American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015: recommendations for the treatment of ankylosing spondylitis and nonradiographic axial spondyloarthritis

OBJECTIVE: To provide evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). METHODS: A core group led the development of the recommendations, starting with the treatment questions. A literature review group conducted systematic literature reviews of studies that addressed 57 specific treatment questions, based on searches conducted in OVID Medline (1946-2014), PubMed (1966-2014), and the Cochrane Library. We assessed the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. A separate voting group reviewed the evidence and voted on recommendations for each question using the GRADE framework. RESULTS: In patients with active AS, the strong recommendations included use of nonsteroidal antiinflammatory drugs (NSAIDs), use of tumor necrosis factor inhibitors (TNFi) when activity persists despite NSAID treatment, not to use systemic glucocorticoids, use of physical therapy, and use of hip arthroplasty for patients with advanced hip arthritis. Among the conditional recommendations was that no particular TNFi was preferred except in patients with concomitant inflammatory bowel disease or recurrent iritis, in whom TNFi monoclonal antibodies should be used. In patients with active nonradiographic axial SpA despite treatment with NSAIDs, we conditionally recommend treatment with TNFi. Other recommendations for patients with nonradiographic axial SpA were based on indirect evidence and were the same as for patients with AS. CONCLUSION: These recommendations provide guidance for the management of common clinical questions in AS and nonradiographic axial SpA. Additional research on optimal medication management over time, disease monitoring, and preventive care is needed to help establish best practices in these areas.(AU)

Observed Incidence of Uveitis Following Certolizumab Pegol Treatment in Patients With Axial Spondyloarthritis.

OBJECTIVE: Axial spondyloarthritis (axial SpA) is characterized by inflammation of the spine and sacroiliac joints and can also affect extraarticular sites, with the most common manifestation being uveitis. Here we report the incidence of uveitis flares in axial SpA patients from the RAPID-axSpA trial, including ankylosing spondylitis (AS) and nonradiographic (nr) axial SpA. METHODS: The RAPID-axSpA (NCT01087762) trial is double-blind and placebo-controlled to week 24, dose-blind to week 48, and open-label to week 204. Patients were randomized to certolizumab pegol (CZP) or placebo. Placebo patients entering the dose-blind phase were re-randomized to CZP. Uveitis events were recorded on extraarticular manifestation or adverse event forms. Events were analyzed in patients with/without history of uveitis, and rates reported per 100 patient-years. RESULTS: At baseline, 38 of 218 CZP-randomized patients (17.4%) and 31 of 107 placebo-randomized patients (29.0%) had past uveitis history. During the 24-week double-blind phase, the rate of uveitis flares was lower in CZP (3.0 [95% confidence interval (95% CI) 0.6-8.8] per 100 patient-years) than in placebo (10.3 [95% CI 2.8-26.3] per 100 patient-years). All cases observed during the 24-week double-blind phase were in patients with a history of uveitis; in these patients, rates were similarly lower for CZP (17.1 [95% CI 3.5-50.1] per 100 patient-years) than placebo (38.5 [95% CI 10.5-98.5] per 100 patient-years). Rates of uveitis flares remained low up to week 96 (4.9 [95% CI 3.2-7.4] per 100 patient-years) and were similar between AS (4.4 [95% CI 2.3-7.7] per 100 patient-years) and nr-axial SpA (5.6 [95% CI 2.9-9.8] per 100 patient-years). CONCLUSION: The rate of uveitis flares was lower for axial SpA patients treated with CZP than placebo during the randomized controlled phase. Incidence of uveitis flares remained low to week 96 and was comparable to rates reported for AS patients receiving other anti-tumor necrosis factor antibodies.

Mycobacterial diseases and antitumour necrosis factor therapy in USA.

OBJECTIVE: In North America, tuberculosis and nontuberculous mycobacterial (NTM) disease rates associated with antitumour necrosis factor α (anti-TNFα) therapy are unknown. METHODS: At Kaiser Permanente Northern California, the authors searched automated pharmacy records to identify inflammatory disease patients who received anti-TNF therapy during 2000-2008 and used validated electronic search algorithms to identify NTM and tuberculosis cases occurring during anti-TNF drug exposure. RESULTS: Of 8418 anti-TNF users identified, 60% had rheumatoid arthritis (RA). Among anti-TNF users, 18 developed NTM and 16 tuberculosis after drug start. Anti-TNF associated rates of NTM and tuberculosis were 74 (95% CI: 37 to 111) and 49 (95% CI: 18 to 79) per 100 000 person-years, respectively. Rates (per 100, 000 person-years) for NTM and tuberculosis respectively for etanercept were 35 (95% CI: 1 to 69) and 17 (95% CI: 0 to 41); infliximab, 116 (95% CI: 30 to 203) and 83 (95% CI: 10 to 156); and adalimumab, 122 (95% CI: 3 to 241) and 91 (95% CI: 19 to 267). Background rates for NTM and tuberculosis in unexposed RA-patients were 19.2 (14.2 to 25.0) and 8.7 (5.3 to 13.2), and in the general population were 4.1 (95% CI 3.9 to 4.4) and 2.8 (95% CI 2.6 to 3.0) per 100, 000 person-years. Among anti-TNF users, compared with uninfected individuals, NTM case-patients were older (median age 68 vs 50 years, p<0.01) and more likely to have RA (100% vs 60%, p<0.01); whereas, tuberculosis case-patients were more likely to have diabetes (37% vs 16%, p=0.02) or chronic renal disease (25% vs 6%, p=0.02). CONCLUSIONS: Among anti-TNF users in USA, mycobacterial disease rates are elevated, and NTM is associated with RA.

