|Year : 2020 | Volume
| Issue : 5 | Page : 6-12
Current concepts in the pathogenesis of spondyloarthritis
Nibha Jain, Arumugam Moorthy
University Hospitals of Leicester NHS Trust, Leicester, UK
|Date of Web Publication||23-May-2020|
Dr. Arumugam Moorthy
Consultant Rheumatologist, University Hospitals of Leicester NHS Trust, Leicester
Source of Support: None, Conflict of Interest: None
Pathogenesis of spondyloarthritis (SpA) is multifactorial and still not understood entirely. The role of genetics including human leukocyte antigen B27 has been investigated extensively, which along with genome-wide association studies has helped us understand and postulate various theories. Environmental factors including gut dysbiosis, mechanical stress, and transduction have been implicated in the pathogenesis. Recently, the interleukin (IL)-17/IL-23 pathway has been major focus due to it being therapeutic target. Herein, we reviewed various recent developments and current concepts in the pathogenesis of SpA.
Keywords: Interleukin 17, interleukin 23, pathogenesis, spondyloarthritis
|How to cite this article:|
Jain N, Moorthy A. Current concepts in the pathogenesis of spondyloarthritis. Indian J Rheumatol 2020;15, Suppl S1:6-12
| Introduction|| |
Spondyloarthritis (SpA), is a chronic inflammatory autoimmune condition predominantly affects the axial joints with some peripheral and extra-articular involvement. Spondyloarthropathy patients present with severe, chronic pain which in severe cases can lead to fusion of spine and disability. There have been significant developments in the last decade with better understanding of its pathogenesis and treatment options. However, the complete picture still remains elusive. Recently there has been more focus on role of Gut microbiome and biomechanical stress acting as an initiating and/or propagating factor of inflammation as a companion to genetics. In this review we have tried to compile the current concepts in the pathogenesis of SpA including genetics (GWAS) and environmental factors.
| Search Strategy|| |
We adhered to a search strategy for writing narrative reviews as per guidelines. We searched Pubmed central during a period 9th-19th December 2019 with the search terms “Pathogenesis” and “spondyloarthritis,” for articles published in last 5 years, and retrieved 2520 results. The abstracts and titles of these articles were screened to identify relevant studies and articles. In addition, we also took help from the musculoskeletal librarian of our department.
| Genetics|| |
More than 40 years after the discovery of this Major Histocompatibility Complex (MHC) linkage, it is still unclear how Human Leukocyte Antigen-B27 (HLA-B27) gene predisposes to SpA. HLAB27 accounts for 20–25 % of the total heritability and 40 % of the genetic risk while less than 10% of HLA-B27 carriers in the general population develop spondyloarthropathy.
In a Spanish registry (REGISPONSER) including 2367 Caucasian patients fulfilling European Spondyloarthropathy Study Group (ESSG) criteria for spondyloarthritis, the presence of HLA-B27 was found to be related to an earlier disease onset and higher family aggregation. Absence of HLA-B27 was associated with higher frequency of peripheral arthritis, dactylitis, and extra-articular manifestations. Interestingly HLAB27 positive was not related to a higher burden of disease or anytime uveitis.
Many theories have been put forward regarding HLA B27 as below:
Unfolded Protein Response
HLA B27 is a class 1 allele with quaternary structure accommodating complementary antigen in its grove. The heavy chain component associates with β2-microglobulin (β2m) and antigenic peptide in Endoplasmic reticulum (ER). One of the peptide-trimming peptidases is encoded by ER aminopeptidase 1 (ERAP-1). A significant association has been found between ERAP1 polymorphisms (rs30187 and rs27037) and increased risk of AS susceptibility.
The unfolded protein response (UPR) hypothesis postulates that this reduced rate of folding might trigger an intracellular signalling response in the ER. This has been shown to generate Interleukin -23 (IL-23) in macrophages, an activator of the pro-inflammatory Th17 lymphocytes.
The discovery of T lymphocytes that are responsive to peptides derived from self-antigens in SpA has led to Molecular mimicry or Arthritogenic peptide hypothesis. T cells reacting to self-peptides escape selection in Thymus and lead to production of autoreactive T cells.
The heavy chain components of HLAB27 form homodimers that activate pro-inflammatory NK cells and T lymphocytes. HLA- B27 homodimers bind with increased affinity to killer cell immunoglobulin like receptor 3DL2 (KIR3DL2), which is expressed on IL-17+CD4+ T cells from the blood and synovial fluid of patients with AS6.
