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Spondyloarthritis: update on pathogenesis and management

      Abstract

      A great deal of progress has occurred in the past few years in elucidating the causes and designing new treatments for ankylosing spondylitis and other types of spondyloarthritis. In addition to the human leukocyte antigen (HLA)-B27 and other major histocompatibility complex (MHC) genes, chromosomal regions and genes elsewhere in the genome are being implicated both in disease susceptibility and severity. The various ways HLA-B27 may function in causing spondyloarthritis now are better understood to encompass not only antigen presentation but also other mechanisms, possibly all being operative in pathogenesis (misfolding of the HLA-B27 molecule, impaired intracellular killing of bacteria, and HLA-B27 itself serving as an autoantigen). Specific enteric and sexually acquired infections can trigger reactive arthritis, though no specific microbe has been identified in other forms of spondyloarthritis. Intestinal inflammation with impairment of the gut:blood barrier may be operative in driving ankylosing spondylitis and enteropathic arthritis. A number of treatments have been tried in spondyloarthritis, including older agents such as methotrexate and sulfasalazine but also newer drugs such as pamindronate. The recent introduction of tumor necrosis factor (TNF) blockers in the treatment of spondyloarthritis has offered the most hope in not only relieving symptoms and signs of both peripheral arthritis and enthesitis but also spinal disease, which often has been refractory to other agents. Their high cost and considerable side effect profile, however, have necessitated the establishment of guidelines for their use in these diseases in order to target the patient in whom they are likely to have the most benefit.

      Keywords

      The term “spondyloarthritis” (otherwise known as spondyloarthropathy) encompasses a heterogeneous group of inflammatory diseases characterized by spinal and peripheral joint oligoarthritis, inflammation of the attachments of ligaments and tendons to bones (enthesitis), and, at times, mucocutaneous, ocular, and/or cardiac manifestations. The term derives from the Greek terms spondylos (vertebra), arthron (joint), and itis (inflammation)—ie, arthritis of the peripheral and spinal joints. These disorders show striking familial aggregation and are typically associated with HLA genes of the major histocompatibility complex (MHC), particularly HLA-B27.
      • Arnett F.C.
      Seronegative spondyloarthropathies.
      • van der Linden S.J.
      • van der Heijde D.
      Spondylarthopathies ankylosing spondylitis.
      The family of diseases encompassed by spondyloarthritis includes: ankylosing spondylitis; reactive arthritis, known previously as Reiter’s syndrome; psoriatic arthritis and/or spondylitis; enteropathic arthritis and/or spondylitis (associated with the inflammatory bowel diseases, ulcerative colitis, or Crohn’s disease); juvenile spondyloarthritis; and undifferentiated spondyloarthritis, which encompasses patients expressing elements of but failing to fulfill accepted criteria for one of the above diseases. In addition, isolated acute anterior uveitis and spondylitic heart disease (complete heart block and/or lone aortic regurgitation) associated with HLA-B27 also may be classified within the spectrum of spondyloarthritis.
      • Martin T.M.
      • Smith J.R.
      • Rosenbaum J.T.
      Anterior uveitis current concepts of pathogenesis and interactions with spondyloarthopathies.
      • Bergfeldt L.
      HLA-B27-associated cardiac disease.
      Recent advances in molecular genetics and immunology, the development of validated disease outcome measures, and the introduction of novel effective treatments for spondyloarthritis have changed the manner and scope in which these disorders are being addressed, both clinically and investigationally. Summarized here are recent developments in understanding the pathogenesis and treatment.

      Pathogenesis

      Genetics of spondyloarthritis

      Familial aggregation

      Susceptibility to ankylosing spondylitis is clearly attributable to genetic factors, with well-documented familial aggregation and a concordance rate in identical twins as high as 63% (compared to 23% in nonidentical twins).
      • Brown M.A.
      • Laval S.H.
      • Brophy S.
      • Calin A.
      Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis.
      • Brown M.A.
      • Kennedy L.G.
      • MacGregor A.J.
      • et al.
      Susceptibility to ankylosing spondylitis in twins the role of genes, HLA, and the environment.
      Familial aggregation in other types of spondyloarthritis has been less extensively studied.

