Rheumatoid Arthritis (1 of 23)

Rheumatoid Arthritis (1 of 23)

1

Patient presents w/ signs & symptoms of rheumatoid arthritis (RA)

2
4

DIAGNOSIS

No

ALTERNATIVE

Is RA conﬁrmed?

DIAGNOSIS

Yes

AB

Pharmacological therapy

• Conventional synthetic disease-modifying anti-rheumatic drug (DMARD)
(csDMARD) monotherapy [Methotrexate (preferred), Leﬂunomide or Sulfasalazine]
• Adjunctive therapy [corticosteroids, nonsteroidal anti-inﬂammatory drugs (NSAIDs)]

Non-pharmacological therapy
CONTINUE

3

TREATMENT
Symptoms improved at 3 mth & treatment goal achieved at 6 mth?
Yes Yes

• Consider decreasing dose if in sustained remission

No

A

Add any one of the following:

AB

• TNF inhibitor¹or

3

• Change to or add a

No

• Non-TNF

Are poor prognostic factors

second csDMARD biological¹or

present?
Non-pharmacological

• Jak-inhibitor

therapy

B

Nonpharmacological therapy

TREATMENT See next page

¹In patients who cannot use csDMARDs as comedication, interleukin-6 receptor antagonists & targeted synthetic DMARDs (tsDMARDs) have some advantages over other biological DMARDs (bDMARDs)

Not all products are available or approved for above use in all countries. Speciﬁc prescribing information may be found in the latest MIMS.

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TREATMENT OF PATIENTS W/ POOR PROGNOSTIC FACTORS CONT’D

CONTINUE

3

TREATMENT

• Consider decreasing dose or increasing interval if in

Yes

sustained remission

No

AB

• Switch to another TNF inhibitor or non-TNF biological¹or
• Jak-inhibitor

Non-pharmacological therapy

3

Yes
No

¹In patients who failed one TNF inhibitor therapy, consider giving a second TNF inhibitor or changing to an agent from a diﬀerent class

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1 RHEUMATOID ARTHRITIS (RA)

•

A chronic, inﬂammatory arthritis of unknown etiology - Most common autoimmune inﬂammatory arthritis in adults - Persistent synovitis leads to joint destruction & deformity

Etiology

••

Smoking increases incidence for developing RA in anti-citrullinated protein antibody (ACPA)-positive patients Bacteria (eg Escherichia coli, Helicobacter pylori, Mycobacteria, Mycoplasma, Streptococcus), viruses (eg Epstein-Barr virus, rubella, parvovirus) & periodontal disease (Porphyromonas gingivalis) is strongly associated w/ the occurrence of RA

Clinical Manifestations

General

••••

Joint pain &/or swelling Morning stiffness lasting ≥1 hour Myalgia, fatigue, weight loss, low-grade fever, depression Typically involves the joints of the fingers, wrists, toes - Upper & lower extremity joints are also affected (eg shoulders, elbows, knees & ankles) Syndrome of polymyalgia rheumatica may occasionally be present

•

Early Rheumatoid Arthritis

•

Duration of occurrence of RA signs & symptoms is <6 months & meets the classiﬁcation criteria for RA

Established Rheumatoid Arthritis

Duration of occurrence of RA signs & symptoms is ≥6 months & meets the classiﬁcation criteria for RA

•

Palindromic Rheumatism

•

Follows an episodic pattern - Joints may be aﬀected for hours to days followed by symptom-free periods lasting for days to months

Undiﬀerentiated Arthritis

•

May indicate onset of a polyarticular disease - Interval between monoarthritis & polyarthritis may extend from days to week in patients w/ progressive disease Large joints are frequently aﬀected (eg shoulder, wrist, hip, knee, ankles) History of joint trauma may be the initiating event

••

Extra-articular Involvement

•••

Anemia, fatigue, pleuropericarditis, interstitial lung disease, neuropathy, scleritis, Sjogren’s syndrome, vasculitis Subcutaneous rheumatoid nodules on extensor surfaces of elbows & over Achilles tendons Splenomegaly