HLA-C*07 in axial spondyloarthritis
In a recent study from German cohort, 79% of the AS patients were HLA-C*07 negative compared to 35% of the HCs (p < 0.001). This association of HLA-C*07 negativity with genetic susceptibility to axSpA was found to be independent of HLA-B27.
Genome-wide association studies (GWASs) have identified common single nucleotide polymorphisms (SNPs) in non-HLA-B genes highly significant for association with SpA. GWAS have been instrumental in identifying immune pathways deserving of further inquiry. A noteworthy study in 2013 from the International Genetics of Ankylosing Spondylitis Consortium (IGAS) studying 10,619 AS subjects and 15,145 controls of European, East Asian, and Latin American ancestry brought the number of AS-associated gene loci up to 31.
| Genome Wide Association Study|| |
With the development of GWAS methods there has been identification of a considerable number of genetic variants which have revealed the importance of non-MHC genes. HLA-B27 contributes around ~20% to heritability while ~7% of the heritable risk originates from non-MHC variants.
Genome-wide association studies (GWASs) have identified common single nucleotide polymorphisms (SNPs) in non-HLA-B genes which have shown to be associated with AS. Some of the non-MHC SNPs confers protection against development of AS by loss of function genes. (e.g., IL23R R381Q and ERAP1 rs30187). International Genetics of Ankylosing Spondylitis Consortium (IGAS) was a major study that brought the number of AS-associated gene loci up to 31. Each of the non-HLA-B27 gene SNPs individually confers a tiny amount of risk, with odds ratios ≤1.65. Certain overlap with related conditions like IBD have also been found showing 11 loci with ulcerative colitis and 12 with Crohn's disease while some SNP associations were shown to be in the opposite direction (alternate allele) such as multiple sclerosis (LTBRTNFRSF1A, NPEPPS-TBKBP1-TBX21, ZMIZ1) and type I diabetes mellitus (SH2B3, IL27).
GWAS has also been instrumental in identifying genes that influence the IL-17/IL-23 pathway including cytokines and cytokine receptors (IL23R, IL12B, IL6R, IL1R1, IL1R2, IL27), signalling molecules immediately downstream of the IL-23R (JAK2 and STAT3, TYK2), and gene products transducing signals from infectious stimuli (e.g., CARD9).
One of the strongest single disease risk loci, apart from HLA-B27 itself, is ERAP1 in HLA-B27- positive individuals, ERAP2 has been shown to be significant at the genome-wide level in HLA-B27-negative individuals.
Some variations can reduce function of ERAP1 and ERAP2 thus proving protective while increase ER stress and alter HLAB27 folding thus leading to development of AS.
ERAP1 is also involved in the development of juvenile idiopathic arthritis, psoriasis, and Behcçet's disease, while ERAP2 is related to Crohn's disease and psoriasis, as well as birdshot Chorioretinopathy.
Still all these genetic loci combined account for <5 % of the heritability, showing there is still some missing heritability. Several theories have been put forward like epistatic interactions between ERAP1 and HLAB27, multiple genes influencing IL17/IL23 pathways, Th17 cell regulations (Th1 vs Th17 expression).
But still a lot needs to be learned about genetics and immune interactions.
| Environmental Factors|| |
Lack of twin concordance rate of 100% in AS implicates environmental factors as a major contributor to its pathogenesis.
Gut Microbiome and SpA
Almost 7–10%of AS patients develop overt IBD and 50–60 % of patients of SpA have subclinical gut inflammation. Patients with AS have been shown to have increased IL-23R+IL-17 producing γδ T cells, which reside in the gut, providing a potential link between gut and joint diseases., Subclinical gut inflammation is also marked by a predominance of CD163+ and M2 wound repair macrophages.
Higher faecal calprotectin levels in SpA patients compared to control and IgA elevation during the active stage of AS point towards microscopic gut inflammation in them.
In the HLA-B27 transgenic rat model, a germ-free environment prevented disease, which occurred on transfer of common gut microbes.
Due to dysbiosis there is zonulin-dependent alterations of gut-epithelial and gut-vascular barriers. The leakage of epithelial and endothelial surface layers results in translocation of lipopolysaccharide and intestinal fatty acid binding protein in to systemic circulation. As a result, there is downregulation of expression of CD14 on circulating monocytes leading to an “anergic” phenotype. In the gut, IL-23 induces innate immune cells such as mucosal-associated invariant T cells, γδ _T cells, and innate lymphoid cells of group. These cells also translocate to systemic circulation.
