1. Approach to Diagnosis and Treatment of Inflammatory Arthritis
Dr. L. Perlin
St. Michale’s Hospital
Division of Rheumatology

2. The Case Ms. M.J. 61 year old woman - early Sept. 2007:
left foot MTP pain (fell in Dec. 2007)
X ray: no fracture - resolved 3 weeks
- Oct. 2007:
left shoulder pain - resolved 1 week
- Nov. 2007:
right wrist pain and swelling - resolved 48 hr
- Dec Feb. 2008
episodic monoarticular flares wrists, MTP’s
knees and shoulders

3. The Case Ms. M.J. continued - Dx: Palindromic Rheumatism
- Tests normal except: RF 28IU
CRP 10
- Treated: NSAIDS
- Feb June 2008:
additive arthritis in 13 joints
4 with effusions

5. The Case What is the diagnosis? What is the treatment?
Ms. M.J. – Summary
61 year old woman with new onset inflammatory, large and small joint, somewhat asymmetric polyarthritis
What is the diagnosis?
What is the treatment?

6. DIAGNOSIS OF INFLAMMATORY POLYARTHRITIS
History and Physical exam - most important diagnostic tools.
Epidemiology, family history, pattern of joint involvement, presence of inflammatory back disease & EAF may be helpful in diagnosis.
Synovial fluid analysis (Cell count, Culture, Crystal analysis)
Basic laboratory tests are non-diagnostic. Always do a urinalysis & creatinine. RF, ANA & x-rays should be done only if the clinical picture warrants.

7. Inflammatory Polyarthritis
Rheumatoid Arthritis is common ~1%
Damage occurs very early
Mortality rates increased in poorly controlled disease
DMARDS improve clinical outcome if used in early RA – delay is detrimental
Identify, refer, treat EARLY

8. Difficulties Encountered in Assessing Early Inflammatory Arthritis
Initial diagnosis may be unclear – RA clinical features are non-specific ie: RA is distinguished by chronicity
In patients eventually diagnosed with RA
at onset:
- 60% normal acute phase reactants
- 70% have normal X rays
- 60% are RF negative
Early NSAID response may suggest cure

9. Who to Treat? Who to Refer?
Patients with features of an early inflammatory arthritis:
- joint swelling
- MCP and MTP involvement
- a good anti-inflammatory response
- symmetric distribution of symptoms
- family history
- significant early morning stiffness

10. Who to Treat?
Consider DMARD therapy for all patients with early inflammatory polyarthritis where persistent disease is likely
Most important determinant of chronicity is disease duration > 12 weeks.

11. Management of Early Inflammatory Arthritis
no yes
Symptomatic treatment Duration > 12 weeks
no yes
Recurrence after shot of CS yes ACR classification criteria +
no no yes
Self-limiting disease undifferentiated confirmed
arthritis RA
LEAP alogarithm

12. Management of Rheumatoid Disease
NSAIDS and analgesics and corticosteroid
DMARDS - methotrexate
- sulfasalazine
- hydroxychloroquine
- leflunomide
Biologics
- TNF inhibition: infliximab,
etanercept, adalimumab
- Inhibitor T cell activation: abatacept
- B cell inhibition: rituximab
- IL 1 inhibition: anakinra

13. Disease Modifying Anti-Rheumatic Drugs
Must change course of RA over 1 year evidenced by sustained improvement in
physical function
decreased inflammation
slowing or prevention of structural joint damage
ACR

14. ACR Improvement Criteria
Disease Activity Score Statistically derived index validated
Tender Joint count
Swollen joint count
ESR
General health index
DAS 28
- modified to be used with 28
joint count
ACR 20 denotes 20% improvement in:
Tender joint count (TJC)
Swollen joint count (SJC)
and
3 of the following 5 areas:
Patient pain assessment
Patient global assessment
Physician global assessment
Patient self-assessed disability
Acute phase reactant (ESR or CRP)
ACR 50 denotes 50% improvement
ACR 70 denotes 70% improvement

15. Definition of active RA disease
> 6 tender and >3 swollen joints
&
ESR> 30mm/hr or
at least 45 min am stiffness
DAS > 5.1 (scale 0 -10)

16. DMARDS Early mild disease Anti-malarials eg hydroxychloroquine
mechanism - decrease protease function
- inhibit Ag processing
- decrease cytokine release
dose < 6.5 mg/ kg/ day
toxicity ocular, neuromyopathy, rash
Sulfasalazine
mechanism - unknown; scavenge O2 radicals
dose gm/day
toxicity hypersensitivity, granulocytopenia,
headache, G-I

