The American Journal of Medicine
Volume 118, Issue 6 , Pages 592-603, June 2005

Spondyloarthritis: update on pathogenesis and management

  • John D. Reveille, MD

      Affiliations

    • Corresponding Author InformationRequests for reprints should be addressed to: John D. Reveille, MD, The University of Texas-Houston Health Science Center, MSB 5.270, 6431 Fannin, Houston, TX 77030.
    • ,
  • Frank C. Arnett, MD

Division of Rheumatology, Department of Internal Medicine, The University of Texas-Houston Health Science Center

Article Outline

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:  Ankylosing spondylitis , Spondyloarthritis , Genetics , Treatment , Pathophysiology

 

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-B27.1, 2 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.3, 4

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.

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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).5, 6 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.7 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,2, 8 as well as 70% with reactive arthritis,9 60% with psoriatic spondylitis, 25% with peripheral psoriatic arthritis (although no association with psoriasis itself),8 70% with spondylitis associated with inflammatory bowel disease (but no association with inflammatory bowel disease itself),1, 2, 8 and 50% with acute anterior uveitis occurring without other stigmata of spondyloarthritis.3 No association of HLA-B27 is seen in patients with spondyloarthritis in Africa.10

Over 25 molecular subtypes of HLA-B27 have been described thus far.11 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,11 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).12, 13, 14 The other subtypes of HLA-B27 are too rare to have had disease associations established.

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  • Figure 1. 

    The 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-B27.10, 116

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”15, 16 (Figure 2). This occurs as a result of B27 misfolding within the endoplasmic reticulum, a unique and inherent “defect” of this HLA molecule.

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  • Figure 2. 

    Unique 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.16 HLA-B27 homodimers also are detectable at the cell surface in patients with spondyloarthritis,17 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.7

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,18 as well as from molecular mimicry between endogenous B27 peptides and environmental antigens.19, 20 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.21, 22 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,23 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.24 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.5, 6, 7 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-DRB1.25, 26 MHC-class I related chain gene A (MICA),27 TNF-alpha,28, 29 heat shock protein-70,30 transporter associated with antigen processing (TAP)-1,31 and low-molecular-mass polypeptide (LMP)-2 genes.32 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).33 HLA-DRB1*0103 is associated with enteropathic peripheral arthritis34 and HLA-DRB1*08 with acute anterior uveitis.35

Table 1. Genetic factors implicated in spondyloarthritis+
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†DRB1*0103
HLA-B13, B37, B57, B58, Cw6‡
Non-MHC genesCYP2D6§, interleukin-1 Bn.s.∥NOD2NOD2

+ 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).36, 37, 38 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,39 as well as at least 7 regions on other chromosomes40, 41, 42 (Figure 3). Scans in families with inflammatory bowel disease have identified 7 genomic susceptibility regions (Figure 2).41, 43, 44 However, only the region at chromosome 16q12 has been universally replicated.41 The nucleotide oligomerization domain gene (NOD-2), located in this region, has been implicated in susceptibility to Crohn’s disease.44 This gene also has been linked to psoriasis and psoriatic arthritis,42 although not to ankylosing spondylitis.45, 46

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  • Figure 3. 

    Chromosomal 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.47, 48 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.47, 48

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.49

A number of other non-MHC candidate genes have been studied in ankylosing spondylitis, with inconsistent associations found, including interleukin-1 receptor antagonist,50, 51, 52, 53 and the progressive ankylosis (ANKH) gene.54, 55 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.56, 57, 58, 59

Both susceptibility to and severity of psoriatic arthritis have been associated with a variety of cytokine genes, including TNF,60 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.61

Infectious agents as triggers of spondyloarthritis 

Reactive arthritis 

The most frequent type of reactive arthritis in “developed” countries follows urogenital infections with Chlamydia trachomatis.2, 62 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,63 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.64 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.65 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.1, 18 It also may be important that there are high serum IgA levels in ankylosing spondylitis,66 although studies searching for elevated levels of specific IgA antibodies to a variety of organisms have been unrewarding.67

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.68 In psoriatic arthritis, though earlier studies suggested a link between psoriasis and streptococcus,69 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.70, 71 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.72

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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,73 including disease activity,74 functional impairment,75, 76 loss of spinal mobility and chest expansion,77 and quality of life.78, 79 These instruments are quick, validated, and easy to administer, and they are used in clinical trials.

Table 2. Measurements of disease outcome in ankylosing spondylitis73
• Disease activity
○ Bath Ankylosing Spondylitis Disease Activity Index74
○ Patient and Physician Global Assessments73
• Function
○ Bath Ankylosing Spondylitis Functional Index75
○ Health Assessment Questionnaire-Spondylitis (HAQ-S)76
• Metrometry
○ Schöber’s test (lumbar flexion)73, 113⁎
○ Chest expansion73, 114†
○ Occiput-to-wall distance73, 115‡
○ Bath Ankylosing Spondylitis Metrometry Index77§
• Quality of life
○ Medical Outcomes Study Short Form-36 (MOS-SF-36)78
○ Ankylosing Spondylitis Quality of Life Index79
• Imaging
○ Standard radiographs
■ Bath Ankylosing Spondylitis Radiographic Index80§
■ Modified Stokes Ankylosing Spondylitis Scoring System81
○ Magnetic resonance imaging82

⁎ 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 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.

‡ 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.

§ 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.

The Bath Ankylosing Spondylitis Radiographic Index was designed to quantitate radiographic severity.80 It has been extensively validated, though its insensitivity to change over time has limited its usefulness in clinical trails.81 Another measure, the modified Stokes Ankylosing Spondylitis Scoring System, is currently being developed and validated for this purpose.81 Magnetic resonance imaging offers hope as a means not only of quantifying disease activity and response to treatment82 but also of reaching earlier diagnosis of ankylosing spondylitis.

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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.83, 84

Table 3. Treatment 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.85, 86 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.87

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.88, 89 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.90 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.91 Recent long-term followup data, however, suggest that tetracycline treatment does not change the natural history of the disease.92 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.93

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 scanning94 (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.95 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 label96 and placebo-controlled clinical trials, with up to 2 years of follow up.97 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 MRI82 (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,98 although reports of patients developing systemic lupus erythematosus or other connective tissue disease are extremely rare.

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  • Figure 4. 

    Sacroiliac 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 spondylitis99, 100 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.101 In psoriatic arthritis,102 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.103

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).104

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.105, 106 Treatment should consist of calcium replacement, bisphosphonates, and other standard treatments for osteoporosis.107 In addition, treatment with anti-TNF blockers has been reported as effective in restoring bone mineral density.108

Surgical treatment 

Total hip arthropathy is the most common surgical procedure in patients with ankylosing spondylitis.109 Heterotopic new bone formation can be a potential problem.110

Spinal fracture 

Patients with ankylosing spondylitis, even those with mild disease, are at increased risk for vertebral fracture, often resulting in neurologic compromise.111 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.112

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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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PII: S0002-9343(05)00002-1

doi:10.1016/j.amjmed.2005.01.001

The American Journal of Medicine
Volume 118, Issue 6 , Pages 592-603, June 2005

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