1. RHEUMATOID ARTHRITIS (2) By Ahmed M. Ali, PhD.

2. The Mediators of Joint Destruction
Immune Destruction
Cytokines
TNFα
Chemokines
IL-1, IL-6
MMP
VEGF
VEGF = Vascular Endothelial
Growth Factor
MMP = Matrix Metalloproteinase

3. The Natural Course of RA
Undifferentiated
Polyarthritis
Early RA – Mild Disease
Severe RA with Deformities

4. Management of RA

5. Goals of Treatment To relieve pain and inflammation.
To prevent joint destruction and deformity.
To preserve or improve functional activities.
To control systemic involvement.
To slow disease progression.
To restore patients’ normal lifestyle.

6. Non-Drug Treatment

7. I. Diet and weight control

8. II. Physiotherapy
Physiotherapy help to reduce pain and swelling, improve joint movement, strengthen joints, prevents disuse atrophy and minimizes deformity.
Physiotherapy includes flexibility/stretching exercise, heat therapy, cold therapy, electrotherapy and hydrotherapy.

9. III. Occupational therapy
This therapy involves joint protection using appliances and splints (supportsجبائر) that reduce inflammation and maintain normal joint alignment (normal position).

10. IV. Surgical intervention
Surgery can be effective in relieving pain, restoring function and repairing damaged joints when drug therapy fails to achieve these goals.
Surgical procedures include major joint replacement (artificial joints) and carpal tunnel decompression.
Surgical interventions are required in 25% of RA cases.

11. Keypoints Erosive changes occur early in disease.
A brief delay of therapy can have a harmful impact on the course of disease years later.
Early DMARD therapy is required to arrest disease progression.
Bridge the gap initially with NSAIDs and glucocorticoids.
Use biologics only for refractory cases (cautions; ↑cost).
Surgical treatment options in selected patients.
The Therapeutic Window of Opportunity
Recent research has confirmed that early, aggressive treatment with disease-modifying antirheumatic drugs (DMARDs) is critical for optimizing long-term results in patients with rheumatoid arthritis.1
Among the findings leading to this conclusion are those showing that approximately 75% RA patients show evidence of joint erosions during the first 2 years of their disease. The rate of progression, expressed as newly eroded joints or increased radiographic damage, is highest during the early years of the disease.2
Others studies have shown that even a brief delay (as little as 8 to 9 months) in starting DMARD therapy can have a significant impact on disease parameters many years later.
Research suggests that:2
Early and aggressive DMARD therapy suppresses the inflammatory response can reset the rate of radiographic progression.
Reliance on the traditional “pyramid approach” to therapy, which involved the initial prescription of aspirin and NSAIDs and then individual DMARDs is no longer recognized as effective. Moreover, combination therapy is not necessarily more toxic than monotherapy.
O’Dell JR. Treating rheumatoid arthritis early: A window of opportunity? Arthritis Rheum. 2002;46:
Van der Heijde DM. Joint erosions and patients with early rheumatoid arthritis. Br J Rheum. 1995;34 (suppl 2):74-78.

12. Drug Treatment of RA

13. Fast-acting agents (simple analgesics, NSAIDs and corticosteroids) are used to relieve symptoms of RA (pain & inflammation) in combination with Slow-acting agents or the disease-modifying antirheumatic drugs (DMARDs) to control disease progression.

14. DMARDs suppress inflammatory markers of disease activity (e. g
DMARDs suppress inflammatory markers of disease activity (e.g., ESR, CRP) and improve joint function but do not necessarily prevent long-term disability.
Early use of DMARDs preserves joint function and reduces bone erosion.
C-reactive protein (CRP) is a good indicator of disease activity and used to monitor response to drug therapy. CP*

15. Medical Management – Drug Classes
NSAIDs: Cox-1 & Cox-2 inhibitors
Glucocorticoids: Prednisolone, Methylprednisolone
IAS: Intra articular steroids
DMARDs: MTX, SSZ, HCQ, Leflunomide
Immunosuppressive Rx: Azathioprine (AZT), CyS
Cytotoxic agents: Cyclophosphamide
Biologics: TNF-α antibodies, IL-1 R antagonist
Old drugs: Gold salts, D-Penicillamine

16. Renal and GI homeostasis
NSAIDS in RA
NSAIDs
COX 1
COX2
Selective COX 2 Inhibitors (COXIBs)
Improved GI tolerability
Reduced effects on RBF
No effect on platelets
May have CV adverse effects
Examples: Celecoxib, Etoricoxib, Meloxicam
Constituent pathway
Renal and GI homeostasis
Inducible pathway
Inflammation

17. NSAIDs Class of Drugs Non-Selective (COX1/COX2) Ibuprofen Ketoprofen
Diclofenac
Aceclofenac
Piroxicam
Lornoxicam
Naproxen
Indomethacin
NSAIDs used as analgesics
Ketorolac
Aspirin
Selective COX-2 inhibitors
Celecoxib, Etoricoxib
Meloxicam
Analgesics
Tramadol
Paracetamol

18. Pros and Cons of NSAID Therapy
Effective control of inflammation and pain
Effective reduction of tissue swelling
Improve mobility, flexibility, range of motion
Improve quality of life
Relatively low-cost
CONS
Does not affect disease progression
GI toxicity common
Renal complications (e.g. Irreversible renal insufficiency, papillary necrosis)
Hepatic dysfunction
CNS toxicity