      HLA-B27 and spondyloarthritis

      HLA-A, -B, and -C (class I) molecules are expressed on the surface of all nucleated cells. They are composed of a polypeptide (the “heavy” or “alpha” chain) complexed on the surface of the cell with a “light” or beta chain (beta 2 microglobulin). The “classical” function of HLA-class I molecules is to present intracellular peptides (ie, viral, bacterial, or tumor peptides affecting the host cell) to the T cell antigen receptor on cytotoxic (CD8 positive) T lymphocytes and to activating an inhibitory killer immunoglobulin and immunoglobulin-like transcript receptors on natural killer cells.
      • Allen R.L.
      • Raine T.
      • Haude A.
      • et al.
      Leukocyte receptor complex-encoded immunomodulatory receptors show differing specificity for alternative HLA-B27 structures.
      Killing of the abnormal cell then ensues.
      HLA-B27 is a polymorphic form of HLA-B molecule that is found in up to 95% patients of European ancestry with ankylosing spondylitis,
      • van der Linden S.J.
      • van der Heijde D.
      Spondylarthopathies ankylosing spondylitis.
      • Brown M.A.
      • Wordsworth B.P.
      • Reveille J.D.
      Genetics of ankylosing spondylitis.
      as well as 70% with reactive arthritis,
      • Ekman P.
      • Kirveskari J.
      • Granfors K.
      Modification of disease outcome in Salmonella-infected patients by HLA-B27.
      60% with psoriatic spondylitis, 25% with peripheral psoriatic arthritis (although no association with psoriasis itself),
      • Brown M.A.
      • Wordsworth B.P.
      • Reveille J.D.
      Genetics of ankylosing spondylitis.
      70% with spondylitis associated with inflammatory bowel disease (but no association with inflammatory bowel disease itself),
      • Arnett F.C.
      Seronegative spondyloarthropathies.
      • van der Linden S.J.
      • van der Heijde D.
      Spondylarthopathies ankylosing spondylitis.
      • Brown M.A.
      • Wordsworth B.P.
      • Reveille J.D.
      Genetics of ankylosing spondylitis.
      and 50% with acute anterior uveitis occurring without other stigmata of spondyloarthritis.
      • Martin T.M.
      • Smith J.R.
      • Rosenbaum J.T.
      Anterior uveitis current concepts of pathogenesis and interactions with spondyloarthopathies.
      No association of HLA-B27 is seen in patients with spondyloarthritis in Africa.
      • Reveille J.D.
      • Ball E.J.
      • Khan M.A.
      HLA-B27 and genetic predisposing factors in spondyloarthropathies.
      Over 25 molecular subtypes of HLA-B27 have been described thus far.
      • Mody G.M.
      • Parke F.A.
      • Reveille J.D.
      Articular manifestations of human immunodeficiency virus infection.
      The most common subtypes (HLA-B*2705, B*2702, B*2704, B*2707) are clearly associated with risk for spondyloarthritis. Two subtypes of HLA-B27, HLA-B*2706 (found in Southeast Asia), and B*2709 (found in Sardinia) appear not to be associated with spondylitis,
      • Mody G.M.
      • Parke F.A.
      • Reveille J.D.
      Articular manifestations of human immunodeficiency virus infection.
      possibly due to amino acid differences in the “B” pocket of the HLA antigen binding cleft which alter the composition of peptides presented by these HLA-B27 subtypes (Figure 1).
      • Montserrat V.
      • Marti M.
      • Lopez de Castro J.A.
      Allospecific T cell epitope sharing reveals extensive conservation of the antigenic features of peptide ligands among HLA-B27 subtypes differentially associated with spondyloarthritis.
      • Hillig R.C.
      • Hulsmeyer M.
      • Saenger W.
      • et al.
      Thermodynamic and structural analysis of peptide- and allele-dependent properties of two HLA-B27 subtypes exhibiting differential disease association.
      • Hulsmeyer M.
      • Fiorillo M.T.
      • Bettosini F.
      • et al.
      Dual, HLA-B27 subtype-dependent conformation of a self-peptide.
      The other subtypes of HLA-B27 are too rare to have had disease associations established.
      Figure thumbnail gr1
      Figure 1The crystallized structure of HLA-B27, looking down into the antigen binding cleft. Seen here is the crystallized HLA-B27 molecule, with the viewer looking down into the antigen binding cleft. The positions in the molecule of the amino acid differences defining first 11 HLA-B27 subtypes are depicted, as well as the “B” pocket of the antigen binding cleft, which has a unique structure in HLA-B27 molecules, and the lysine amino acid residue at position 70, unique to HLA-B27.
      • Reveille J.D.
      • Ball E.J.
      • Khan M.A.
      HLA-B27 and genetic predisposing factors in spondyloarthropathies.
      • Ezquerra A.
      • Bragado R.
      • Vega M.A.
      • et al.
      Primary structure of papain-solubilized human histocompatibility antigen HLA-B27.
      The exact mechanism underlying the effect of HLA-B27 on disease susceptibility still has not been determined. Moreover, why HLA-B27-associated diseases attack certain organ systems, such as the joint, the spine, the gut and the eye, and not others, is unknown. HLA-B27 molecules do have some unique properties not described in other types of HLA-B. Free heavy chains of HLA-B27 have been shown in vitro to be expressed on the cell surface and maintain their peptide-binding groove in the absence of β2-microglobulin (Figure 2). Moreover, the heavy chains of the HLA-B27 molecule have another unique characteristic: that is for two heavy chains to adhere to each other via disulfide binding through their cysteine-67 residues in the extracellular α1 domain to form a “homodimer”
      • Dangoria N.S.
      • DeLay M.L.
      • Kingsbury D.J.
      • et al.
      HLA-B27 misfolding is associated with aberrant intermolecular disulfide bond formation (dimerization) in the endoplasmic reticulum.
      • Bird L.A.
      • Peh C.A.
      • Kollnberger S.
      • et al.
      Lymphoblastoid cells express HLA-B27 homodimers both intracellularly and at the cell surface following endosomal recycling.
      (Figure 2). This occurs as a result of B27 misfolding within the endoplasmic reticulum, a unique and inherent “defect” of this HLA molecule.
      Figure thumbnail gr2
      Figure 2Unique intracellular and extracellular functions of HLA-B27 which may affect susceptibility of spondyloarthritis. a) The HLA-B27 heavy chain is transcribed off of ribosomes in macrophages, folded onto B2 microglobulin, and antigenic peptide loaded via the TAP proteins onto it in the endoplasmic reticulum. Thence the trimolecular peptide complex (HLA-B27 heavy chain, B2 microglobulin and peptide) travels to the cell surface, where the antigenic peptide is presented either to the α:β T cell receptor on CD8 positive T lymphocytes or to the killer immunoglobulin (KIR) receptor on natural killer (NK) cells; b) the HLA-B27 heavy chain misfolds in the endoplasmic reticulum, forming B27 homodimers and other misfolding, where it either: b1) accumulates there causing a proinflammatory ER stress response; or b2) the B27 homodimers migrate to the cell surface where they either become antigenic themselves or present peptides to receptors on other inflammatory cells; c) intracellular impairment of peptide processing or loading into HLA-B27 by viruses or intracellular bacteria causes a selective impairment of the immune response; or d) the trimolecular complex present processed peptide to the α:β T cell receptor on CD4 positive T lymphocytes, or free HLA-B27 heavy chains or HLA-B27 homodimers are recognized as antigenic by the T cell receptor thence, or processed antigenic fragments of HLA-B27 are presented to the T cell receptor of CD4 positive T lymphocytes.
      The accumulation of misfolded HLA-B27 protein may result in a proinflammatory “unfolded protein response” intracellularly in the endoplasmic reticulum.
      • Bird L.A.
      • Peh C.A.
      • Kollnberger S.
      • et al.
      Lymphoblastoid cells express HLA-B27 homodimers both intracellularly and at the cell surface following endosomal recycling.
      HLA-B27 homodimers also are detectable at the cell surface in patients with spondyloarthritis,
      • Kollnberger S.
      • Bird L.
      • Sun M.Y.
      • et al.
      Cell-surface expression and immune receptor recognition of HLA-B27 homodimers.
      where they can bind peptides and present them to T lymphocytes or natural killer cells, particularly when the cell’s ordinary antigen-presenting function is impaired. Alternative recognition of different forms of HLA-B27 by leukocyte receptors could influence the development of spondyloarthritis.
      • Allen R.L.
      • Raine T.
      • Haude A.
      • et al.
      Leukocyte receptor complex-encoded immunomodulatory receptors show differing specificity for alternative HLA-B27 structures.
      On the other hand, spondyloarthritis may result from the ability of HLA-B27 to bind a unique antigenic peptide, either bacterial or self-derived. Disease would thus occur from an HLA-B27-restricted cytotoxic T-cell or natural killer cell response to this peptide, found only in joints and other affected tissues (Figure 2). Such a peptide could be bound and presented by all disease-associated HLA-B27 subtypes but not by other HLA-class I molecules. Evidence for this hypothesis comes from the identification of HLA-B27-restricted peptides from Chlamydia trachomatis,
      • Kuon W.
      • Holzhutter H.G.
      • Appel H.
      • et al.
      Identification of HLA-B27-restricted peptides from the Chlamydia trachomatis proteome with possible relevance to HLA-B27-associated diseases.
      as well as from molecular mimicry between endogenous B27 peptides and environmental antigens.
      • Fiorillo M.T.
      • Maragno M.
      • Butler R.
      • et al.
      CD8(+) T-cell autoreactivity to an HLA-B27-restricted self-epitope correlates with ankylosing spondylitis.
      • Dulphy N.
      • Peyrat M.A.
      • Tieng V.
      • et al.
      Common intra-articular T cell expansions in patients with reactive arthritis identical beta-chain junctional sequences and cytotoxicity toward HLA-B27.
      However, a specific “arthritogenic peptide” has yet to be demonstrated.
      Intracellular persistence of arthritogenic microorganisms may contribute to the cellular basis for reactive arthritis, but the molecular basis of the bactericidal pathways in synoviocytes has not been fully resolved. HLA-B27-positive monocytes in vitro kill Salmonella less efficiently than controls, and they show upregulated production of interleukin 10 and, to a lesser extent, tumor necrosis factor (TNF) alpha.
      • Ekman P.
      • Saarinen M.
      • He Q.
      • et al.
      HLA-B27-transfected (Salmonella permissive) and HLA-A2-transfected (Salmonella nonpermissive) human monocytic U937 cells differ in their production of cytokines.
      • Inman R.D.
      • Payne U.
      Determinants of synoviocyte clearance of arthritogenic bacteria.
      HLA-B27-associated modulation of cytokine response profiles may have importance in the pathogenesis of reactive arthritis.
      HLA-B27 (or peptides derived therefrom) also could act as autoantigens, being recognized by T-cell receptors on CD4+ T cells,
      • Boyle L.H.
      • Goodall J.C.
      • Opat S.S.
      • Gaston J.S.
      The recognition of HLA-B27 by human CD4(+) T lymphocytes.
      either itself or via its presentation by HLA-class II (DR, DQ, and DP) molecules.

