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  1. Abstract and Introduction Abstract Purpose of review: Although originally described in the context of systemic lupus erythematosus, antiphospholipid syndrome was then recognized as a primary antiphospholipid syndrome without any underlying autoimmune disease in almost half of the cases. However, cases of primary antiphospholipid syndrome were reported to evolve into systemic lupus erythematosus over time suggesting that these apparently different diseases areomehow related. Recent findings: Peculiar biological systemic lupus erythematosus markers such as an autoantibody response against chromatin antigens and complement activation have been also described in patients with primary antiphospholipid syndrome. Distinct polymorphisms of common genetic factors have been associated with systemic lupus erythematosus and primary antiphospholipid syndrome supporting the notion that these entities are indeed variants within a continuum of the same disease. Summary: A multiorgan involvement that cannot be explained by the thrombophilic state per se and similar to the well known clinical manifestations in lupus is reported in patients with primary antiphospholipid syndrome. Further studies, mainly genetic, will better underline the proximity between primary antiphospholipid syndrome and systemic lupus erythematosus. Introduction Antiphospholipid syndrome (APS) was first described in a group of patients with systemic lupus erythematosus (SLE) who had increased levels of anticardiolipin antibodies (aCL) and clinical features of recurrent thrombosis, thus defined as secondary APS.[1] By 1985 it had become apparent that some of these patients exhibited no features of underlying connective tissue disease, and the concept emerged that APS could exist as a primary syndrome. At this stage, the term primary APS (PAPS) was established, relating to a group of patients in whom recurrent thrombosis, and or fetal losses, were associated with antiphospholipid antibodies (aPL) [aCL, lupus anticoagulant, and anti-β2 glycoprotein I antibodies (anti-β2 GPI)] and lacking any evidence of underlying connective tissue diseases.[2–4] After 25 years 'in the air' and the reported cases of PAPS evolving into full-blown SLE, the hypothesis that the syndrome represents wide spectrum of diseases rather than discrete disease entities has been raised. In this respect, multiorgan involvements and serological markers that could not be explained by APS per se suggested that differences between SLE and APS, once very well defined, are at least discussed now.[5] In this study we review in a systematic manner the findings that support the proximity between PAPS and SLE.
  2. The Proximity between Primary Antiphospholipid Syndrome and Systemic Lupus Erythematosus: Common Clinical Manifestations The Following Clinical Manifestations are Commonly Present in Both SLE and PAPS Skin Manifestations Livedo reticularis is a skin vasculopathy that has been frequently described in patients with both PASP and SLE. However, livedo reticularis is more frequently detected in APS associated to SLE than in the primary form.[6,7] We also reported that livedo reticularis was associated with thrombocytopenia, cardiac valves dysfunction, epilepsy, and arthritis.[8] It is useful to speculate that skin involvement may identify patients with a more systemic disorder and potentially closer to SLE-like disease ( Table 1 ). Hematological Manifestations In one of the reported cases in which PAPS evolved into SLE 12 years after the first thrombotic episode, antinuclear antibodies (ANAs), thrombocytopenia, antidouble stranded (ds)DNA antibodies and positive Coombs' test were all present.[9] The association of autoimmune hemolytic anemia (AIHA) and cardiac valvular vegetations/thickening (P < 0.0001), arterial thrombosis (P < 0.02), livedo reticularis (P < 0.0001) and central nervous system (CNS) signs of epilepsy or chorea (P < 0.02 and P < 0.03, respectively) was reported in another study enrolling 308 PAPS patients.[10] Altogether these findings would suggest that hematological manifestations may define a subgroup of patients with a significant risk for subsequent development of SLE. However, definite conclusions cannot be drawn at the moment on the basis of the literature data and specific prospective studies are needed. Renal Manifestations Kidney involvement by aPL was originally associated with thrombotic events in medium-large venous/arterial vessels or less frequently with thrombotic microangiopathy.[4] More recently, nonthrombotic lesions could be found in kidneys of patients with PAPS, establishing the term aPL-associated nephropathy to indicate such kidney damage.[11] Moreover, association between the persistent presence of aPL and the risk to develop an end-stage renal insufficiency was reported in lupus patients with renal involvement. A chronic renal vasculopathy specifically mediated by aPL was thought to be responsible.[12,13] Apart from these findings, conditions like glomerulonephritis have been reported in patients with 'classical' PAPS, suggesting that inflammatory processes could possibly develop in some patients, so suggesting that a continuum between these two diseases may exist also for kidney involvement.[14] Central Nervous System Manifestations