In transgenic rat model it was found that the effects of HLA– B27 on gut microbiota and dysbiosis in SpA are highly dependent on the host genetic background and/or environment, despite convergence of dysregulated immune pathways. HLA–B27–transgenic Lewis and Fischer rats developed gut inflammation, while dark agouti (DA) rats were resistant to its effect. Interestingly, DA rats lacked segmented filamentous bacteria (SFB) that promote CD4+Th17 cell development, which may explain their resistance to disease. SFB are required for Th17 cell development and are known to colonize ileal epithelium. These results implicated an ecological model of dysbiosis, with the effects of multiple microbes contributing to the aberrant immune response, rather than a single or small number of microbes driving pathogenesis.
Can the microbiota be a potential therapeutic target?
Gut microbiota can be a therapeutic target following hypothesis have been proposed.
In unidirectional model wherein dysbiosis occurs early in life (antibiotic exposure/ breastfeeding/ delivery mode etc.) there is a permanent alteration in the development of the gut mucosal immune system. In another hypothesis it has been suggested that the balance between microbiota and immune system is more alterable and prone to therapeutic target. Restoration of gut homeostasis can thus be a potential target in managing SpA.
In a study investigating the modifications of intestinal microbiota composition in patients suffering from SpA three months after an anti-TNF-α treatment, 16S rDNA sequencing of 38 stool samples from 19 spondyloarthritis patients was done. A particular taxonomic node was found before anti- TNF-α treatment that could predict the clinical response as a biomarker, with a higher proportion of Burkholderiales order. These results would need confirmation in a larger cohort and could potentially predict response to TNF therapy.
Biomechanical stress and SpA
Entheseal involvement in SpA separates it from other Rheumatic diseases. The predilection of weight bearing joint involvement in SpA points towards some biomechanical factors in the pathogenesis of SpA.
The enthesis is a unique site, juxtaposing synovium, tendon, and bone and transducing immense mechanical forces. It is responsible for stable anchoring and smooth transduction of mechanical forces.
Mechanistic studies in mice have suggested that IL 23 has a key role in enthesitis with the site harbouring IL 23 responsive cells. In a mouse TNF overexpression model (the TNF ΔARE mice) it was found that decreasing the weight on limbs by suspension decreased the development of enthesitis and subsequent arthritis and osteoproliferation in this model.
Mechanical stress induces the release of prostaglandin which signals sclerostin inhibition and thus disinhibiting osteoblast stimulation. Experimental models of enthesitis is in its infancy with limited accessibility to human entheseal tissue. We need further evidence connecting role of mechanical stress and SpA developments and potential role id modification of disease progression.
| Il17/23 Axis in the Immuno-Pathogenesis of Spondyloarthropathy|| |
IL-17 in the immune-pathogenesis of spondyloarthritis
IL-23/IL-17 pathway dysfunction has been identified in many diseases including psoriasis, IBD, rheumatoid arthritis and SpA with them acting as major cytokines in axSpA and psoriatic arthritis. The pro-inflammatory cytokines IL-23 and IL-17 are important targets for current anti-inflammatory drug therapies, and activation of the IL-23–IL-17 pathway is required during immune activation in host defence against invading pathogens, as well as for maintaining the barrier function of mucosal and other body surfaces.
Several cell types have been shown to produce IL-17, including T cells, innate lymphoid cells, natural killer (NK) cells, neutrophils and macrophages. Th17 cells are the main cell type in the production of IL-17 and were found to be increased AS patients. Th17 cells expressing KIR3DL2 respond to the HLA-B27 homodimer and lead to UPR.
IL-17A signalling in IL-17 receptor- bearing target cells (fibroblasts, epithelial cells and synoviocytes leads to transcription of pro- inflammatory cytokines (IL-6, TNF and IL-1) and chemokines (CC- chemokine ligand 20 (CCL20), CCL2 and CCL7). IL-17A also regulates production of antimicrobial peptides (defensins and S100 proteins) and increases production of G-CSF and GM-CSF. Several reports have shown that IL-17F functions in a similar manner to IL-17A, though with less potency. There is lack of robust evidence confirming the presence and function of IL-17F in SpA, however, it has the potential to contribute to SpA pathology dual blockade of these cytokines can further reduce inflammation compared to IL-17 A alone. IL-23 is required for sustained IL-17 production. IL-17 can contribute to bone destruction by inducing production of RANKL and the induction of osteoclastogenesis. This destructive effect can be exacerbated in the presence of TNF IL-17 also produces IL-22 which has been implicated in enthesitis. The IL-22- producing entheseal resident cells activate osteoblast-mediated bone remodelling, suggesting IL-22 may coordinate with the IL-17/IL-23 pathway in inflammatory bone remodelling.