Physical Findings

•••

Joint pain & swelling are the key features of RA Limited or restricted range of motion Hand & foot involvements are common in the early course of RA - Symmetric polyarthritis involving the interphalangeal thumb joints, metacarpophalangeal (MCP) &/or proximal interphalangeal (PIP) joints of the hands & the metatarsophalangeal (MTP) joints of the feet strongly suggests RA

•

Deformities due to joint & tendon destruction are late manifestations of RA - Ulnar deviation or drift - Radial deviation of wrist - Boutonnière & swan-neck deformities - Hammer toes - Joint ankylosis (uncommon) - Genu varus or valgus may also be seen secondary to erosion of femoral condyles & tibial plateau

Severity of Disease

•

RA can be characterized as mild, moderate or severe which is best applied to untreated patients

Mild Disease

•

Patients meet the criteria for RA, have <6 inﬂamed joints, w/ absence of extra-articular involvement & evidence of bone erosions or cartilage loss on X-ray

Moderate Disease

••

Patients have 6-10 inﬂamed joints Presence of some of the following: Elevated erythrocyte sedimentation rate (ESR) &/or C-reactive protein (CRP), positive rheumatoid factor (RF) &/or ACPA, appearance of inﬂammation as well as minimal joint space narrowing & small peripheral erosions on X-ray, absence of extra-articular disease

Severe Disease

••

Patients have >20 inﬂamed joints, elevated ESR &/or CRP Presence of ≥1 of the following clinical features: Anemia of chronic disease &/or hypoalbuminemia, positive RF &/or ACPA, appearance of bone erosions & cartilage loss on X-ray, presence of extra-articular disease

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2 DIAGNOSIS

••

Based on clinical signs & symptoms, lab results & imaging features Early diagnosis is essential in disease impact reduction on diﬀerent systems

New Classiﬁcation Criteria for Rheumatoid Arthritis

•

Developed by the American College of Rheumatology (ACR) Board of Directors & European League Against Rheumatism (EULAR) Executive Committee

••••

Can be applied to patients at more than one point in the evolution of their signs & symptoms Limited only to patients w/ clinical synovitis in at least 1 joint & synovitis not secondary to other disease A total score of ≥6/10 is needed to classify a patient as having deﬁnite RA Number & site of involved joints - 5 points for >10 joints, including at least 1 small joint¹- 3 points for 4-10 small joints¹- 2 points for 1-3 small joints¹- 1 point for 2-10 large joints (eg shoulders, elbows, hips, knees, ankles) Serological abnormality (at least 1 test result is needed) - 3 points for high-positive [>3x upper limit of normal (ULN)] RF or ACPA - 2 points for low-positive (≤3x ULN) RF or ACPA Acute-phase reactants abnormality (at least 1 test result is needed) - 1 point for abnormal CRP or ESR

•••

Symptom duration - 1 point for ≥6 weeks

Lab Exams

Rheumatoid Factor (RF)

••

Present in approximately 60-80% of patients w/ RA Not recommended in monitoring patients w/ RA but useful in diagnosis especially if measured w/ ACPA - Presence of both RF & ACPA show a more severe disease RF titers rarely change w/ disease activity

•

Anti-citrullinated Protein Antibody (ACPA)

••

Shows similar diagnostic sensitivity as RF but w/ higher speciﬁcity rate of approximately 95-98% Not recommended in monitoring patients w/ RA

Acute Phase Reactants

••

Inflammatory markers ESR & CRP are not specific for RA but reflect the degree of synovial inflammation Monitoring of these acute phase reactants can be used to assess disease activity

Complete Blood Count (CBC)

•

May show anemia of chronic disease, leukocytosis & thrombocytosis

Imaging Studies

X-ray

••••

Commonly used to assess the presence of joint damage secondary to RA Early changes include soft-tissue swelling & juxta-articular demineralization Later changes involve erosions through the cortex of the bone & around the margins of the joint Decreased sensitivity if taken during the 1st 6 months of the course of the disease

