Systemic lupus erythematosus and rheumatoid arthritis

Figure 6.
Rheumatoid factor 
Anti-perinuclear factor (APF) antibodies and anti-keratin antibodies (AKA) 
were the first anti-citrullinated antibodies to be associated with RA. The antigen 
was identified as filaggrin and APF and AKA were renamed anti-filaggrin 
antibodies (AFA).
69; 70
The AFA test had poor sensitivity and was difficult to 
perform. It was hypothesised that the fillagrin could contain citrullinated 
residues and different enzyme linked immunosorbent assays (ELISAs) were 
constructed with different citrulline-containing peptide variants. Sera from RA 
patients recognized these citrullinated peptides with high sensitivity and 
specificity.
71
Citrullination is a post-translational modification of proteins in 
which the amino acid arginine is converted to citrulline by the enzyme 
peptidylarginine deiminase (PAD) in presence of calcium ions (Ca
2+
) (Figure 7) 
- 24 -

---

Figure 7.
Citrullination. An arginine residue is converted to citrulline under the influence of PAD 
and Ca
2+ 
Several proteins, such as filaggrin
72
, keratin
73
, myelin basic protein
74
, 
vimentin
75
, 
α
-enolase
76
, fibrinogen/fibrins
77
, type I collagen
78
, and type II 
collagen undergo citrullination.
79
Citrullinated filaggrin, vimentin, and fibrin 
have been detected in synovial joint fluid from patients with RA.
77; 80
However, 
the pathologic role of citrullinated peptides/proteins is not fully elucidated. 
PADs cannot catalyze the deimination under physiological conditions and the 
key event is a high Ca
2+
influx in order to activate the enzymes. Apoptosis is a 
process in which calcium levels are elevated 
81
and may, therefore, be one of the 
mechanisms inducing production of citrullinated peptides/proteins.
Knowledge regarding citrullinated peptides lead to the development of synthetic 
antigens, called cyclic citrullinated peptides, used in ELISAs to detect ACPAs.
82
The presence of ACPAs has a higher specificity for RA compared with RFs, 
although with a similar sensitivity.
68
ACPAs and RFs of all isotypes have been 
detected in samples from patients with RA donated years prior to any symptoms 
of disease.
83
Consequently both these auto-antibodies have prognostic value. 
Higher levels of RFs have been found in more severe forms of RA
84; 85
whilst 
the presence of ACPAs predicts a more aggressive disease course with an 
increased disease activity and a more severe radiological damage.
86-90
Smoking 
is one of the main environmental risk factors for RA 
91
, especially seropositive 
RA,
92; 93
and has been shown to enhance the expression of PAD2 in the lungs, 
resulting in citrullinated proteins.
94
Smoking has also been shown to increase 
the risk of developing ACPAs in individuals carrying the 
HLA-SE
alleles.
95; 96
There are other auto-antibodies associated with RA, although with lower 
sensitivity and specificity compared with either RFs and ACPAs: anti-BiP/p68, 
anti-calpastatin, anti-collagen type II, anti-RA33, and anti-Sa antibodies.
68