6. Pathophysiology of AS
Due to multiple causes threre is increased expression of IL23
IL23 acts on resident T cells to produce IL22, IL 17 and TNF
among other cytokines.
IL 22 has a bone forming properties, where as IL 17 is
osteoclastogenic.
7. NSAID
The efficacy and effectiveness of NSAID therapy have been
well established (level A evidence).
For prolonged periods of up to a year, there may be
improvement in spinal mobility and acute-phase reactants.
8. Selective cyclooxygenase-2 (COX-2) inhibitors have similar
efficacy (level A evidence).
Continuous use for 2 years can retard radiographic
progression
Those with high risk of radiographic progression can
continue with continuous therapy.
9. NSAIDs
DRUGS MAX DAILY HALF LIFE(hrs) SPECIAL
PRECAUTIONS
ACETYL SALICYLIC
ACID
3000mg 4-6 Hepatic failure,
renal insufficiency
DICLOFENAC 225mg 2 SAME
INDOMETHACIN 200mg 2-13 USED IN PDA
ETODOLAC 1200mg 6-7
IBUPROFEN 3200mg 2 HEPATIC DISEASE
PIROXICAM 20mg 3-86 GERIATRIC AND
LIVER DISEASE
CELECOXIB 400mg 11 CI TO
SULFONAMIDE
USE
ETORICOXIB 120mg 22 HEPATIC AND
RENAL DISEASE
10. A nonselective NSAID is appropriate for most patients ,
relatively young and without comorbidity.
A COX-2–selective agent used in the presence of risk factors
for peptic ulceration
Though both categories may exacerbate inflammatory
bowel disease.
Once-daily drug regimens may improve patient compliance.
11. Up to 2 weeks may be required to demonstrate maximal
symptomatic benefit.
If symptomatic relief is inadequate, a switch to another
NSAID may be worthwhile.
Failure of two NSAIDs (TOTAL 4 MONTHS)should prompt
an exploration of other management strategies
14. SULFASALAZINE
Patients with (peripheral) polyarthritis—mostly those
with psoriatic arthritis, but also AS patients with
peripheral joint involvement—had a significant but
modest response.
Indication:
Concomitant peripheral joint involvement and
inadequate response to NSAIDs and physical
modalities.
In case of pure axial symptoms where bDMARDs can
not be given due to toxicity contraindication or
cost.(ASAS-EULAR)
15. sulfasazine
Baseline < 3 month 3-6 m0nths > 6
months
CONTRAINDICATI
ON
CBC, LFT, Cr, ;
vaccinate:
influenza,
Pneum
Every 2-4
wk
Every 8-12
wk
Every 8-12
wk
Sulfa allergy,
Plt <50,000/mL3,
LFT >2 X ULN,
acute HBV/HCV,
some classes
of chronic
HBV/HCV
16. Methotrexate:
The evaluation of methotrexate in AS has been limited to
case reports and open analyses, mostly reported in
abstract form.
There is Level B evidence that methotrexate is not effective
in AS.
According latest ASAS/EULAR criteria : may be considered
in purely axial symptomps where bDMARDs cant be given
due to toxicity contraindications cost.
17. Methotrexate
Baseline < 3 month 3-6 m0nths > 6 months
CBC, LFT, Cr,
HBV,
HCV;
vaccinate:
influenza,
Pneumococc
us,
HBV
Every 2-4 wk Every 8-12
wk
Every 8-12 wk
18. Contraindication of
methotrexate
Active infection,
Symptomatic pulmonary disease,
WBC <3000/mm3,
Platelet <50,000/ml3,
CrCl <30 ml/min,
History of myelodysplasia or recent lymphoproliferative
disorder,
LFT >2 x Upper Limit of Normal,
Acute or chronic HBV or HCV,
Pregnancy, lactation
19. Leflunomide:
No promising result seen in axial or peripheral symptoms.
Not usually recommended.
Latest ACR/EULAR criteria: may be considered in purely axial
symptomps where bDMARDs cant be given due to toxicity
contraindications cost.
ACR-SAA-SPARTAN criteria(2019) not recommending it.
20. Leflunomide:
Baseline < 3 month 3-6
months
> 6
months
CONTRAINDICATION
CBC, LFT, Cr
; vaccinate:
influenza,
Pneumococ
cus,
HBV
Every 2-4
wk
Every 8-12
wk
Every 8-
12 wk
• Active infection
• WBC <3000/mm3,
• Plt <50,000/mL3,
• History of
myelodysplasia or
recent
lymphoproliferative
disorder,
• LFT >2 X ULN,
• Acute or chronic HBV
or HCV,
• Pregnancy, lactation
21. Corticosteroids
Effective for local intra-articular treatment in AS including
the SI joints, if given under fluoroscopic guidance (level B
evidence).