      Other MHC genes

      HLA-B27 constitutes only part of the overall risk for spondyloarthritis. Less than 5% of HLA-B27 positive people in the general population develop these diseases.
      • van der Linden S.M.
      • Valkenburg H.A.
      • de Jongh B.M.
      • Cats A.
      The risk of developing ankylosing spondylitis in HLA-B27 positive individuals. A comparison of relatives of spondylitis patients with the general population.
      On the other hand, 20% of HLA-B27 positive relatives of patients with ankylosing spondylitis will themselves become affected. Family studies have suggested that HLA-B27 contributes only about 37% of the overall genetic risk for spondyloarthritis.
      • Brown M.A.
      • Laval S.H.
      • Brophy S.
      • Calin A.
      Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis.
      • Brown M.A.
      • Kennedy L.G.
      • MacGregor A.J.
      • et al.
      Susceptibility to ankylosing spondylitis in twins the role of genes, HLA, and the environment.
      • Allen R.L.
      • Raine T.
      • Haude A.
      • et al.
      Leukocyte receptor complex-encoded immunomodulatory receptors show differing specificity for alternative HLA-B27 structures.
      The entire effect of the MHC, on the other hand, is about 50%. Other MHC genes also have been implicated in ankylosing spondylitis in addition to B27, including HLA-DRB1.
      • Brown M.A.
      • Kennedy L.G.
      • Darke C.
      • et al.
      The effect of HLA-DR genes on susceptibility to and severity of ankylosing spondylitis.
      • Said-Nahal R.
      • Miceli-Richard C.
      • Gautreau C.
      • et al.
      The role of HLA genes in familial spondyloarthropathy a comprehensive study of 70 multiplex families.
      MHC-class I related chain gene A (MICA),
      • Singal D.P.
      • Li J.
      • Zhang G.
      Microsatellite polymorphism of the MICA gene and susceptibility to rheumatoid arthritis.
      TNF-alpha,
      • Gonzalez S.
      • Torre-Alonso J.C.
      • Martinez-Borra J.
      • et al.
      TNF-238A promoter polymorphism contributes to susceptibility to ankylosing spondylitis in HLA-B27 negative patients.
      • Hohler T.
      • Schaper T.
      • Schneider P.M.
      • et al.
      Association of different tumor necrosis factor alpha promoter allele frequencies with ankylosing spondylitis in HLA-B27 positive individuals.
      heat shock protein-70,
      • Vargas-Alarcon G.
      • Londono J.D.
      • Hernandez-Pacheco G.
      • et al.
      Heat shock protein 70 gene polymorphisms in Mexican patients with spondyloarthropathies.
      transporter associated with antigen processing (TAP)-1,
      • Fraile A.
      • Collado M.D.
      • Mataran L.
      • et al.
      TAP1 and TAP2 polymorphism in Spanish patients with ankylosing spondylitis.
      and low-molecular-mass polypeptide (LMP)-2 genes.
      • Maksymowych W.P.
      • Tao S.
      • Vaile J.
      • et al.
      LMP2 polymorphism is associated with extraspinal disease in HLA-B27 negative Caucasian and Mexican Mestizo patients with ankylosing spondylitis.
      However, their proximity to the HLA-B27 gene has made it difficult to assign a definite role for any MHC gene other than B27. Psoriasis per se is not associated with HLA-B27, but instead with other HLA-B and -C genes (Table 1).
      • Murray C.
      • Mann D.L.
      • Gerber L.N.
      • et al.
      Histocompatibility alloantigens in psoriasis and psoriatic arthritis. Evidence for the influence of multiple genes in the major histocompatibility complex.
      HLA-DRB1*0103 is associated with enteropathic peripheral arthritis
      • Orchard T.R.
      • Thiyagaraja S.
      • Welsh K.I.
      • et al.
      Clinical phenotype is related to HLA genotype in the peripheral arthropathies of inflammatory bowel disease.
      and HLA-DRB1*08 with acute anterior uveitis.
      • Laval S.H.
      • Timms A.
      • Edwards S.
      • et al.
      Whole-genome screening in ankylosing spondylitis evidence of non-MHC genetic-susceptibility loci.
      Table 1Genetic factors implicated in spondyloarthritis
      Only genetic factors implicated in ankylosing spondylitis, reactive arthritis, psoriatic arthritis/spondylitis, and enteropathic arthritis/spondylitis are shown here. The genetics of undifferentiated spondylitis, juvenile spondyloarthritis, and acute anterior uveitis has not been sufficiently examined thus far to implicate non-MHC genes.
      FactorAnkylosing spondylitisReactive arthritisPsoriatic arthritis/spondylitisEnteropathic arthritis/spondylitis
      HLA-B27 frequency90–95%70–80%24%/60%7%/70%
      Other MHC genesHLA-B60, DRB1*0101HLA-DR4HLA-B38, B39, DR4
      Associations seen in psoriatic arthritis.
      DRB1*0103
      HLA-B13, B37, B57, B58, Cw6
      Associations seen in psoriasis.
      Non-MHC genesCYP2D6
      CYP2D6 = cytochrome P450 2D6 gene, otherwise known as debrisoquine hydroxylase.
      , interleukin-1 B
      n.s.
      n.s. = no associations seen thus far.
      NOD2
      NOD2 = nucleotide oligomerization domain.
      NOD2
      NOD2 = nucleotide oligomerization domain.
      + Only genetic factors implicated in ankylosing spondylitis, reactive arthritis, psoriatic arthritis/spondylitis, and enteropathic arthritis/spondylitis are shown here. The genetics of undifferentiated spondylitis, juvenile spondyloarthritis, and acute anterior uveitis has not been sufficiently examined thus far to implicate non-MHC genes.
      Associations seen in psoriatic arthritis.
      Associations seen in psoriasis.
      § CYP2D6 = cytochrome P450 2D6 gene, otherwise known as debrisoquine hydroxylase.
      n.s. = no associations seen thus far.
      NOD2 = nucleotide oligomerization domain.

