
down hillsofrather thanand
the joint flat ground
6–10 repetitions steps perrange
of each day Daily
Join a club that involves physical activity (e.g., hiking)
of movement Walkwithin
work on sandits residual range of motion Use a calendar to record the days that physical
Walk the dog
Isometric Maintain or increase muscle LowPerform cleaning
to moderate: and otherMVC
40%–60% household tasks more
1–10 submaximal activity goals have
contractions been metDaily
involving
Play with the kids or grandkids
resistance strength vigorously key muscleUse an exercise
groups; hold thediary or physical activity log book
Take up gardening Substitute walking for dancing, swimming, orcontraction
cycling for 1–6 sec
Wash the car
Isotonic Maintain or increase muscle Low: 40% 1 RM 10–15 repetitions, 1–3 sets 2–3 days/week
Take the stairs instead
resistance of the elevator
strength Moderate: 40%–60% 1 RM 8–10 repetitions, 1–3 sets
Stand up in meetings rather than sitting High: >60% 1 RM 6–8 repetitions, 1–3 sets
Have “walking meetings”
Aerobic Maintainat work rather than
or increase sitting
physical Low to moderate: 40%–60% of VO2max/ Accumulation of 30–60 min/day 3–5 days/week
Get off the bus or subway
fitnessoneandstop early health
general HRmax Exercise may be performed in one
Stand up while talking on the phone RPE: 12–14 = 60%–65% VO2max (continuous) session per day or in
shorter bouts to accumulate the
desired volume of exercise per day

HR max, Age-predicted heart rate maximum; MVC, maximal voluntary contraction (measurement of isometric strength); 1 RM, one repetition maximum (measurement of isotonic or dynamic strength); RPE, rating of
perceived exertion; VO2 max, maximal aerobic capacity (measurement of aerobic fitness).
Table 55.3
Examples of aids, devices, and adaptions that can be used to maximize functional independence
Functional limitation Underlying impairment Adaptive aid, device, or environmental modification
Difficulty gripping to use utensils to Wrist or hand muscle weakness, limited wrist and Use large handles that fit over utensils. Use an electric opener for
eat or for cooking hand joint range of motion, decreased sensation cans or lid lifter to break the suction on vacuum lids.
Difficulty reaching to eat or for Shoulder or elbow pain, limited range of motion, or Use long-handled or angled utensils. Use a straw in drinks. Use
personal hygiene muscle weakness long-handled back scrubber or toe washer.
Difficulty bending to put on shoes Reduced spinal or hip range of motion, pain, lower Sit to put on shoes and socks. Use long-handled shoe horn and sock
and socks limb muscle weakness aid.
Difficulty standing and balancing to Reduced balance, muscle weakness, pain, or Use a shower seat, nonslip mat in the shower, and wall rails. Use
shower fatigue extendable shower head. Use cloth robe to dry after showering.
Difficulty with rising from sitting Lower limb muscle weakness, pain, decreased joint Use a raised toilet seat, with an armrest if required. Install rails and
range of motion bars.
Climbing stairs Reduced balance, muscle weakness, pain, or Install rails, ramps, or a stair lift.
fatigue
Walking outdoors Reduced balance, muscle weakness, pain, or Use a cane, with attachment to improve base stability or change grip
fatigue if necessary. Use a walking frame or wheelchair for longer distances.
 Poor prognostic factors

• Moderate (after csDMARD therapy) to high disease

activity according to composite measures
• High acute phase reactant levels
• High swollen joint counts
• Presence of RF and/or ACPA, especially at high levels
• Combinations of the above
• Presence of early erosions
• Failure of two or more csDMARDs
 Treat-to-target strategy