Use of oral steroid did not improved final outcome(50%
BASDAI reduction), but reduced mean BASDAI in 50mg/day
for 2 weeks.
Use of systemic steroid in strongly not recommended.
Local steroid is considered in peripheral arthritis with less
than 2 joints involvement. (ACR-SAA-SPARTAN criteria)
22. Thalidomide
Level B evidence
Not usually indicated due to frequent side effects of
drowsiness, constipation, dizziness.
Major side effect: teratogenicity and peripheral
neuropathy
Not recommended in latest guideline.
23. Bisphosphonates
A controlled dose-response (60 mg vs. 10 mg) evaluation of
a bisphosphonate, pamidronate, given intravenously
a monthly basis for 6 months showed evidence of
symptomatic efficacy, primarily in patients with only axial
disease (level B evidence).
Bisphosphonate Neridronate showed cilinically significant
imporovement on 6 month treatment.
Latest guideline not recommend use of pamidronate.(SAA-
ACR-SPARTAN)
26. With advancement in the knowledge of molecular
pathophysiology, the pharmacological management has
changed drastically.
First TNF inhibitor has approved about 2 decades ago.
First IL 17 inhibitors approved in 2016.
Several trials are going on .
28. TNFi
It has been observed that:
There is TNF expression in SI joint biopsies of AS patients
Overexpression of TNF leads to sacroiliitis in animal models.
29. TRIALS WITH TNF INHIBITORS SUGGESTS IMPROVEMENT IN:
Health-related quality of life.
Patient-reported outcomes.
Anaemia.
C-reactive protein (CRP) levels.
Sleep quality.
Control inflammation in the spine, measured by various
sequences.,
TNF inhibitor therapy does not attenuateradiographic
progression in AS.
TNFi
30. Five anti-TNF agents are of proven benefit in AS according to
pivotal phase III trials (level A evidence):
Infliximab : IgG1 chimeric monoclonal antibody, Fab portion
derived from mouse.
Etanercept : Recombinant TNF receptor IgG1 fusion protein.
Adalimumab :Human monoclonal antibody
Golimumab : Human monoclonal antibody
Cetrolizumab :Pegylated Fab fragment of humanized TNF
inhibitor monoclonal antibody
31. Mechanism of action of TNF
inhibitors:
Decrease Production of Other Inflammatory Mediators
Cytokines (e.g., IL-1, IL-6, GM-CSF)
Chemokines (e.g., IL-8)
Degradative enzymes (e.g., MMPs)
Other mediators (e.g., C-reactive protein)
Alter Vascular Function, Leukocyte Traffic and Activation
Decreased adhesion molecule expression and function
Angiogenesis inhibition
32. Monocytes and Macrophages
Modulate HLA-DR expression
Possibly increase apoptosis (?)
Modulate the Function of Immunocompetent Cells T Cells
Normalize activation threshold for CD3–T cell receptor signaling
Alter Th1/Th2 phenotype, cytokine secretion
Increase regulatory T cell number and function
Induce apoptosis (?)
33.
34. Infliximab :IgG1 chimeric
monoclonal antibody
,Fab portion derived
from the mouse.
Dose : 3 to 5 mg/kg
every 6 to 8 weeks
Loading at 0,2, and 6
weeks.
It is not recommended
in nr-axSpA.
35. Etanercept :
recombinant 75-kD TNF
receptor IgG1 fusion
protein
Dose: subcutaneous
injection either once (50
mg) or twice (25 mg)
weekly.
Usually not preferred in
associated Ant. Uveitis
or IBD
36. Adalimumab and
Golimumab:
human recombinant
monoclonal
antibodies.
Dose: Subcutaneous
injection
40mg on alternate
week OR 50mg
monthly
38. PRECAUTIONS BEFORE
STARTING TNFi
Contraindications/ safety precaution:
Prior history of demyelinating diseases.
Malignancy or premalignant state(exclude BCC and after
10 years)
Moderate to severe congestive heart failure(NYHA III-IV)
Latent TB or hepatic viral infection.
Patients with active infection or with high risk of infection
History of lupus.
Pregnant or breastfeeding women.
Hypersensitivity
39. Side effects:
Infection: increased chance of LRTI and Skin infection
Malignancy: Non melanoma skin cancer
Demyelination .
Hematologic abnormalities: Myelosuppression
Congestive heart failure
Autoantibodies(ANA,Anti ds-DNA)
Hepatotoxicity
Dermatological reactions
Lupus like syndromes
40. Before starting TNFi:
Mantoux Test/IFN gamma based assey.