      Non-MHC genes and susceptibility to spondyloarthritis

      Two approaches have been taken to identify non-MHC genes involved in susceptibility to spondyloarthritis: genomewide scans and candidate gene analyses. Genomewide scans involve examining families with affected sibling pairs for large numbers of DNA markers distributed at regular intervals throughout the genome, much like mile markers on a highway. If the disease gene in question happens to be located near 1 of these markers, or if its contribution to disease susceptibility is large (like B27 itself), then it may be identified by virtue of linkage to the marker. If on the other hand the disease gene is located equally spaced between 2 markers or provides only a small disease contribution, it may be missed by this technique.
      Genomewide linkage scans from Britain, North America, and France have implicated numerous non-MHC genomic regions wherein candidate genes for spondylitis susceptibility can be sought (Figure 3).
      • Monowarul Islam S.M.
      • Numaga J.
      • Fujino Y.
      • et al.
      HLA-DR8 and acute anterior uveitis in ankylosing spondylitis.
      • Zhang G.
      • Luo J.
      • Bruckel J.
      • et al.
      Genetic studies in familial ankylosing spondylitis susceptibility.
      • Miceli-Richard C.
      • Zouali H.
      • Said-Nahal R.
      • et al.
      Significant linkage to spondyloarthropathy on 9q31–34.
      Although no genomewide scans have been conducted in psoriatic arthritis, those in psoriasis itself have mapped a major susceptibility locus near HLA-C in the MHC,
      • Nair R.P.
      • Stuart P.
      • Henseler T.
      • et al.
      Localization of psoriasis-susceptibility locus PSORS1 to a 60-kb interval telomeric to HLA-C.
      as well as at least 7 regions on other chromosomes
      • Tomfohrde J.
      • Silverman A.
      • Barnes R.
      • et al.
      Gene for familial psoriasis susceptibility mapped to the distal end of human chromosome 17q.
      • Becker K.G.
      • Simon R.M.
      • Bailey-Wilson J.E.
      • et al.
      Clustering of non-major histocompatibility complex susceptibility candidate loci in human autoimmune diseases.
      • Rahman P.
      • Bartlett S.
      • Siannis F.
      • et al.
      CARD15 a pleiotropic autoimmune gene that confers susceptibility to psoriatic arthritis.
      (Figure 3). Scans in families with inflammatory bowel disease have identified 7 genomic susceptibility regions (Figure 2).
      • Becker K.G.
      • Simon R.M.
      • Bailey-Wilson J.E.
      • et al.
      Clustering of non-major histocompatibility complex susceptibility candidate loci in human autoimmune diseases.
      • Hugot J.-P.
      • Laurent-Puig P.
      • Gower-Rousseau C.
      • et al.
      Mapping of a susceptibility locus for Crohn’s disease on chromosome 16.
      • Bonen D.K.
      • Cho J.H.
      The genetics of inflammatory bowel disease.
      However, only the region at chromosome 16q12 has been universally replicated.
      • Becker K.G.
      • Simon R.M.
      • Bailey-Wilson J.E.
      • et al.
      Clustering of non-major histocompatibility complex susceptibility candidate loci in human autoimmune diseases.
      The nucleotide oligomerization domain gene (NOD-2), located in this region, has been implicated in susceptibility to Crohn’s disease.
      • Bonen D.K.
      • Cho J.H.
      The genetics of inflammatory bowel disease.
      This gene also has been linked to psoriasis and psoriatic arthritis,
      • Rahman P.
      • Bartlett S.
      • Siannis F.
      • et al.
      CARD15 a pleiotropic autoimmune gene that confers susceptibility to psoriatic arthritis.
      although not to ankylosing spondylitis.
      • Crane A.M.
      • Bradbury L.
      • van Heel D.A.
      • et al.
      Role of NOD2 variants in spondylarthritis.
      • Miceli-Richard C.
      • Zouali H.
      • et al.
      CARD15/NOD2 analyses in spondylarthropathy.
      Figure thumbnail gr3
      Figure 3Chromosomal regions implicated in susceptibility to spondyloarthritis and related diseases. Included here are regions on chromosomes 2q, 6p (the major histocompatibility complex [MHC]), 6q, 10q, 11q and 16q where linkage to ankylosing spondylitis (AS) have been reported; regions on 1q and 9p in acute anterior uveitis (AAU); a region on 9q linked to spondyloarthritis (SpA); 9 regions linked to psoriasis susceptibility (PSORS 1-7; PSORS 9); a locus on 16q linked to psoriatic arthritis (PsA) susceptibility; and (IBD 1-6, IBD 9). Chromosomal locations of IBD and PSORS genes are listed at www.ncbi.nlm.nih.gov/entrez/dispomim.cg.

      Candidate gene analyses of non-MHC genes

      Few candidate genes have been definitively implicated outside of the MHC. The first to be identified was debrisoquine hydroxylase (also known as cytochrome P450 [CYP] 2D6), located on chromosome 22q.
      • Beyeler C.
      • Armstrong M.
      • Bird H.A.
      • et al.
      Relationship between genotype for the cytochrome P450 CYP2D6 and susceptibility to ankylosing spondylitis and rheumatoid arthritis.
      • Brown M.A.
      • Edwards S.
      • Hoyle E.
      • et al.
      Polymorphisms of the CYP2D6 gene increase susceptibility to ankylosing spondylitis.
      This gene is involved in the metabolism of xenobiotics, which include certain drugs, metals, industrial and naturally occurring chemicals, and which promote inflammation via T cells. The “pm” (poor metabolizer) genotype has been found in both German and British spondylitis patients.
      • Beyeler C.
      • Armstrong M.
      • Bird H.A.
      • et al.
      Relationship between genotype for the cytochrome P450 CYP2D6 and susceptibility to ankylosing spondylitis and rheumatoid arthritis.
      • Brown M.A.
      • Edwards S.
      • Hoyle E.
      • et al.
      Polymorphisms of the CYP2D6 gene increase susceptibility to ankylosing spondylitis.
      Interleukin-1 is a pivotal cytokine in initiating the inflammatory process. A recent study of British families has implicated genes within the interleukin-1 gene complex, specifically interleukin-1B.
      • Timms A.E.
      • Crane A.M.
      • Sims A.M.
      • et al.
      The interleukin 1 gene cluster contains a major susceptibility locus for ankylosing spondylitis.
      A number of other non-MHC candidate genes have been studied in ankylosing spondylitis, with inconsistent associations found, including interleukin-1 receptor antagonist,
      • McGarry F.
      • Neilly J.
      • Anderson N.
      • et al.
      A polymorphism within the interleukin 1 receptor antagonist (IL-1Ra) gene is associated with ankylosing spondylitis.
      • van der Paardt M.
      • Crusius J.B.
      • Garcia-Gonzalez M.A.
      • et al.
      Interleukin-1beta and interleukin-1 receptor antagonist gene polymorphisms in ankylosing spondylitis.
      • Maksymowych W.P.
      • Reeve J.
      • Reveille J.D.
      • et al.
      High throughput single nucleotide polymorphism (SNP) analysis of the interleukin-1 receptor antagonist (IL-1 RN) locus in patients with ankylosing spondylitis (AS) by MALDI-TOF mass spectroscopy.
      • Jin L.
      • Zhang G.
      • Akey J.M.
      • et al.
      Lack of linkage of IL1RN genotypes with ankylosing spondylitis susceptibility.
      and the progressive ankylosis (ANKH) gene.
      • Tsui F.W.
      • Tsui H.W.
      • Cheng E.Y.
      • et al.
      Novel genetic markers in the 5’-flanking region of ANKH are associated with ankylosing spondylitis.
      • Timms A.E.
      • Zhang Y.
      • Bradbury L.
      • et al.
      Investigation of the role of ANKH in ankylosing spondylitis.
      Yet other genes that have not been found to be associated with spondylitis include interleukin-6, transforming growth factor-β, androgen receptor genes, and interleukin-10 genes.
      • Mori K.
      • Ushiyama T.
      • Inoue K.
      • Hukuda S.
      Polymorphic CAG repeats of the androgen receptor gene in Japanese male patients with ankylosing spondylitis.
      • Collado-Escobar M.D.
      • Nieto A.
      • Mataran L.
      • et al.
      Interleukin 6 gene promoter polymorphism is not associated with ankylosing spondylitis.
      • Goedecke V.
      • Crane A.M.
      • Jaakkola E.
      • et al.
      Interleukin 10 polymorphisms in ankylosing spondylitis.
      • Howe H.S.
      • Cheung P.L.
      • Kong K.O.
      • et al.
      Transforming growth factor beta-1 and gene polymorphisms in oriental ankylosing spondylitis.
      Both susceptibility to and severity of psoriatic arthritis have been associated with a variety of cytokine genes, including TNF,
      • Balding J.
      • Kane D.
      • Livingstone W.
      • et al.
      Cytokine gene polymorphisms association with psoriatic arthritis susceptibility and severity.
      which may explain, at least in part, the reason for the utility of TNF blockers in patients with this disease.

      Genes and severity of spondylitis

      Disease severity in ankylosing spondylitis also has a hereditary component. Several regions on other chromosomes have been implicated, specifically an area on chromosome 18, with disease activity and functional impairment with a region on chromosome 2q.
      • Brown M.A.
      • Brophy S.
      • Bradbury L.
      • et al.
      Identification of major loci controlling clinical manifestations of ankylosing spondylitis.