• Treat active RA in adults with the aim of achieving a

target of remission or low disease activity if
remission cannot be achieved (treat-to-target).
• Consider making the target remission rather than
low disease activity for people with an :
• increased risk of radiological progression (presence of
anti-CCP antibodies
• erosions on X-ray at baseline assessment).
• high C-reactive protein (CRP)
Perioperative and Pregnancy
Management
Perioperative medication management recommendations for drugs in use for rheumatoid arthritis
DMARDs: CONTINUE these medications through surgery. Dosing Interval Continue/Withhold
Methotrexate Weekly Continue
Sulfasalazine Once or twice daily Continue
Hydroxychloroquine Once or twice daily Continue
Leflunomide (Arava) Daily Continue
Doxycycline Daily Continue
BIOLOGIC AGENTS: STOP these medications prior to surgery and schedule surgery at the Schedule Surgery (relative to
end of the dosing cycle. RESUME medications at minimum 14 days after surgery in the last biologic agent dose
absence of wound healing problems, surgical site infection, or systemic infection. Dosing Interval administered) druing
Adalimumab (Humira) Weekly or every 2 weeks Week 2 or 3
Etanercept (Enbrel) Weekly or twice weekly Week 2
Golimumab (Simponi) Every 4 weeks (SQ) or Week 5
every 8 weeks (IV) Week 9
Infliximab (Remicade) Every 4, 6, or 8 weeks Week 5, 7, or 9
Abatacept (Orencia) Monthly (IV) or weekly (SQ) Week 5
Week 2
Certolizumab (Cimzia) Every 2 or 4 weeks Week 3 or 5
Rituximab (Rituxan) 2 doses 2 weeks apart Month 7
every 4–6 months
Tocilizumab (Actemra) Every week (SQ) or Week 2
every 4 weeks (IV) Week 5
Anakinra (Kineret) Daily Day 2
Secukinumab (Cosentyx) Every 4 weeks Week 5
Ustekinumab (Stelara) Every 12 weeks Week 13
Belimumab (Benlysta) Every 4 weeks Week 5
Tofacitinib (Xeljanz): STOP this medication 7 days prior to surgery. Daily or twice daily 7 days after last dose
SEVERE SLE-SPECIFIC MEDICATIONS: CONTINUE these medications in the
perioperative period. Dosing Interval Continue/Withhold
Mycophenolate mofetil Twice daily Continue
Azathioprine Daily or twice daily Continue
Cyclosporine Twice daily Continue
Tacrolimus Twice daily (IV and PO) Continue
NOT-SEVERE SLE: DISCONTINUE these medications 1 week prior to surgery Dosing Interval Continue/Withhold
Mycophenolate mofetil Twice daily Withhold
Azathioprine Daily or twice daily Withhold
Cyclosporine Twice daily Withhold
Tacrolimus Twice daily (IV and PO) Withhold

Adapted from Goodman SM, Springer B, Guyatt G, et al. 2017 American College of Rheumatology/American Association of Hip and Knee Surgeons Guideline for the Perioperative Management of Antirheumatic Medication
in Patients with Rheumatoid Diseases Undergoing Elective Total Hip and Total Knee Arthroplasty. Arthritis & Rheumatology and Journal of Arthroplasty. 16 June 2017.
 Table 7.1 Continued

Pregnan
individual clinical judgment whether to continue these agents when pregnancy Treatment Risk Profile Recommendation
ensues, or to initiate them for active RA when a patient is considering becom- Sulfasalazine Available data suggests low risk; May be used during
no large well-controlled studies. pregnancy; use should
ing pregnant, or in the setting of a patient who has child-bearing potential with

CHAPTER 7
be accompanied by folic
inadequate birth control. acid-containing vitamin
supplements.
Leflunomide Animal studies show Contraindicated in
increased risk for congenital pregnancy.
Reccomendation for use OAINS
Table 7.1 Recommendations and
for Use DMARDs
of Anti during pregnancy
Inflammatory and malformations; minimal data in
humans.
Disease Modifying Antirheumatic Drugs during Pregnancy
Hydroxychloroquine Small studies show no Teratogenic is unlikely;
Treatment Risk Profile Recommendation increased risk for congenital compatible with pregnancy.
malformations; not adequately
Anti-inflammatory agents studied in RA patients.
Azathioprine No increased risk for structural Compatible with pregnancy.
Corticosteroids Increase in oral clefts; dose- May be used during defects.
related intrauterine growth pregnancy with minimal risk; Cyclosporine No increased risk for structural Compatible with pregnancy.
restriction. lower doses will minimize defects.
risk. Chlorambucil Insufficient data to determine Contraindicated in
teratogenic risk. pregnancy.
Nonsteroidal anti- Low risk for congenital May be used during first Cyclophosphamide Risk for growth abnormalities, Contraindicated in
inflammatory drugs malformations and miscarriage; trimester; discontinue use craniofacies, limb development, pregnancy.
and neurodevelopment.

Disease modifying antirheumatic drugs
Methotrexate
7-Weisman_Chap07.indd 45
46
significant risk after 32 weeks’ at or beyond 32 weeks’
Biologics
gestation. gestation.
Etanercept Insufficient data to determine Physician discretion
teratogenic risk. recommended.
Dose-related abnormalities Contraindicated in Infliximab Insufficient data to determine Physician discretion
teratogenic risk. recommended.
of growth, craniofacies, pregnancy; treatment
Adalimumab Insufficient data to determine Physician discretion
limb development, and should be discontinued teratogenic risk. recommended.
neurodevelopment. at least 3 months prior to Golimumab Insufficient data to determine Physician discretion
conception. teratogenic risk. recommended.
Certolizumab pegol Insufficient data to determine Physician discretion
(continued) teratogenic risk. recommended.
Rituximab Insufficient data to determine Physician discretion
teratogenic risk. recommended.
Abatacept Insufficient data to determine Physician discretion
teratogenic risk. recommended.
Anakinra Insufficient data to determine Physician discretion
teratogenic risk. recommended.
Tocilizumab Insufficient data to determine Physician discretion
teratogenic risk. recommended.
6/29/2011 7:00:32 PM
Adapted from Chambers 2006 and Østensen and Nelson 2004.
Wassalamualaikum ww

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