  3. Central nervous system involvement in SLE is common and results in different clinical manifestations. Whereas ischemia secondary to vasculitis was reported to represent the most important cause of the CNS manifestations in SLE, a noninflammatory vasculopathy was associated with aPL.[15] In this regard, brain endothelial cells display a higher and firmer expression of β2GPI on cell membranes that may offer a suitable target for β2GPI-dependent aPL.[16] The antibody binding has been reported as a potential cause of perturbation/damage of the cerebral microcirculation and eventually of the clinical manifestations such as seizures, cognitive dysfunction or psychosis.[17] Alternatively anti- β2GPI antibodies themselves may react with β2GPI expressed on the neuronal cell membranes as recently suggested by some groups. The same antibodies may also affect the endothelium of the blood–brain barrier making it much more permeable to proinflammatory mediators or serum autoantibodies potentially active on neuronal tissues. Hence, similar CNS manifestations may be supported by different mechanisms all of which are present in both SLE and PAPS patients. In this regard it is very difficult to state whether CNS involvement does represent a bridge between the two diseases or simply a coincidence The Slow March from Primary Antiphospholipid Syndrome to Systemic Lupus Erythematosus Follow-up studies reported cases in which PAPS developed into a complete picture of SLE with an incidence ranging from 4 to 10%. The expression 'intermediate' APS or lupus-like APS disease was coined to identify those patients displaying minor features resembling SLE but in the absence of the full set of the ACR classification criteria.[18,19] A family history of lupus, the presence of Raynaud phenomenon, migraine, multiple sclerosis-like features, hemolytic anemia, low C3 and C4, and Coombs' positivity, were found in one study to confer a statistically significant risk for subsequent development of SLE (P < 0.05).[20] Comparable finding was reported in another study showing that PAPS may be a forerunner of a full-blown lupus.[21] In order to test the inflammation and immune activation hypothesis in primary thrombotic APS (PAPS) and to identify clinical and laboratory factors related to inflammation and immune activation. PAPS (n = 41) patients were compared with patients with inherited thrombophilia (n = 44) and controls (CTR, n = 39). IgGaCL, IgG anti-β2-glycoprotein I (β2GPI), high-sensitivity CRP (hs-CRP), serum amyloid A (SAA), CRP bound to oxidized low-density lipoprotein-β2GPI complex (CRP-oxLDL- β2GPI) (as inflammatory markers) neopterin (NPT), soluble CD14 (sCD14) (as immune activation markers) were assessed. PAPS showed higher plasma levels of hs-CRP (P = 0.0004), SAA (P < 0.01), CRP-oxLDL-β2GPI (P = 0.0004), NPT (P < 0.0001), and sCD14 (P = 0.007) than inherited thrombophilia and CTR. Two regression models were applied to the PAPS group: in the first, IgG aCL and IgG β2GPI were included amongst the independent variables and in the second they were excluded. In the first model, SAA (as the dependent variable) independently related to the thrombosis number (P = 0.003); NPT (as the dependent variable) independently related to thrombosis type (arterial, P = 0.03) and number (P = 0.04)
  4. (as the dependent variable) independently related to IgG β2GPI (P = 0.0001), age (0.001) and arterial thrombosis (P = 0.01); CRP-oxLDL-β2GPI (as the dependent variable) independently related to IgG β2GPI (P = 0.0001). In the second model, sCD14 and NPT independently related to each other (P = 0.002) (this was noted also in the inherited thrombophilia group) (P < 0.0001) and CRP-oxLDL-β2GPI independently predicted SAA (P = 0.002). Thus, low-grade inflammation and immune activation occur in thrombotic PAPS and relate to clinical features and aPL levels.[22••] Altogether, the above studies point to the fact that the progression from PAPS to SLE disease is possible. In many of these cases it takes place only after a long period of time during the follow-up. Lupus Serological Markers in Primary Antiphospholipid Syndrome Many Serological Markers that are Considered Specific in Lupus are Found also in PAPS. Anti-nuclear Antibodies The presence of antinuclear antibodies at titer higher than 1: 320 as well as anti- dsDNA or antiextractable nuclear antigens (ENAs) have been initially regarded as exclusion criteria for primary APS. Certainly, the frequency of these autoantibodies is higher in patients with APS within SLE or lupus-like disease suggesting that these antibodies are more linked to lupus itself than to APS. Nevertheless and contrary to old beliefs, many studies reported on the occurrence of antinuclear antibodies in APS without a full-blown systemic disease supporting the idea that an antinuclear autoimmune signature may be present in the syndrome.