      Infectious agents as triggers of spondyloarthritis

      Reactive arthritis

      The most frequent type of reactive arthritis in “developed” countries follows urogenital infections with Chlamydia trachomatis.
      • van der Linden S.J.
      • van der Heijde D.
      Spondylarthopathies ankylosing spondylitis.
      • Khan M.A.
      Update on spondyloarthropathies.
      Postdysenteric reactive arthritis, more commonly encountered in “less technologically advanced” countries follows various Shigella and Salmonella (especially typhimurium and enteriditis) species, as well as Campylobacter jejuni and fetus and, in Europe, Yersinia enterocolitica. Microorganisms implicated in reactive arthritis share common biologic features: they can invade mucosal surfaces and replicate intracellularly, and they contain lipopolysaccharide in their outer membrane. Of particular note, intact antigens from Salmonella, Yersinia, and Chlamydia have been found in synovial tissues and synovial fluids of patients with reactive arthritis,
      • Nikkari S.
      • Rantakokko K.
      • Ekman P.
      • et al.
      Salmonella-triggered reactive arthritis use of polymerase chain reaction, immunocytochemical staining, and gas chromatography-mass spectrometry in the detection of bacterial components from synovial fluid.
      often many years after the initial infection. While only bacterial fragments of the enteric pathogens have been found, evidence for viable Chlamydia trachomatis and perhaps Chlamydia pneumoniae have been demonstrated in several studies.
      • Gerard H.C.
      • Branigan P.J.
      • Schumacher Jr, H.R.
      • Hudson A.P.
      Synovial chlamydia trachomatis in patients with reactive arthritis/Reiter’s syndrome are viable but show aberrant gene expression.
      Chlamydia and other organisms also have been reported in the joints of healthy individuals, a finding that calls into question the pathogenic importance of these findings.
      • Schumacher Jr, H.R.
      • Arayssi T.
      • Crane M.
      • et al.
      Chlamydia trachomatis nucleic acids can be found in the synovium of some asymptomatic subjects.
      Other data, however, support the likelihood that bacterial persistence plays an important role in reactive arthritis, including the finding of circulating specific IgA antibodies and synovial T-cell proliferation to the initiating infectious agent.
      • Arnett F.C.
      Seronegative spondyloarthropathies.
      • Kuon W.
      • Holzhutter H.G.
      • Appel H.
      • et al.
      Identification of HLA-B27-restricted peptides from the Chlamydia trachomatis proteome with possible relevance to HLA-B27-associated diseases.
      It also may be important that there are high serum IgA levels in ankylosing spondylitis,
      • Cowling P.
      • Ebringer R.
      • Ebringer A.
      Association of inflammation with raised serum IgA in ankylosing spondylitis.
      although studies searching for elevated levels of specific IgA antibodies to a variety of organisms have been unrewarding.
      • Stone M.A.
      • Payne U.
      • Schentag C.
      • et al.
      Comparative immune responses to candidate arthritogenic bacteria do not confirm a dominant role for Klebsiella pneumonia in the pathogenesis of familial ankylosing spondylitis.

      Infection and other spondyloarthritis

      Older studies implicating Klebsiella pneumonia as a trigger for ankylosing spondylitis have not been confirmed. A recent analysis of fecal microflora in patients with spondylitis have instead implicated Bacteroides.
      • Stebbings S.
      • Munro K.
      • Simon M.A.
      • et al.
      Comparison of the faecal microflora of patients with ankylosing spondylitis and controls using molecular methods of analysis.
      In psoriatic arthritis, though earlier studies suggested a link between psoriasis and streptococcus,
      • Cassandra M.
      • Conte E.
      • Cortez B.
      Childhood pustular psoriasis elicited by the streptococcal antigen a case report and review of the literature.
      no definitive bacterial trigger has been identified for psoriasis or psoriatic arthritis.

      The gut and spondyloarthritis

      More than 50% of patients with ankylosing spondylitis and spondyloarthritis have microscopic ileal inflammation seen on ileocolonoscopy.
      • Mielants H.
      • Veys E.M.
      • Goemaere S.
      • et al.
      Gut inflammation in the spondyloarthropathies: clinical, radiologic, biologic and genetic features in relation to the type of histology: a prospective study.
      • Leirisalo-Repo M.
      • Turunen U.
      • Stenman S.
      • et al.
      High frequency of silent inflammatory bowel disease in spondylarthropathy.
      Gut inflammation in ankylosing spondylitis appears to be immunologically related to that seen in Crohn’s disease. These observations have raised speculation that the inciting and/or perpetuating event in the spondyloarthritis may be a breakdown of the gut:blood barrier to intestinal bacteria, though such has yet to be proven. It has been established that patients with ankylosing spondylitis and their relatives have increased intestinal permeability compared to healthy controls.
      • Martinez-Gonzalez O.
      • Cantero-Hinojosa J.
      • Paule-Sastre P.
      • et al.
      Intestinal permeability in patients with ankylosing spondylitis and their healthy relatives.

