concurrent symposium- spondyloarthritis - axial spa - hla b27 & beyond - dr. s chandrashekara

Axial Spondyloarthropathy HLA B 27and beyond

Dr Chandrashekara SChanRe Rheumatology and Immunology Centre

Banaglore

Saga Of HLA B 27

Described in association with Navjo’s Arthritis (1971-73) Evolved over last 4 decades.

Disease HLA B27 frequency % (approximate)

Disease % of HLA B 27 positivity

Ankylosing spondylitis 96%

Undifferentiated spondyloarthropathy 70%

Reactive arthritis 30-70%

Colitis-associated spondyloarthritis 33-75%

Psoriatic spondyloarthritis 40-50%

Juvenile enthesitis-related arthritis 70%

Saga Of HLA B 27

Described in association with Navjo’s Arthritis (1971-73) Evolved over last 4 decades.

Few features which make them different from other arthritis• Axial disease• Enthesis involvement• Ostoesclerotic than porosis• Extra-articular features like uveitis, colitis.• No described autoantibody

The facts on HLA B 27• 10% of HLA B27 develop AS and 5% of AS are HLA B 27 negative

(Brown et al 1996 )• 150 variants are described- some protective and some have higher

susceptibility. • HLA-B27 contributes about 1/3 of effect. The recurrence risks in

different degrees of relatives were: (Brown 2000)Monozygotic twins 63%First degree relatives 8.2%Second degree relative 1.0%

The other observations are• The associated features like Anterior uveitis, bowel inflammation and

few inflammatory condition are seen associated with HLA B 27 and can occur in isolation.• The disease has flares and in majority has saw tooth coarse.• Infective organism like Kliebsella and salmonella antigen have been

associated in causation• Respond to Anti-TNF, Anti-IL 17 strategies and respond inadequately

to anti-IL 6 and Anti –B cell strategies.• Male dominant disease.

Is there a second or multiple hit required Are there environmental factors which influence the changeAre these changes- inducible, reversible or permanent changesWhat are the process which are rate limiting and critical from therapeutic and pathogenesis process.

What may add to push• Genome-wide association study of ankylosing spondylitis identifies nonMHC

susceptibility loci. • ERAP in B27+ IL23R, • IL-12B (p40) and other genes involved in Th17 responses (eg STAT3) (The Australo-Anglo-American

Spondyloarthritis Consortium (TASC); the Wellcome Trust Case Control Consortium 2 (WTCCC2), Nat Genet. 2011 Jul 10;43(8):761-767).

Clinical and Experimental Immunology, 183: 30–36

What are the mechanisms one can explain• Arthritogenic peptide • Intracellular stress following

B27 misfolding (Colbert, Powis, Antoniou, Goodall, Gaston) • Innate immune recognition

of aberrant B27

Nat Rev Rheumatol 2010 6:399

ERAP 1 and its influence on functioning of HLA

www.pnas.org/cgi/doi/10.1073/pnas.1408882111

KIR- Killer-cell immunoglobulin-like receptors (KIRs

Different receptors it can react….

Both in vitro study suggest HLA B27 or related class I molecule are essential for the development of diseases.

Therapeutic implicationsIS Sulfasalazine an useful drugAnti AS drugs

Int. J. Mol. Sci. 2016, 17, 46 4 of 9Int. J. Mol. Sci. 2016, 17,

HD 6 antibody acting on heterodimer reduce inflammation..

Thank You

The three theory which are proposed to explain the role of HLA B 271. Arthritogenic peptide2. Mis-folding of HLA B 273. Direct trigger of HLA B 27 the pro-inflammatory receptors4. All of the above

• Ans- D

Blocking HLA B (27)2 and its dimer can be a critical therapeutic interventionA. Dimer of B 27 alpha B. A variant of B 27C. Represent the loci of HLA B27D. All of the above

Ans• Ans A

Disclosures• Have received the speaker grants from different phrmaceuticlas like-

Pfizer, IPCA, • Advisory board member • The current presentation has no conflict of interest.• Few of the figures are used from the literature are duly

acknowledged.