[5,23] Antinucleosome antibodies (anti-NCS) are reported to be highly sensitive and specific for SLE and to correlate with the disease activity. They may appear in the early stages of the disease, in many cases even before anti-dsDNA antibodies themselves, being a marker to identify potential patients who may develop SLE. Studies with small series of patients reported a high prevalence of anti-NCS antibodies in PAPS. A recent multicenter study[24••] confirmed these findings showing that up to 50% of PAPS displayed medium/high titer of anti-NCS autoantibodies. In spite of a follow-up of at least 2 years in the last study, the number of patients evolving into SLE was very small and comparable to that previously reported. Hence we do not have a sound demonstration that anti-NCS autoantibodies may predict the evolution of the syndrome. Complement Activation in Primary Antiphospholipid Syndrome Complement consumption by immune complexes is widely accepted as a key pathogenic mechanism in SLE tissue damage. There is sound evidence that complement activation is required both in experimental models of aPL-mediated fetal loss and thrombosis.[25,26••] The presence of aPL ('first hit') increases the risk for thrombophilia. Then, innate immunity (i.e. toll-like receptors and the activation of
  5. complement) by sensing microbial agents might synergize ('second hit') and contribute to the development of clotting events.[27] At the present time there are few clues regarding the involvement of complement in the pathogenesis of APS. The prevalence of hypocomplementemia was assessed in a large number of patients diagnosed either with SLE or with PAPS in association with the main clinical, hematological and immunological features of these diseases.[28] Patients with PAPS displayed low complement values in 33/57 (47%), and those were associated with higher prevalence of livedo reticularis (P = 0.02), thrombocytopenia (P = 0.004), and positive anti-dsDNA antibodies (P = 0.04), pointing to the fact that these patients are viewed as a subset of patients with SLE-related markers. On the contrary, a more recent study confirmed significantly lower complement levels in primary APS patients compared with patients with non-SLE connective tissue diseases (C3, 81.07 ± 17.86 vs. 109.8 ± 22.76 mg/dl, P = 0.000005; C4, 13.04 ± 8.49 vs. 21.70 ± 6.96 mg/dl, P = 0.0001; CH50, 31.32 ± 8.76 vs. 41.40 ± 7.70 mg/dl, P = 0.000004) or healthy volunteers. Most primary APS patients showed elevated serum C3a and C4a, and PAPS patients with low serum C3 or C4 had significantly higher levels of C3a or C4a compared with healthy controls. No patients had low serum complement regulatory factors suggesting complement activation rather than a deficiency. Although no relationship was found with the clinical manifestations of the syndrome, hypocomplementemia was significantly more frequent in patients with lupus anticoagulant.[29•] In any case, complement involvement appears to be a pathogenic mechanism common to both APS and SLE. Again, it is very difficult to state whether such a fact represents a bridge between the two diseases or simply a coincidence. Does a Genetic Background Explain the Proximity or the Difference between Primary Antiphospholipid Syndrome and Systemic Lupus Erythematosus? The evidence for a genetic background in SLE has been known for at least 20 years based on the studies on twins, on familiar clustering, on ethnic associations as well as on murine in-vivo models. Linkage analysis and association studies have identified several candidate genes for lupus susceptibility.[30] It is widely accepted that SLE susceptibility requires multiples genes, each of them displaying only a small or moderate effect individually. A 'threshold liability' hypothesis has been suggested: the individual probability to develop the disease would depend on the presence of a certain number of susceptibility alleles, but the disease would be the result of the eventual interaction between the genome and the environment. In a similar way, proofs of the genetic background of APS lie on familiar clustering of cases, on murine models and on the association with human leukocyte antigens (HLAs) (Table 2).[31–34,35•,36••] The ability to mount a response against phospholipid- binding proteins has been associated with some HLA alleles (HLA-DR4, HLA-DR7, HLA-DRw53 and HLA-DQB1*0302). Such an association was found both in PAPS and in APS secondary to SLE, whereas a completely different pattern of HLA allele association was reported in lupus patients in comparison with PAPS. This finding