Magnetic Resonance Imaging (MRI)

•••

More sensitive than standard radiography for detecting bone destruction Detects bone erosions & subclinical synovitis earlier in the course of the disease May be used in patients w/ suggestive cervical myelopathy

Ultrasonography

••

Alternative method to estimate the degree of inflammation & volume of inflamed tissue As w/ MRI, shows features of joint inflammation that are not physically evident (eg subclinical synovitis for suspected RA) & detects bone erosions in early disease

••

May also be used to assess joints for intra-articular steroid injections Should not be used for routine disease activity monitoring in adults w/ RA

¹Eg MCP joints, PIP joints, 2nd-5th MTP joints, thumb interphalangeal joint, wrists

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3 ASSESSMENT OF DISEASE ACTIVITY

••

Several indices are developed to assess disease activity which are useful in monitoring the response to therapy & in deﬁning remission Preferred RA disease activity measurements by ACR for regular clinical use include the Disease Activity Score in 28 Joints (DAS28) w/ ESR or CRP Level, Simpliﬁed Disease Activity Index (SDAI), Clinical Disease Activity Index, Patient Activity Scale-II & Routine Assessment of Patient Index Data 3 Scores are categorized to low, moderate & high disease activity

•

Disease Activity Score 28 (DAS28)

•

Assesses the patient’s RA disease by measuring the following: - Number of swollen joints in the hands (interphalangeal thumb joints, MCP &/or PIP joints), wrists, shoulders, knees, elbows & feet (2nd to 5th MTP joints)
- Serum ESR & CRP - Visual Analogue Score to analyze patient’s global assessment of disease activity on the day of examination ꢀe results are combined & assessed based on the total score: - <2.6: Disease remission

•

- 2.6-3.2: Low disease activity - 3.2-5.1: Moderate disease activity - >5.1: High disease activity

Clinical Remission

•

ꢀe goal of treatment is clinical remission (reached after 6 months of therapy) or if unlikely, at least a low disease activity - Modify treatment if improvement is inadequate (<50% of disease activity) after 3 months of therapy

Deﬁnition of Remission in Rheumatoid Arthritis Clinical Trials

••

Two definitions proposed by the ACR/EULAR to define clinical remission in RA include the following, suggested to be used in clinical trials as an outcome measure: - 1 Boolean-based definition - 1 based on a composite index of RA activity Boolean-based definition - may be done at any time point, patient should have all of the following: - Tender joint count ≤1 (include feet & ankles in the evaluation of the joints) - Swollen joint count ≤1 (include feet & ankles in the evaluation of the joints) - CRP ≤1 mg/dL - Patient global assessment ≤1 (on a scale of 0-10): Based on the patient’s current feeling about their disease Index-based definition - at any time point, patient should have a SDAI score of ≤3.3 Sustained remission is ≥6 months according to the ACR/EULAR Boolean- or index-based definition Persistent remission according to ACR/EULAR is associated w/ the lowest flare risk & dose tapering

•••

Poor Prognostic Factors

•••••

High count of swollen joints Evidence of early erosions Presence of RF &/or ACPA, particularly at high levels High levels of acute phase reactants Moderate or high disease activity persisting despite treatment w/ csDMARDs based on composite measures including joint counts

••

Treatment failure w/ ≥2 csDMARDs Other factors such as female gender, older age, smoking history & presence of obesity or anemia

4 ALTERNATIVE DIAGNOSIS

••

Systemic diseases

••••••••••

Spondyloarthropathies Psoriatic arthritis Reactive arthritis
- Rheumatic fever - Infective endocarditis

- Still’s disease

Infectious arthritis

Crystal-induced arthritis Endocrinopathies Fibromyalgia
- Sarcoidosis Other connective tissue syndromes - Scleroderma - Sjogren’s syndrome - Systemic lupus erythematosus - Systemic vasculitides - Mixed connective tissue disease
Osteoarthritis Hemochromatosis Paraneoplastic syndromes