      Outcome measures in ankylosing spondylitis

      As is summarized in Table 2, a number of measures have been developed to assess disease status in ankylosing spondylitis,
      • van der Heijde D.
      • Bellamy N.
      • Calin A.
      • et al.
      Preliminary core sets for endpoints in ankylosing spondylitis assessments in Ankylosing Spondylitis Working Group.
      including disease activity,
      • Garrett S.
      • Jenkinson T.R.
      • Kennedy L.G.
      • et al.
      A new approach to defining disease status in ankylosing spondylitis. The Bath ankylosing spondylitis disease activity index.
      functional impairment,
      • Calin A.
      • Garrett S.
      • Whitelock H.C.
      • et al.
      A new approach to defining functional ability in ankylosing spondylitis. The Bath ankylosing spondylitis functional index.
      • Daltroy L.H.
      • Larson M.G.
      • Roberts N.W.
      • Liang M.H.
      A modification of the Health Assessment Questionnaire for the spondyloarthropathies.
      loss of spinal mobility and chest expansion,
      • Jenkinson T.R.
      • Mallorie P.A.
      • Whitelock H.C.
      • et al.
      Defining spinal mobility in ankylosing spondylitis (AS). The Bath AS Metrology Index.
      and quality of life.
      • Ware Jr., J.E.
      • Sherbourne C.D.
      The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection.
      • Haywood K.L.
      • Garratt A.M.
      • Jordan K.
      • et al.
      Disease-specific, patient-assessed measures of health outcome in ankylosing spondylitis reliability, validity and responsiveness.
      These instruments are quick, validated, and easy to administer, and they are used in clinical trials.
      Table 2Measurements of disease outcome in ankylosing spondylitis
      • van der Heijde D.
      • Bellamy N.
      • Calin A.
      • et al.
      Preliminary core sets for endpoints in ankylosing spondylitis assessments in Ankylosing Spondylitis Working Group.
      • Disease activity
       ○ Bath Ankylosing Spondylitis Disease Activity Index
      • Garrett S.
      • Jenkinson T.R.
      • Kennedy L.G.
      • et al.
      A new approach to defining disease status in ankylosing spondylitis. The Bath ankylosing spondylitis disease activity index.
       ○ Patient and Physician Global Assessments
      • van der Heijde D.
      • Bellamy N.
      • Calin A.
      • et al.
      Preliminary core sets for endpoints in ankylosing spondylitis assessments in Ankylosing Spondylitis Working Group.
      • Function
       ○ Bath Ankylosing Spondylitis Functional Index
      • Calin A.
      • Garrett S.
      • Whitelock H.C.
      • et al.
      A new approach to defining functional ability in ankylosing spondylitis. The Bath ankylosing spondylitis functional index.
       ○ Health Assessment Questionnaire-Spondylitis (HAQ-S)
      • Daltroy L.H.
      • Larson M.G.
      • Roberts N.W.
      • Liang M.H.
      A modification of the Health Assessment Questionnaire for the spondyloarthropathies.
      • Metrometry
       ○ Schöber’s test (lumbar flexion)
      • van der Heijde D.
      • Bellamy N.
      • Calin A.
      • et al.
      Preliminary core sets for endpoints in ankylosing spondylitis assessments in Ankylosing Spondylitis Working Group.
      • Ward M.M.
      • Kuzis S.
      Ceiling effects and the Schober test.
      The Schöber’s test is measured as the increase with forward flexion of a 10-centimeter segment marked on the patient’s back with the inferior mark at the level of the posterior superior iliac spines. Less than 5 centimeters is regarded as abnormal in an adult.113
       ○ Chest expansion
      • van der Heijde D.
      • Bellamy N.
      • Calin A.
      • et al.
      Preliminary core sets for endpoints in ankylosing spondylitis assessments in Ankylosing Spondylitis Working Group.
      • Sahin G.
      • Calikoglu M.
      • Ozge C.
      • et al.
      Respiratory muscle strength but not BASFI score relates to diminished chest expansion in ankylosing spondylitis.
      Chest wall expansion is measured with a tape measure placed circumferentially around the chest wall at the fourth intercostal space.114 Less than 2.5 centimeters is regarded as abnormal in an adult.
       ○ Occiput-to-wall distance
      • van der Heijde D.
      • Bellamy N.
      • Calin A.
      • et al.
      Preliminary core sets for endpoints in ankylosing spondylitis assessments in Ankylosing Spondylitis Working Group.
      • Heuft-Dorenbosch L.
      • Vosse D.
      • Landewe R.
      • et al.
      Measurement of spinal mobility in ankylosing spondylitis comparison of occiput-to-wall and tragus-to-wall distance.
      To measure the occiput-to-wall distance, the patient stands with heels and buttocks touching the wall behind and with the knees straight. The patient is asked how far back he/she can get the head, still keeping the chin in the normal position. In the straight position, the distance between the posterior convexity of the occiput and the wall is measured to the nearest 0.1 centimeter. The better of 2 attempts is recorded.115 Anything other than zero is regarded as abnormal.
       ○ Bath Ankylosing Spondylitis Metrometry Index
      • Jenkinson T.R.
      • Mallorie P.A.
      • Whitelock H.C.
      • et al.
      Defining spinal mobility in ankylosing spondylitis (AS). The Bath AS Metrology Index.
      The Bath Ankylosing Spondylitis Metrometry Index consists of 5 simple clinical measurements: cervical rotation, tragus to wall distance, lateral flexion, modified Schöber’s, and intermalleolar distance. These are better explained in references 77, 113, and 115.
      • Quality of life
       ○ Medical Outcomes Study Short Form-36 (MOS-SF-36)
      • Ware Jr., J.E.
      • Sherbourne C.D.
      The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection.
       ○ Ankylosing Spondylitis Quality of Life Index
      • Haywood K.L.
      • Garratt A.M.
      • Jordan K.
      • et al.
      Disease-specific, patient-assessed measures of health outcome in ankylosing spondylitis reliability, validity and responsiveness.
      • Imaging
       ○ Standard radiographs
        ■ Bath Ankylosing Spondylitis Radiographic Index
      • MacKay K.
      • Mack C.
      • Brophy S.
      • Calin A.
      The Bath ankylosing spondylitis radiology index (BASRI) a new validated approach to disease assessment.
      The Bath Ankylosing Spondylitis Metrometry Index consists of 5 simple clinical measurements: cervical rotation, tragus to wall distance, lateral flexion, modified Schöber’s, and intermalleolar distance. These are better explained in references 77, 113, and 115.
        ■ Modified Stokes Ankylosing Spondylitis Scoring System
      • Wanders A.J.
      • Landewe R.B.
      • Spoorenberg A.
      • et al.
      What is the most appropriate radiologic scoring method for ankylosing spondylitis? A comparison of the available methods based on the Outcome Measures in Rheumatology Clinical Trials filter.
       ○ Magnetic resonance imaging
      • Braun J.
      • Baraliakos X.
      • Golder W.
      • et al.
      Improvement of spinal inflammation in ankylosing spondylitis (AS) by infliximab therapy as assessed by magnetic resonance imaging (MRI) using a novel evaluated spinal scoring system.
      low asterisk The Schöber’s test is measured as the increase with forward flexion of a 10-centimeter segment marked on the patient’s back with the inferior mark at the level of the posterior superior iliac spines. Less than 5 centimeters is regarded as abnormal in an adult.
      • Ward M.M.
      • Kuzis S.
      Ceiling effects and the Schober test.
      Chest wall expansion is measured with a tape measure placed circumferentially around the chest wall at the fourth intercostal space.
      • Sahin G.
      • Calikoglu M.
      • Ozge C.
      • et al.
      Respiratory muscle strength but not BASFI score relates to diminished chest expansion in ankylosing spondylitis.
      Less than 2.5 centimeters is regarded as abnormal in an adult.
      To measure the occiput-to-wall distance, the patient stands with heels and buttocks touching the wall behind and with the knees straight. The patient is asked how far back he/she can get the head, still keeping the chin in the normal position. In the straight position, the distance between the posterior convexity of the occiput and the wall is measured to the nearest 0.1 centimeter. The better of 2 attempts is recorded.
      • Heuft-Dorenbosch L.
      • Vosse D.
      • Landewe R.
      • et al.
      Measurement of spinal mobility in ankylosing spondylitis comparison of occiput-to-wall and tragus-to-wall distance.
      Anything other than zero is regarded as abnormal.
      § The Bath Ankylosing Spondylitis Metrometry Index consists of 5 simple clinical measurements: cervical rotation, tragus to wall distance, lateral flexion, modified Schöber’s, and intermalleolar distance. These are better explained in references
      • Jenkinson T.R.
      • Mallorie P.A.
      • Whitelock H.C.
      • et al.
      Defining spinal mobility in ankylosing spondylitis (AS). The Bath AS Metrology Index.
      ,
      • Ward M.M.
      • Kuzis S.
      Ceiling effects and the Schober test.
      , and
      • Heuft-Dorenbosch L.
      • Vosse D.
      • Landewe R.
      • et al.
      Measurement of spinal mobility in ankylosing spondylitis comparison of occiput-to-wall and tragus-to-wall distance.
      .
      The Bath Ankylosing Spondylitis Radiographic Index was designed to quantitate radiographic severity.
      • MacKay K.
      • Mack C.
      • Brophy S.
      • Calin A.
      The Bath ankylosing spondylitis radiology index (BASRI) a new validated approach to disease assessment.
      It has been extensively validated, though its insensitivity to change over time has limited its usefulness in clinical trails.
      • Wanders A.J.
      • Landewe R.B.
      • Spoorenberg A.
      • et al.
      What is the most appropriate radiologic scoring method for ankylosing spondylitis? A comparison of the available methods based on the Outcome Measures in Rheumatology Clinical Trials filter.
      Another measure, the modified Stokes Ankylosing Spondylitis Scoring System, is currently being developed and validated for this purpose.
      • Wanders A.J.
      • Landewe R.B.
      • Spoorenberg A.
      • et al.
      What is the most appropriate radiologic scoring method for ankylosing spondylitis? A comparison of the available methods based on the Outcome Measures in Rheumatology Clinical Trials filter.
      Magnetic resonance imaging offers hope as a means not only of quantifying disease activity and response to treatment
      • Braun J.
      • Baraliakos X.
      • Golder W.
      • et al.
      Improvement of spinal inflammation in ankylosing spondylitis (AS) by infliximab therapy as assessed by magnetic resonance imaging (MRI) using a novel evaluated spinal scoring system.
      but also of reaching earlier diagnosis of ankylosing spondylitis.