17. DMARDS Moderate - Severe disease Methotrexate / Leflunomide
Mechanism - inhibit purine/pyrimidine
biosynthesis
Dose MTX mg/wk
oral/sc/IM
- Leflunomide mg/d
Toxicity hepatic, pulmonary, heme,
infection, GI, skin, mm ulcer
Caution teratogenetic

18. Combination DMARD therapy
MTX + SSZ + OH-Chloroquine
O’Dell 1995
MTX + CSA
Tugwell 1995
MTX + Etanercept
MTX + Remicade
MTX + Adalimumab
MTX + Leflunomide
excellent safety & improved efficacy over MTX alone

19. RESEARCH HAS BRIDGED THE GAP BETWEEN BASIC AND CLINICAL RESEARCH
Biologic Drugs
RESEARCH HAS BRIDGED THE GAP BETWEEN BASIC AND CLINICAL RESEARCH
Over one and a half million patients treated worldwide with biologic agents

20. ODB Indications for Biologic Drugs
RA: Failure of DMARD therapy
Failure or Intolerance to
MTX 20mg/week sc or po x 3 months
Arava 20 mg po x 3 months
Any combination DMARD
JIA
Same
PSA
Same plus failed SSZ therapy

21. Biologic Drugs Tumor Necrosis Factor α (TNFα) Inhibitors
Infliximab (Remicade)
Etanercept (Enbrel)
Adalimumab (Humira)
Interleukin-1 Receptor antagonist (IL-1Ra)
Anakinra (Kineret)
Fusion protein blocks T cell activation
Abatacept (Orencia)
CD 20 (B cell) Chimeric Antibody
Rituximab

22. Biologic Drugs Approved in Canada
Robert C Offer, Rheumatoid Arthritis,
National Grand Rounds Vol 1 Issue

23. Rationale for TNFα Blockade
Cytokines are small molecules whose function is to communicate between cells
Tumor necrosis factor α = gatekeeper of inflammatory cascade
Cytokines can be either pro-inflammatory or anti-inflammatory

24. Proinflammatory and anti-inflammatory cytokines in RA
Rheumatoid Arthritis by Boulos Haraoui & Edward Keystone
5-5
Mechanisms in Rheumatology ©2001

25. Matrix metalloproteinases in RA
Rheumatoid Arthritis by Boulos Haraoui & Edward Keystone
5-6
Mechanisms in Rheumatology ©2001

26. Etanercept 1st biologic agent approved for RA
Agent approved as monotherapy for RA, JIA PSA and AS.
Soluble TNFα Receptor administered sc
25 mg 2x/wk or 50 mg qwk pre-filled syringe
>300,000 patients treated to date

27. TNFα and it’s Receptor

28. Recombinant TNFα Soluble Receptor

29. Infliximab
Monoclonal chimeric human / mouse antibody administered intravenously at 3- 5 mg/kg at 0, 2, 6 and q8 weekly
Increased dose 35 mg/kg and /or at more frequent intervals if fail to respond or maintain response
Patients: 9 year experience
Approved concomitant with MTX for RA

30. Chimeric monoclonal antibody against TNFα

31. Monoclonal antibody against TNFα

32. Adalimumab 1st fully humanized monoclonal IgG antibody
High binding affinity and specificity for TNFα
Half life = 14 days
Subcutaneous dosing 40 mg q2 weekly
Clinical trials show improved efficacy with concomitant MTX

33. Effectiveness of Biologic Drugs
Decrease symptoms/signs of inflammation
ACR criteria, Eular criteria, DAS
Inhibit radiologic progression
Modified Sharp score
Improve Functional outcome
Health Assessment Questionnaire, SF36S

34. Efficacy of Biological agents in RA
All effective; randomized, DB, placebo controlled studies
No head to head clinical trials of 3 TNFα drugs
Choice
Patient preference/access
Remuneration by physician
Switch for lack of efficacy / adverse events
Benefit seen in 1/3

35. Adverse Effects of TNF Inhibitors
Serious Infections TB
Intracellular organisms
Skin and soft tissue
Malignancy
? Lymphoma
? Solid Tumors

36. Adverse Effects of TNF Inhibitors
Autoantibodies
Optic neuritis, demyelination
Cytopenias
Increase LFT
ILD
Vasculitis; 39 cases reported
Pregnancy: ? no increased risk
No live vaccines