HIV, Hepetitis B and C serology.
Pneumococcal and influenza vaccination 1 month prior the
starting.
Complete blood count.
Liver Function Test.
41. IL 17 i:
First drug secukinumab approved by FDA on 2016.
Secukinumab is a fully humanized monoclonal
antibody against IL17A
Dose is : 150mg every 4 weesks is the maintainace
dose
Another IL17A inhibitor Ixekizumab approved by FDA
in 2019.
Clinical trials are ongoing for secukinumab and
Ixekizumab.
42. Secukinumab
ASAS20 response rates of 61.1% with secukinumab
150 mg versus 28.4%with placebo treatment seen at
week 16.
INDICATION:
Active axial spondyloarthritis with
inadequate response to NSAIDs and
primary nonresponse or contraindication to
TNFi.
43. Secukinumab
ADVERSE effects:
VERY COMMON(>10%): URTI
COMMON(1-10%): Oral herpes, Runny nose, Diarrhoea
Serious Inflammatory Bowel disease can happen or
exacerbates.
Patients on seculkinumab monitored for IBD symptoms.
44. Biosimilars
These are more affordable biotherateutic agents similar in
terms of quality safety and efficacy to an original licensed
agent .
ACR-SAA-SPARTAN strongly recommends continuing
treatment with originator anti-TNF in a stable AS patient.
There are now biosimilars available for Infliximab, Etanercept
and adalimumab.
CT-P13:(infliximab biosimilar) -Anti-TNF Approved for use in
AS
SB4(etanercept biosimilar)- Anti-TNF Approved for use in AS
45. tsDMARDS:
JAK inhibitors are also known as Target Specicfic
DMARDs
No JAK inhibitors are yet approved for ankylosing
spondylitis
Tofacitinib,JAK 1/3 inhibitor, is highlighted in 2019
ACR-SAA-SPARTAN recommendation .
Study showed 5-10mg twice daily dose for 12 weeks
improves ASAS20 score significantly than placebo.
46. 2016 Update of ASAS- EULAR
treatment guideline in Patients with
Axial Spondyloarthritis (SpA)
50. ASAS-EULAR 2016:
In this criteria all five TNFi have been indicated for AS.
Etanercept,adalimumab,golimumab and certolizumab
are considered in nr-axSpA.
IL17i secukinumab indicated only for AS.
51. ACR-SAA-SPARTAN
GUIDELINE(2019)
Sulfasalazine, Methotrexate and Tofacitinib are
recommended.(low to moderate LoE)
In Active AS on NSAIDs: Sulfasalazine or methotrexate
recommended only in prominent peripheral arthritis or
where TNFi not available.(very low to moderate LoE)
In Active nr-axialSpA: Very low LoE.
LoE: Level of evidence
52. ACR-SAA-SPARTAN
GUIDELINE(2019)
Tofacitinib(JAK 1/3 inhibitor) is consideder as a
treatment option in axial SpA.
In contraindication to TNFi except infection.
IL17i to be considered in active disese with
Congestive heart failure
Demyelinating disease
Primary nonresponder to TNFi
53. Extra-articular menifestations
Attacks of uveitis are usually managed effectively with local
glucocorticoid administration in conjunction with mydriatic agents，
Opthalmologist opinion should be considered.
Monoclonal antibodies TNFi are preffered in recurrent uveitis.
For IBD no NSAIDs are recommended as a preferred choice.
Monoclonal antibody TNFi are preferred in IBD.
54. Osteoporosis
DEXA is recommended after 10 years of disease more likely
with active disease.
Syndesmophytes can increase BMD redings artifactually.
Anti TNF has been shown to increase BMD of spine and hip in
a study.
No specific recommendation on bisphosphonates or
denosumab.
55. Cardiac manifestations
Coexistent cardiac disease may require pacemaker
implantation and/or aortic valve replacement.
But Routine ECG or Echocardiogram is strongly not
recommended.(ACR-SAA-SPARTAN 2019)
56. Recent advancement
secukinumab (anti- IL- 17A) monoclonal antibodies has
been approved by FDA in AS in 2016
Ixekizumab (anti IL17A) has been approved in AS and nr-
axSpA by FDA in 2019.
Anti IL-17 Brodalumab, Netakimab and Bimekizumab shown
efficacy and now under phase 3 trial.
IL-23 inhibitor Tildrakizumab showed efficacy and under
phase 3 trial.
JAK inhibitor Tofacitinib ,Filgotinib and Upadacitinib shown
efficacy and under trial.
Namilumab,human monoclonal antibody (IgG1 kappa)
against GM-CSF: in phase 2a trial