Effects of the IL-23–IL-17 pathway on bone in spondyloarthritis
Bone changes in SpA include systemic bone loss, articular erosions and entheseal bone formation. IL-17A promotes osteoclastogenesis directly, as well as indirectly, through the production or induction of receptor-activator of nuclear factor-κB ligand (RANKL) expression. IL-17A exhibits differential effects on the maturation of osteoblast precursor cells to osteoblasts depending upon the stage of differentiation of the cellular precursor. IL-17A blockade inhibits articular bone erosion and might also retard systemic bone loss in PsA and AS and enthesophyte formation in PsA. The direct effects of IL-17 and IL-23 on osteoclasts and on bone resorption results in catabolic effect on bone. The indirect effects of IL-23 and IL-17 causing periosteal repair leads to? paradoxical anabolic effect.
The IL-23–IL-17 pathway as a therapeutic Treat to target in axial spondyloarthritis
Clinical trials have shown that IL-17 inhibitors are efficacious in patients with SpA, however IL-23 blockade failed to show such an effect. This discrepancy might be because of the unique immunopathological microenvironment that occurs in SpA. IL-17 secretion might take place in the absence of IL-23 and many cell types other Th17 cells produce IL-17 which is partially independent of IL-23. In fact, the dominant type of IL-17-secreting cell is yet to be defined in axSpA. IL-17 inhibitors and TNF inhibitors are currently the only effective targeted therapies for axSpA. Clinical trials performed with the IL-17- blocking monoclonal antibodies secukinumab  and ixekizumab  have clearly shown the superiority of IL-17 inhibitors over placebo in TNF inhibitor- naïve as well as experienced patients with axSpA.
Long-term data gathered over 2 years and 4 years of treatment with an IL-17 inhibitor or an IL-23 inhibitor are currently only available for Secukinumab, which showed some syndesmophyte progression over this time, albeit at a relatively low level.
To explain the negative results from therapeutic trials with IL-23 inhibitors in AS, it has been speculated that IL-23 might have a pathogenic role in the initiation of AS (or axSpA) but not in maintaining established disease.
| Other Immune Cells and Cytokines in the Pathogenesis of Spa|| |
Pathogenesis of SpA also involves genes that modulate the expression of CD4 and CD8 T cells thus adding another non MHC genetic factor to the list.
Runt-related transcription factor 3 (RUNX3) can stimulate T cell differentiation to CD8+ T Lymphocytes. Its polymorphism (rs11249215/ rs4648889) has shown to be related to increased or decreased expression in AS.
Other polymorphisms like programmed cell death 1 (PDCD1) or T lymphocyte antigen 4 (CTLA-4) have also been implicated in pathogenesis of AS.
Role in innate lymphocytes
RORγt is a Thelper17 (Th17) cell transcriptional regulator and is also expressed by subsets of innate-like T cells, including invariant natural killer T (iNKT) and γδ-T cells. In a study on SpA patients the inflamed joints were found to be enriched with RORγt+ iNKT and γδ-hi T cells, which have been shown to produce IL-23 mediated Th17-like immune responses. These SpA derived iNKT and γδ-T cells showed unique and Th17-skewed phenotype and gene expression profiles. Also RORγt inhibition blocked the function of γδ17 and iNKT17 cell while selectively sparing IL-22+ subsets. Thus there is a distinctive regulation of innate-like T cells in SpA with a Th17-skewed phenotype.
Macrophages (CD68+, CD163+) or osteoclasts have been demonstrated in active joints of AS patients which after treatment have been shown to reduce.
The NK cell are also implicated in the pathogenesis of AS wherein they specifically recognize HLA-B27 molecules through the NK inhibitory receptor KIR3DL1.
Type 3 innate lymphoid cells producing predominantly GM-CSF have been shown to be increased in synovial tissues from patients with spondyloarthritis. GWAS has shown GPR65 a proton sensing receptor to be associated with SpA. GM-CSF+ and IL-17A+GM-CSF+ double-producing CD4 T cells showed increased expression of GPR65, which in being silenced reduced GM-CSF production. GM-CSF and GPR65 may thus serve as targets for therapeutic intervention of spondyloarthritis.