  6. would suggest that a common genetic background between SLE and PAPS may be related just to the ability to produce or not aPL.[31] Regarding the other candidate genes for lupus susceptibility, there are studies only on the association between aPL and FcγR and PDCD1 polymorphisms. In a large international meta-analysis study,[32] FcγRIIA-R/H131 polymorphism displays different effects on APS and SLE. In fact, although the RR genotype was enriched in the entire group of APS cases, this was driven mostly by patients with secondary APS. In another study[33] on the role of an intronic polymorphism in the PDCD1 gene with the risk of sporadic SLE, PDCD1 polymorphism is significantly associated with protection against the occurrence of aPL both in SLE cases and in the general population. In another study,[34] the association of the mannose-binding lectin (MBL) pathway of complement activation with SLE disease activity and/or the production of SLE- related autoantibodies was investigated. MBL pathway activity was found to be reduced in patients carrying MBL variant alleles. In respect to this, anticardiolipin and anti-C1q autoantibodies were observed more frequently in patients with MBL variant alleles. Thus, in patients with SLE, a reduced functional activity of the MBL pathway of complement, in relation to expression of MBL variant alleles, is associated with increased levels of aCL. In a most recent study,[35•] it was shown that activity of the mammalian target of rapamycin (mTOR), which is a sensor of the mitochondrial transmembrane potential, is increased in lupus T cells, and that activation of mTOR causes the loss of TCR in lupus T ells through HRES-1/Rab4-dependent lysosomal degradation. The HRES-1 human endogenous retroviral sequence is centrally located at the 1q42 chromosomal region relative to microsatellites previously associated with SLE. Interestingly, linkage disequilibrium between HRES-1 single-nucleotide polymorphisms (SNPs) at bases 653 and 1259 was reduced in patients with SLE (P = 0.04). The HRES-1 653C/1259C-harboring alleles were associated with the presence of renal disease (P = 0.002), whereas the 956A allele was associated with the APS in APS patients with SLE (P = 0.003).[36••] As a whole these findings do suggest that the ability to produce aPL may be genetically determined. However, full-blown SLE seems to be the result of the coordinated action of several genes that are not always detectable in APS. Further studies may eventually demonstrate whether the difference between SLE and APS is the result of the lack of specific genes able to drive the autoimmune response towards a more systemic disease. Conclusion Although the reviewed literature is not homogeneous regarding the inclusion criteria used, the final message is that PAPS may be systemic in some cases, involving CNS, kidneys, and the skin. In addition, the presence of other autoantibodies apart
  7. from aPL is not very rare and both these aspects should be therefore periodically analyzed. Patients with PAPS, in whom systemic manifestations and anti- dsDNA/nucleosomes antibodies co-exist, should be considered a subset that is located between PAPS and SLE (Fig. 1). It is useful to speculate on the fact that a gradual accumulation of autoantibodies has been reported in clinical lupus. Hence, the appearance of autoantibodies other than aPL may be the expression of a similar phenomenon. Still open is the question why a complete evolution towards lupus is relatively so rare and developing in a long period of time. As mentioned before, it is possible that the lack of the appropriate susceptibility gene panel is responsible for such a block. Figure 1. Systemic clinical manifestations such as CNS, kidney and skin involvement, together with laboratory markers such as antinuclear antibodies and persistent (Enlarge Image) thrombocytopenia may define a subgroup of PAPS closer to full-blown SLE Clinical markers such as glomerulonephritis, livedo reticularis and CNS involvement, together with laboratory markers such as anti-dsDNA antibodies and persistent attenuation of platelets (thrombocytopenia), may define a subgroup of PAPS patients that are of higher potential to develop full-blown SLE. CNS, central nervous system; PAPS, primary antiphospholipid syndrome; SLE, systemic lupus erythematosus. The beneficial effect of hydroxychloroquine, and other immunomodulatory therapies in reducing aCL titers and preventing thrombosis in PAPS patients, has been recently suggested as additional therapeutic options.[37] Theoretically the administration of compounds able to affect the immune response may be beneficial not only in preventing thrombosis but also in inhibiting the development of full-blown SLE in some patients.

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