      Treatment

      Patient education and physiotherapy

      A great deal of educational information is available for patients (eg, www.spondylitis.org and www.arthritis.org) (Table 3). Recreational exercise, either done alone or in groups, reduces pain and stiffness, and back exercise reduces pain and improves function in patients with ankylosing spondylitis, but these effects differ with disease duration. Health status is improved when patients perform recreational exercise at least 30 minutes per day and back exercises at least 5 days per week.
      • Uhrin Z.
      • Kuzis S.
      • Ward M.M.
      Exercise and changes in health status in patients with ankylosing spondylitis.
      • Dagfinrud H.
      • Hagen K.
      Physiotherapy interventions for ankylosing spondylitis.
      Table 3Treatment of spondyloarthritis
      • Patient education (for all patients)
      • Physiotherapy (for all patients, preferably early after diagnosis)
      • Medications
       ○ NSAIDs (for all patients, unless otherwise contraindicated)
       ○ Disease modifying anti-rheumatic drugs (for those with peripheral arthritis not responding to NSAIDs alone)
        ■ Sulfasalazine (especially for peripheral arthritis), 2–3  grams/day orally
        ■ Methotrexate (especially for peripheral psoriatic arthritis), up to 25 milligrams once a week orally or parenterally
       ○ TNF blockers (for those with persistently active AS unresponsive to at least 2 NSAIDs over a 3-month period and, in those with peripheral arthritis, unresponsive to sulfasalazine (2–3 gm/day) or methotrexate (up to 20 mg/wk)
        ■ Etanercept, 25 mg subcutaneously twice a week
        ■ Infliximab, 5 mg/kg intravenously every 6–8 weeks
       ○ Pamindronate, 60 milligrams IV per month for those with active disease unable to take anti-TNF blockers. Not yet FDA approved for spondylitis.
       ○ Corticosteroids
        ■ Systemic
        ■ Intra-articular, intra-lesional
       ○ Treatment of osteoporosis
      • Surgery
       ○ Hip replacement
       ○ Corrective spinal surgery

      Medical treatment

      Nonsteroidal anti-inflammatory drugs (NSAIDs)

      NSAIDs remain the starting point of treatment of spondylitis, and many patients will attain satisfactory symptom control with these agents alone. There are no strong data to suggest the superiority of any specific NSAID in patients with ankylosing spondylitis, although indomethacin or tolmetin appear to be most effective in rheumatologic practice. Selective COX-2 antagonists are recommended mainly for patients with proven peptic ulcer disease.

      Disease modifying anti-inflammatory agents

      The efficacy of sulfasalazine in the treatment of peripheral joint involvement in ankylosing spondylitis has been shown in 10 controlled trials, including 2 large multicenter studies in the US and France.
      • Dougados M.
      • van der Linden S.
      • Leirisalo-Repo M.
      • et al.
      Sulfasalazine in the treatment of spondylarthropathy a randomized, multicenter, double-blind, placebo-controlled study.
      • Clegg D.O.
      • Reda D.J.
      • Abdellatif M.
      Comparison of sulfasalazine and placebo for the treatment of axial and peripheral articular manifestations of the seronegative spondylarthropathies a Department of Veterans Affairs cooperative study.
      Its efficacy in axial disease has not been demonstrated in most studies. Coincident with improvement in peripheral arthritis is a fall in acute phase reactants such as the ESR and CRP. The active ingredient is the sulfapyridine moiety.
      • Taggart A.
      • Gardiner P.
      • McEnvoy F.
      • et al.
      Which is the active moiety of sulfasalazine in ankylosing spondylitis? A randomized controlled study.
      Although studied mainly in uncontrolled open label trials, methotrexate has been shown to be possibly effective in the treatment of peripheral arthritis and psoriasis in patients with spondyloarthritis.
      • Creemers M.C.
      • Franssen M.J.
      • van de Putte L.B.
      • et al.
      Methotrexate in severe ankylosing spondylitis an open study.
      • Altan L.
      • Bingol U.
      • Karakoc Y.
      • et al.
      Clinical investigation of methotrexate in the treatment of ankylosing spondylitis.
      Its efficacy in treating axial arthritis has not been established.

      Corticosteroids

      No controlled trials of glucocorticoids in ankylosing spondylitis have been conducted, though many clinicians utilize them where NSAIDs or disease modifying anti-rheumatic drugs fail to achieve a satisfactory response. With few data to support their efficacy and their potential toxicity (especially osteoporosis), systemic glucocorticoids in the treatment of spondyloarthritis are not recommended unless more effective treatments are unavailable.
      Intra-articular and peritendinous injections of depo-steroid preparations are frequently employed by clinicians for symptomatic relief of local flares, although they have not been extensively studied in controlled trials. One recent study has suggested that CT-guided injections of depo-steroids into the sacroiliac joints are effective in the short-term symptomatic relief of sacroiliitis refractory to NSAIDs.
      • Maugars Y.
      • Mathis C.
      • Berthelot J.M.
      • et al.
      Assessment of the efficacy of sacroiliac corticosteroid injections in spondylarthropathies a double-blind study.
      Injecting around the Achilles’ tendon is generally not recommended because of the risk of tendon rupture.

      Antibiotics

      Earlier data suggested that a 3-month course of antibiotics in the acute phase after disease onset may have a beneficial effect on the course of reactive arthritis, specifically when triggered by Chlamydia trachomatis but not by enteric pathogens.
      • Lauhio A.
      • Leirisalo-Repo M.
      • Lahdevirta J.
      • et al.
      Double-blind, placebo-controlled study of three-month treatment with lymecycline in reactive arthritis, with special reference to chlamydia arthritis.
      Recent long-term followup data, however, suggest that tetracycline treatment does not change the natural history of the disease.
      • Laasila K.
      • Laasonen L.
      • Leirisalo-Repo M.
      Antibiotic treatment and long term prognosis of reactive arthritis.
      In another recent study, however, a 3-month course of ciprofloxacin in the acute phase was found to have a beneficial effect on the long-term prognosis.
      • Yli-Kerttula T.
      • Luukkainen R.
      • Yli-Kerttula U.
      • et al.
      Effect of a three month course of ciprofloxacin on the late prognosis of reactive arthritis.

      Pamindronate

      Pamindronate is a bisphosphonate that has been shown to be effective not only in preventing bone loss but also in reducing disease activity in patients with ankylosing spondylitis, both clinically and on MRI scanning
      • Maksymowych W.P.
      • Lambert R.
      • Jhangri G.S.
      • et al.
      Clinical and radiological amelioration of refractory peripheral spondyloarthritis by pulse intravenous pamidronate therapy.
      (although not in reducing acute-phase reactants such as C-reactive protein or erythrocyte sedimentation rate). It is usually given at 60 mg once a month intravenously. Side effects include nausea and abdominal cramping after the infusion.

      Thalidomide

      An open label trial of thalidomide in a small number of Chinese patients with ankylosing spondylitis showed modest efficacy.
      • Huang F.
      • Gu J.
      • Zhao W.
      • et al.
      One-year open-label trial of thalidomide in ankylosing spondylitis.
      However, given the side effects of this drug (sedation, neuropathy, and teratogenicity), more confirmatory studies are necessary before its use can be recommended.