Role of cytokines other than IL-17/23
On studying the cytokine profile of AS patients in DESIR cohort, it was shown that Increased level of IL-31 could potentially protect against structural damage although it was also related to low BMD.
The level of IL-22 producing regulatory T cells (Tregs) has been found to be lower in AS cases, however its role as a marker of disease activity is still unclear.
Possible role of auto-antibodies
Although increased levels of plasma cells have been found in AS patients with multiple autoantibodies including anti- CD74 and anti-NOG/SOST being demonstrated, the role for B cells in the pathogenesis is still unclear and SpA is still categorised as “Sero-negative” arthritis.
| Epigenetics|| |
In the Epigenetic and gene expression analysis of ankylosing spondylitis-associated loci  variants were found which were enriched in transcriptionally regulated regions in monocytes, CD4+ and CD8+ T cells, natural killer cells, regulatory T cells and B cells and mucosa from the small intestine, sigmoid colon and rectum. RNA sequencing of blood cells from AS patients and controls found various differentially expressed genes where the upregulated genes were enriched in monocytes and downregulated genes were enriched in CD8+ T cells and natural killer cells. These variants have also been found to overlap with epigenetic marks of transcription histone H3 lysine 4 trimethylation (H3K4me3), a histone modification and epigenetic marker of active promoters in memory CD8+ T cells, CD4+ and CD8+ T cells.
| Metabolomics|| |
Metabolomic studies have implicated the importance of the intestinal microbial metabolism as well as fat and choline metabolic pathways in AS. Wang et al performed H NMR-based metabolic profiling on plasma and urine samples obtained from 39 AS patients and 44 non-AS controls as well as hip ligament tissue samples from 30 AS patients and 30 hip fracture patients as controls. They found that 20 metabolites from plasma (n = 13), urine (n = 7), and tissue (n = 2) could serve as potential biomarkers for AS. These metaboliteswere mainly associated with fat metabolism, intestinal microbial metabolism, glucose metabolism, and choline metabolism pathways.
| Bone Remodelling|| |
Osteoblast differentiation and new bone formation
Osteogenic differentiation plays a very important role in pathogenesis of AS by miR-17-5p upregulation and miR-27b-3p downregulation. Studies have shown increased expression of matrix metalloproteinase-2 (MMP-2) in AS fibroblasts with MMP-2 gene silencing reducing the osteogenesis of fibroblasts in AS. The differentiation of fibroblasts into osteoblasts in synovial tissues directly involves TNF-α, VEGF, and MMP-3 with upregulation of the expression of BMPs and VEGF contributing to radiographic progression with new bone formation.
HedgeHog and Wnt/beta-catenin signalling pathways are also involved in osteoblast differentiation. It was found that the functional DKK1 levels were significantly higher in AS patients with no syndesmophyte compared with those with syndesmophyte, suggesting that blunted Wnt signalling suppresses new bone formation.
Macrophage Migration Inhibitory Factor (MIF)-induced osteoblastic mineralization has been shown in AS patients along with raised levels in blood, synovial fluid, and gut.
Decreased bone density and bone erosion
It has been shown that Bone mineral density (BMD) of femoral neck and serum Osteoprotegerin (OPG) levels are reduced in AS patients.
Over-expression of miR-21 has been observed during RANKL-induced osteoclastogenesis in bone marrow-derived monocytes in AS.
A second miRNA, miR-29a, controls TNF-α-mediated bone loss mostly by targeting DKK1 and GSK3β through activating the Wnt/β catenin pathway.
TNF-α may have a mixed effect on bone homeostasis and may actually trigger osteo-proliferation and new bone formation, depending upon the local milieu and concentration of TNF. TNF-α upregulates DKK1 and sclerostin- inhibiting the Wnt-Frizzled pathway and new bone formation. The DKK1 levels have been shown to increase in AS patients with anti-TNF-α treatment.
| Conclusion|| |
The pathogenesis of SpA is still unclear as it is multifactorial. Various hypothesis have been postulated from genetics HLAB27, IL17 pathway, gut microbiome, and biomechanical stress. Given recent developments and understanding of the evolving newer concept in the pathogenesis of SpA, still more work need to be done in this area. Identification of further therapeutic target in SpA based on the current understanding will enable rheumatologists to treat this chronic painful condition more effectively.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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