19. NSAIDs with short half-life
HOURS)) HALF-LIFE TIME
DRUG
NSAIDs with short half-life
0.25
Aspirin
1.1
Diclofenac 3
Etodolac
2.1
Ibuprofen
4.6
Indomethacin
1.8
Ketoprofen
NSAIDs with long half-life 15
Azapropazone 20
Meloxicam 28
Piroxicam 60
Tenoxicam 7
Sulindac 16
Sulindac sulphide (active metabolite) 11
Celecoxib

20. Renal Excretion of some NSAIDs
DRUG
% < 2
Aspirin
< 1 %
Diclofenac %1
Ibuprofen
% < 15
Indomethacin
% 62
Azapropazone
Meloxicam
%10
Piroxicam
% 7
Sulindac

21. Relative risk of GI complications with various NSAIDs
Ibuprofen
Diclofenac
Naproxen
Indomethacin
Piroxicam
Azapropazone

22. NSAIDs Dose Aspirin mg/4 hrs Diclofenac Sodium (Voltaren) mg bid Diclofenac Potassium (Cataflam) mg bid Indomethacin (Indocid) mg/day Ibuprofen (Brufen) mg bid Naproxen (Naprosyn) mg bid Tolmetin (Tolectin) mg bid Sulindac (Hi Dac) mg bid Piroxicam (Feldene) mg qd Celecoxib (Celebrex) mg bid Etoricoxib mg/day

23. Corticosteroids
Corticosteroids can be given orally or injected systemically or locally (intra-articularly) into joints and surrounding tissues.
They are more effective than NSAIDs in reducing inflammation and restoring joint mobility.
Corticosteroids are useful for short-term use during severe flares of disease activity in patients not responding to NSAIDs.
Long-term use of high-dose steroids should be avoided because of serious side effects.

24. Corticosteroids has immunosuppressant effect with increased risk of infection.
Corticosteroids should be discontinued gradually as the patient’s condition improves by tapering the doses. Abrupt discontinuation can lead to flares of the disease.

25. Side effects of Corticosteroids
Weight gain.
Oedema.
Cataract.
Osteoporosis.
Hypertension.
Hyperglycemia.
Muscle wasting
Glaucoma.
Peptic ulceration.
Dermal thinning.
Sodium retention.
Easy bruising.
Depression.
Facial puffiness.
Destruction of large joints
Infection.
Hypokalemia.
Delayed wound healing.
Hyperlipidemia.
Avascular necrosis.
Acne.

26. Pros and Cons of Corticosteroid Therapy
Anti-inflammatory and immunosuppressive effects
Can be used to bridge gap between initiation of DMARD therapy and onset of action
Intra-articular steroid (IAS) injections can be used for individual joint flares
CONS
Does not conclusively affect disease progression
Tapering and discontinuation of use often unsuccessful
Low doses result in skin thinning, ecchymoses, and Cushingoid appearance
Significant cause of steroid-induced osteopenia
An ecchymosis is a subcutaneous spot of bleeding with a diameter >1 Cm 

27. Methotrexate (MTX) MTX is given 10 to 30 mg/week (orally, IM, or SC).
It is DHF reductase inhibitor – Supplemental folic acid is required.
The clinical improvement takes 1-2 months.
Rapid onset (6-10 weeks); tends to produce more sustained results over time than other DMARDs and lowers all-cause mortality.
Can be used when cause of polyarthritis uncertain.
Often combined with other DMARDs like Leflunomide, SSZ, HCQ.
ADRs: Nausea, diarrhea; mouth ulcers; rash, alopecia; Abnormal LFT.
Rare ADRs: low WBC & platelets; pneumonitis; sepsis; liver disease; EBV related lymphoma.
Monitoring: CBC, creatinine, and LFTs monthly for 6 months, then every 1- 2 months. Repeat AST or ALT in 2-4 weeks if initially elevated, and adjust dose as needed.

28. Drug Therapy of RA

29. Biological Agents in RA
TNFα antagonists
Adalimumab (Humira)
Etanercept (Enbrel)
Infliximab (Remicade)
Interleukin-1 antagonist
Anakinra (Kineret)
Suppressors of T-Cell activation
Abatacept (Orencia)
Anti B-Cell monoclonal antibody
Rituximab (Rituxan)

30. Characteristics of Biologicals used in RA
Etanercept
Enbrel®
Infliximab
Remicade®
Adalimumab
Humira®
Anakinra
Kineret®
Abatacept
Orencia®
Rituximab
Rituxan®
Target
TNF
IL-1 Receptor
T-Cell Activation
B-Cell
Half Life
3-5 Days
8-10 Days
10-20 Days
4-6 Hrs
13-16 Days
19 Days
Construct
Human
Chimeric
Dosing
Once Biweekly-weekly
Once every 4-8 weeks
Once every 1-2 weeks
Once Daily
Once Monthly
Twice every 6-12 months
Route SC
I.V.

31. Biologics: Relative Contraindications
Active Hepatitis B Infection
Multiple sclerosis, optic neuritis
Active serious infections
Chronic or recurrent infections
Current neoplasia
History of TB
Congestive heart failure (Class III or IV)

33. Early & Established RA
Early RA: Rheumatoid arthritis with duration of disease/symptoms of < 6 months (duration denotes the length of time the patient has had symptoms/disease, not the length of time since RA diagnosis).
Established RA: RA with duration of disease/symptoms of ≥ 6 months or meeting 1987 ACR RA classification criteria.

35. ACR Guidelines for the Treatment of Rheumatoid Arthritis