      TNFα blockers

      The use of a chimeric monoclonal antibody to TNF alpha (infliximab) at 5 mg/kg intravenously every 6 weeks has been shown to be beneficial in both the axial and peripheral manifestations of ankylosing spondylitis in both open label
      • Brandt J.
      • Haibel H.
      • Cornely D.
      • et al.
      Successful treatment of active ankylosing spondylitis with the anti-tumor necrosis factor alpha monoclonal antibody infliximab.
      and placebo-controlled clinical trials, with up to 2 years of follow up.
      • Braun J.
      • Brandt J.
      • Listing J.
      • et al.
      Two-year maintenance of efficacy and safety of infliximab in the treatment of ankylosing spondylitis.
      The onset of action is quite rapid, usually following the first infusion, with over 80% of patients achieving >20% improvement in measures of disease activity. Improvement also was seen on imaging studies, with clearing of inflammatory lesions suggestive of disease activity on MRI
      • Braun J.
      • Baraliakos X.
      • Golder W.
      • et al.
      Improvement of spinal inflammation in ankylosing spondylitis (AS) by infliximab therapy as assessed by magnetic resonance imaging (MRI) using a novel evaluated spinal scoring system.
      (Figure 4). Anti-TNF treatment is expensive and not without complications. Infusion reactions (flushing, fevers) are common, and anaphylaxis can occur. More feared are infections, especially from M. tuberculosis, mandating that all patients in whom anti-TNF treatment is planned be screened with a tuberculin skin test prior to initiation of anti-TNF therapy. There is no substantive evidence as yet that malignancy is a complication of this treatment long term. Another concern is the development of antinuclear antibodies (and even anti-dsDNA antibodies) following infliximab treatment,
      • De Rycke L.
      • Kruithof E.
      • Van Damme N.
      • et al.
      Antinuclear antibodies following infliximab treatment in patients with rheumatoid arthritis or spondylarthropathy.
      although reports of patients developing systemic lupus erythematosus or other connective tissue disease are extremely rare.
      Figure thumbnail gr4
      Figure 4Sacroiliac joints before (L) and after 3 months (R) of infliximab treatment. The arrows refer to areas of enhancement seen in bone marrow and subchondral bone seen on T2 weighted fat suppressed images that improve post-infliximab therapy.
      The soluble TNF alpha receptor, etanercept, given 25 mg subcutaneously twice weekly has been shown to be effective in the treatment of ankylosing spondylitis
      • Gorman J.
      • Sack K.E.
      • Davis Jr, J.C.
      Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor α.
      • Davis Jr, J.
      • Webb A.
      • Lund S.
      • Sack K.
      Results from an open-label extension study of etanercept in ankylosing spondylitis.
      in studies that have been extended over 24 months. Similar positive results were seen in studies of patients with other types of spondyloarthritis, with improvement seen not only in all clinical and functional parameters but also in MRI-detectable entheseal lesions.
      • Marzo-Ortega H.
      • McGonagle D.
      • O’Connor P.
      • Emery P.
      Efficacy of etanercept in the treatment of the entheseal pathology in resistant spondylarthropathy a clinical and magnetic resonance imaging study.
      In psoriatic arthritis,
      • Mease P.J.
      • Goffe B.S.
      • Metz J.
      • et al.
      Etanercept in the treatment of psoriatic arthritis and psoriasis a randomised trial.
      substantial improvement was seen in both joint and entheseal involvement and in the severity of the psoriatic skin lesions. The Food and Drug Administration has approved the use of etanercept in the treatment of both ankylosing spondylitis and psoriatic arthritis.
      Although no data are yet available on the efficacy of the humanized anti-TNF monoclonal antibody adalimumab in patients with spondyloarthritis, clinical trials are in progress.
      The use of TNF blockers in the treatment of acute anterior uveitis is less clear, however, and needs further study.
      • Smith J.R.
      • Levinson R.D.
      • Holland G.N.
      • et al.
      Differential efficacy of tumor necrosis factor inhibition in the management of inflammatory eye disease and associated rheumatic disease.
      Because of the high cost and potential side effect profiles of anti-TNF agents, guidelines have been formulated for their use. These state that there must be evidence of refractory active disease for at least 4 weeks (by patient and physician assessment) that has not responded to at least 2 NSAIDs, intra-articular steroids (if indicated), and failure of sulfasalazine (in patients with peripheral arthritis).
      • Braun J.
      • Pham T.
      • Sieper J.
      • et al.
      International ASAS consensus statement for the use of anti-tumour necrosis factor agents in patients with ankylosing spondylitis.

      Osteoporosis in ankylosing spondylitis

      Measuring bone mineral density in patients with spondylitis is complicated by false increases in spinal density from dense syndesmophyte formation, leading some to recommend quantitative computer tomography over standard dual energy X-ray absorptiometry (DEXA) for bone mineral density measurements. Nevertheless, up to half of patients with ankylosing spondylitis have been reported as having osteopenia or osteoporosis.
      • Obermayer-Pietsch B.M.
      • Lange U.
      • Tauber G.
      • et al.
      Vitamin D receptor initiation codon polymorphism, bone density and inflammatory activity of patients with ankylosing spondylitis.
      • Maillefert J.F.
      • Aho L.S.
      • El Maghraoui A.
      • et al.
      Changes in bone density in patients with ankylosing spondylitis a two-year follow-up study.
      Treatment should consist of calcium replacement, bisphosphonates, and other standard treatments for osteoporosis.
      • Lange U.
      • Jung O.
      • Teichmann J.
      • Neeck G.
      Relationship between disease activity and serum levels of vitamin D metabolites and parathyroid hormone in ankylosing spondylitis.
      In addition, treatment with anti-TNF blockers has been reported as effective in restoring bone mineral density.
      • Demis E.
      • Roux C.
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      Infliximab in spondylarthropathy-influence on bone density.

      Surgical treatment

      Total hip arthropathy is the most common surgical procedure in patients with ankylosing spondylitis.
      • Sweeney S.
      • Gupta R.
      • Taylor G.
      • Calin A.
      Total hip arthroplasty in ankylosing spondylitis outcome in 340 patients.
      Heterotopic new bone formation can be a potential problem.
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      • Rosenberg A.G.
      • Kull L.
      • Cox D.D.
      Primary noncemented total hip arthroplasty in patients with ankylosing spondylitis clinical and radiographic results at an average follow-up period of 6 years.

      Spinal fracture

      Patients with ankylosing spondylitis, even those with mild disease, are at increased risk for vertebral fracture, often resulting in neurologic compromise.
      • Mitra D.
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      • Speden D.J.
      • Collins A.J.
      The prevalence of vertebral fractures in mild ankylosing spondylitis and their relationship to bone mineral density.
      In general, halo vest immobilization is recommended. Surgical intervention may be necessary when neurological impairment is seen.

      Correction of spinal deformity

      The fixed kyphotic deformities seen in patients with advanced spondylitis can result in substantial functional impairment. Some patients seek surgical correction of their spinal deformities. In general, open, polysegmental, and closing wedge osteotomies are most often performed, with subsequent loss of correction seen least commonly in the latter. In a meta-analysis of the literature between 1945 and 1998, an average correction of 37–40° was seen, with perioperative mortality of 4% due to pulmonary, cardiac, and intestinal complications.
      • Van Royen B.J.
      • De Gast A.
      Lumbar osteotomy for correction of thoracolumbar kyphotic deformity in ankylosing spondylitis a structured review of three methods of treatment.

      Conclusions

      Spondyloarthritis represents a group of diseases heavily influenced by genetic factors, particularly HLA. The biology of HLA-B27 provides an important (but not essential) component of this predisposition. Other genes currently being identified probably work in concert with HLA to further augment susceptibility and modulate severity. Environmental factors (ie, infectious triggers) and possibly breakdown of the gut:blood barrier also appear to play important roles.
      The introduction of anti-TNF blockers in patients with spondyloarthritis has had a major impact on disease control and quality of life, though their expense and side effect profile, particularly infections, remain a concern. Increasing understanding of the genetics and pathogenesis of spondyloarthritis is leading to the development of better treatments that show promise in altering the natural history of this important group of diseases.

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