37. Autoantibodies Infliximab + DSDNA 17% vs. 4% placebo
Etanercept
+ ANA 11% vs. 5% placebo
+ DSDNA 17% vs. 4% placebo
16 Lupus- like syndrome cases
Infliximab
+ANA 26-49%;
+DSDNA 13% vs. 0% placebo;
4 new cases SLE
Antichimeric antibodies 17%
may decrease drug effectiveness of infliximab

38. TNF inhibitors and TB
Mycobacterium tuberculosis currently infects approximately one third of the world's population (close to 2 billion people).
Approximately 2 million people die of TB each year and there are 8 million new cases reported annually.
TNF is essential for formation and sustainment of granuloma, which sequester mycobacteria and prevent their dissemination.
The calculated risk ratio of TB in infliximab-treated patients with RA versus patients with RA not exposed to this agent was 19.9 (95% confidence interval [CI], 16.2–24.8) in the year 2000 and 11.7 (95% CI, 9.5–14.6) in the year 2001.
Screening has almost eliminated this increased risk in Spain and Germany

39. Safety data for 5 years Injection Site Reactions: frequent, mild
Infusion reactions
Congestive Heart Failure: increased risk
Malignancy & Lymphoma: Conflicting data

40. Robert C Offer, Rheumatoid Arthritis, National Grand Rounds, Vol 1 Issue 4 2006

41. Management of TNF Drugs Pre Surgery
No randomized clinical trials
Half life variable
Hold Rx 4x half life pre surgery
Infliximab 4-5 weeks
Etanercept 2 weeks
Adalimumab 8 weeks
Resume post surgery

42. TNF Drugs Rheumatoid Arthritis
70% response; 30% non response
Best clinical & radiological outcome in RA patients failed Methotrexate - early in course of disease
Improved symptom control does not equate to reduction in disease progression or disability
Different mechanism responsible for symptoms and structural damage in TNFα IL-1ra drugs

43. Recombinant Human Interleukin-1 Receptor Antagonist (IL-1Ra)
Competitive inhibitor of Il-1. Therefore must have adequate amounts of IL-1Ra produced to counteract effect of IL-1
41% vs. placebo reduction radiological joint damage
suppresses MMP production
Modest effects on clinical improvement measures
MTX + IL-1Ra >> MTX alone¹
Safety Profile:
Injection site reactions
Infection rarely observed
¹Cohen, A&R, Vol 46, No 3 Mar 2002

44. Abatacept = Orencia
Recombinant fusion protein that blocks co-stimulatory CD 28 molecule and inhibits T cell activation
Approved for RA refractory to TNF-Canada
Admin IV at 10 mg/kg at 0,2,4 and q 4 weekly
Efficacy (with MTX) and decreased structural damage demonstrated
No increased risk of malignancy but post marketing surveillance pending

45. Rituximab = Rituxan
Theraputic B-lymphocyte depletion; “remission induction”
Approved for RA patients who failed TNF and are receiving MTX
43% acheived ACR 50 at 24 weeks c/w 13% on MTX alone
Admin 1000 mg IV day 1 and 15 q 6-16 months (?# of treatments for RA)
Higher incidence of infection; TB screening not required but Hepatitis B is
1st infusion reaction common (treat with steroid)
No live vaccines
Post-marketing data pending

46. Drugs & Pregnancy NSAIDS: safe until week 34 (patent ductus)
OH-chloroquine: safe, ?cleft palate
Sulfasalzine: continue if on it; safe
Imuran: continue if on it; safe
Methotexate: teratogen ??? ok in small doses; stop 3 months before conception
Arava: teratogen may be present for 2 yrs
Cyclophosphamide:? teratogen ? Safe > 2nd trimester
Biologic agents: unknown; stop 3 months before conception
Steroids: non-fluorinated do NOT cross placenta

47. Summary Biologic Agents are: Effective in decreasing inflammation
Effective in decreasing structural change in RA
TNFα inhibitors are effective in RA plus PS, PSA, AS
Effective in improving health outcomes
No head to head trials; limited comparison to combination Rx
? change paradigm; treat in very early disease; step down
Clarify malignancy/infection risk with post market surveillance
30% of patients have no clinical response;
Need to identify those patients with rapidly progressive disease
that will respond to biologic therapy

48. Quality of Life in Rheumatoid Arthritis