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Rheumatoid Arthritis (6 of 23) PRINCIPLES OF THERAPY

Goals of Early Treatment

•

To achieve sustained clinical & radiological remission of disease - Low disease activity within 6 months is a treatment goal alternative in long-standing disease To reduce functional limitations & permanent joint damage

•

Principles of Treatment

•

Management should be based on patient’s disease activity, safety, patient factors (eg comorbidities) & structural damage progression

•

It is recommended that early treatment w/ DMARDs should be initiated as soon as a RA diagnosis is conﬁrmed to control the signs & symptoms of RA & to limit radiographic damage - Baseline studies should be obtained prior to initiation of treatment - Screen for hepatitis B, HIV & tuberculosis infection before initiating treatment w/ biological, targeted synthetic or biosimilar DMARDs
- ACR & EULAR recommends killed (pneumococcal, inﬂuenza, hepatitis B), recombinant (HPV) & live attenuated [herpes zoster (except for TNF inhibitors & non-TNF biologics)] vaccines before initiation of DMARD therapy - Killed & recombinant vaccines may be given during treatment w/ bDMARDs or tsDMARDs - Live-attenuated herpes zoster vaccine should be administered 4 weeks before treatment initiation & never during treatment w/ bDMARDs or tsDMARDs

•••

A treat-to-target strategy is recommended Disease activity should be monitored frequently, ie every 1-3 months Treatment goal is almost reached within 3 months & may be attained by the end of 6 months - During the 3- to 6-month period, meticulous follow-up should be done & existing treatment should be intensiﬁed or changed for another

••

In DMARD-naive patients, csDMARD monotherapy should be considered Methotrexate should be part of the 1st treatment strategy in patients w/ early & established RA - Leﬂunomide or Sulfasalazine should be used when patient has contraindications to Methotrexate therapy

••

As initial short-term treatment, use of low-dose corticosteroids or NSAIDs as either monotherapy or combination therapy w/ DMARDs has been shown to provide beneﬁts for symptomatic control If the treatment goal has not been achieved w/ the 1st DMARD strategy, in the absence of poor prognostic factors, switching to or adding another sDMARD should be considered - If poor prognostic factors are present, addition of a bDMARD or a Jak-inhibitor should be considered

•••

For patients who are unable to tolerate csDMARD comedication therapy, interleukin-6 receptor antagonists & tsDMARDs may have some advantages over other bDMARDs In the presence of treatment failure w/ a bDMARD or tsDMARD, consider switching to another bDMARD or tsDMARD May consider treatment w/ another TNF-inhibitor or other DMARDs if patient is unresponsive to previous treatment w/ a TNF-inhibitor

A

PHARMACOLOGICAL THERAPY

Conventional Synthetic DMARDs (csDMARDs)

•

Have the potential to reduce or prevent radiographic progression, improve joint function, maintain joint integrity, & improve the signs & symptoms of RA

•••

Choice of initial DMARD should be based on patient’s preferences & existing comorbidities Methotrexate, Leﬂunomide or Sulfasalazine should be started as early as possible at the time of diagnosis May take up to 8 weeks for eﬀects to be seen thus bridging therapy w/ corticosteroids is needed

Methotrexate

••••

Should be considered 1st among the csDMARDs for the initial treatment strategy unless contraindicated Preferred agent for most combinations & DMARD of choice due its more favorable efficacy & toxicity profile Can increase the efficacy of bDMARDs if used in combination therapy Considered as one of the most active compounds in terms of frequency of remissions & time to onset of action

Leﬂunomide, Sulfasalazine

••

Recommended as part of the initial treatment strategy in patients w/ contraindication or intolerance to Methotrexate Sulfasalazine is one of the most active compounds in terms of frequency of remissions & time to onset of action - Provides a good risk-beneﬁt ratio

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A

PHARMACOLOGICAL THERAPY (CONT’D)

Conventional Synthetic DMARDs (csDMARDs) (Cont’d) Other csDMARDs

••

Eg Gold salts (parenteral), Hydroxychloroquine Gold salts may be considered as part of the early treatment strategy in patients w/ contraindication to or intolerance of Methotrexate - Patients show improvements from disappearance of rheumatoid nodules, reduction of joint swelling & a fall of CRP levels

•

Hydroxychloroquine is a treatment option used as part of the early treatment strategy for patients w/ mild RA if Methotrexate is unavailable or w/ intolerance - In cases of mild or palindromic cases, Hydroxychloroquine is an alternative to oral Methotrexate, Leﬂunomide or Sulfasalazine
- Shows eﬃcacy as monotherapy or in combination therapy

Targeted Synthetic DMARDs (tsDMARDs)

••

Eg Baricitinib, Tofacitinib, Upadacitinib Janus kinase (Jak) inhibitors are recommended to be added to csDMARDs for patients w/ treatment failure after csDMARDs monotherapy

•

Other new Jak inhibitors include Peﬁcitinib which has been approved in Japan & Filgotinib which is currently undergoing regulatory evaluation

Baricitinib

•

A Jak-1 & Jak-2 inhibitor that showed better eﬃcacy when compared to placebo & other DMARDs used in several studies - In a trial of patients w/ active RA who were receiving background Methotrexate therapy, treatment w/ Baricitinib demonstrated signiﬁcant clinical improvements when compared w/ placebo & Adalimumab in RA patients w/ inadequate response to Methotrexate
- Further studies are needed to prove its superiority over bDMARDs

Tofacitinib

•

A Jak-1 & Jak-3 activity inhibitor that may also affect all the Jak isoforms, showed therapeutic benefits in several clinical trials - In the ORAL Standard trial, significant reductions of signs & symptoms were seen in patients w/ active RA w/ history of Methotrexate therapy given Tofacitinib compared to those given placebo or Adalimumab
- In the ORAL Solo & Step trials & in the ORAL Scan & Sync trials, significantly higher ACR20 response rates were seen in patients given Tofacitinib plus Methotrexate after 3 & 6 months, respectively, compared to placebo plus Methotrexate
- Results of the ORAL Start trial showed significant & clinically meaningful improvements in multiple patient-related outcomes over 24 months w/ Tofacitinib therapy compared to Methotrexate therapy
- ACR50 was demonstrated in the ORAL Strategy trial where Tofacitinib plus Methotrexate was given for 6 months, compared to Adalimumab plus Methotrexate & Tofacitinib monotherapy

Upadacitinib

•

A Jak-1 inhibitor that underwent phase III trial testing as monotherapy & combination therapy in various RA populations - Results of the Long-Term Extension (LTE) of SELECT-MONOTHERAPY study showed that Upadacitinib monotherapy, when compared to patients who received continued Methotrexate, resulted in continued improvements in the signs & symptoms of RA through 84 weeks
- Results of the LTE of SELECT-COMPARE study showed higher levels of clinical response, including remission, in patients who received Upadacitinib plus Methotrexate than w/ Adalimumab plus Methotrexate through 72 weeks
- Both SELECT-EARLY & SELECT-COMPARE studies demonstrated radiographic inhibition of structural joint damage in patients receiving Upadacitinib monotherapy or in combination w/ Methotrexate at approximately 96 weeks

•

Indicated for moderate to severe active RA in adults w/ inadequate response or intolerance to ≥1 DMARDs (w/ or without Methotrexate or other csDMARDs)

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A

PHARMACOLOGICAL THERAPY (CONT’D)

Biological DMARDs (bDMARDs)

Generally target cytokines or their receptors or are directed against other cell surface molecules

•

TNF Inhibitors

••

Eg Adalimumab, Certolizumab pegol, Etanercept, Golimumab, Inﬂiximab Binds to TNF-α & blocks interaction w/ cell-surface TNF-α receptors to neutralize its biological function (ie changes in adhesion molecule levels that causes leukocyte migration)