Endotoxin-induced uveitis is primarily dependent on radiation-resistant cells and on MyD88 but not TRIF.

TLR4 activation by LPS (endotoxin) is mediated by the MyD88 and TRIF intracellular signaling pathways. We determined the relative activation of these pathways in murine ocular tissue after LPS exposure. Additionally, we explored whether BM-derived or non-BM-derived cells were the major contributors to EIU. Mice deficient in TRIF or MyD88 and their congenic (WT) controls received 250 ng ultrapure LPS ivt at 0 h. Ocular inflammation was assessed by histological analysis at 4, 6, and 24 h, and additionally, in MyD88(-/-) mice, intravital microscopy was performed at 4 h and 6 h to assess adherent, rolling, and infiltrating cells in the iris vasculature and tissue. Cytokines associated with the MyD88 and TRIF intracellular signaling pathways were analyzed in ocular tissue at 4 h. BM chimeric mice (WT→WT, TLR4(-/-)→WT, WT→TLR4(-/-)) received 250 ng LPS by ivt injection, and ocular tissues were examined by histology at 6 h. Lack of MyD88 resulted in a markedly diminished cellular response and reduced production of MyD88-related cytokines 4 h post-LPS treatment. In contrast, lack of TRIF led to reduced production of TRIF-related cytokines and no change in the cellular response to LPS. Therefore, the MyD88 pathway appears to be the dominant TLR4 pathway in EIU. Only WT → TLR4(-/-) chimeric mice were resistant to EIU, and this suggests, surprisingly, that non-BM-derived (radiation-resistant) cells in the eye play a greater role than BM-derived cells.

HLA-DRB1*0102 is associated with TINU syndrome and bilateral, sudden-onset anterior uveitis but not with interstitial nephritis alone.

BACKGROUND: Tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare form of uveitis. Previously, the authors had demonstrated a strong association of human leukocyte antigen (HLA) DRB1*0102 with TINU. Here, the authors performed HLA analysis on subjects with isolated bilateral sudden-onset uveitis (as in the TINU subtype) or with isolated tubulointerstitial nephritis (TIN). METHODS: Patients with sudden onset, anterior, bilateral uveitis not fulfilling a diagnosis of TINU were identified. Pathology reports were reviewed to identify subjects with biopsy-proven TIN. Molecular typing of the HLA-DRB1 gene was performed by the Luminex technology-based sequence-specific oligonucleotide (SSO) hybridisation method (One Lambda, Canoga Park, California). HLA-DRB1 allele frequencies were compared with normal published controls (http://www.ncbi.nlm.nih.gov/projects/gv/mhc/ihwg.cgi dbMHC Europe cohort) and the published TINU cohort (n=18). RESULTS: The authors included 28 subjects with uveitis and 14 with TIN. There was a significantly higher frequency of DRB1*0102 in the isolated uveitis cohort versus in normal controls (10.7% vs 0.6%, respectively, p<0.0001; RR 14.3 (6.9-29.8)). None of the nephritis patients showed this HLA subtype. Another association with HLA-DRB1*08 was seen in the isolated uveitis cohort with an allele frequency of 10.7% versus 2.7% in normal controls (p=0.0019; RR 4.0 (1.8-9.0)). In contrast, the HLA-DRB1*08 was not different from controls in the TINU cohort (allele frequency 2.8%, p=not significant). CONCLUSION: The incidence of HLA-DRB1*0102 is increased in sudden-onset bilateral anterior uveitis, as seen in patients with TINU. The same allele does not appear to occur in increased frequency in patients with isolated TIN. HLA DRB1*0102 might predispose to this subset of uveitis.

Use of methotrexate in patients with uveitis.

Methotrexate has been frequently employed to treat ocular inflammatory diseases including uveitis, scleritis, and orbital inflammatory disease. It is effective for intraocular lymphoma when given directly into the eye. No study has assessed its efficacy for eye disease in a randomised, placebo controlled design. This report reviews the literature relevant to methotrexate's utility in the treatment of ocular inflammatory disease.

Gender and laterality affect recurrences of acute anterior uveitis.

AIM: Acute anterior uveitis (AAU) associated with HLA-B27 or axial spondyloarthritis (axial SpA) is primarily unilateral and recurrent. We tested the hypotheses that disease laterality and gender affected recurrences of AAU. METHODS: We studied 207 AAU subjects who were either HLA-B27 positive or had a verified history of axial SpA with documentation of the first uveitis episode. We recorded gender, laterality, duration, and time between episodes. RESULTS: Of 207 subjects, 126 (60.9%) had axial spondyloarthritis. Of the 179 with known HLA-B27 status, 174 (97.2%) were HLA-B27 positive. The initial episode of AAU occurred slightly more often in the right eye, 109 (52.6%), than in the left, 91 (44.0%) or bilaterally, 7 (3.4%), but the difference between right and left was not significant (p=0.23). Interestingly, 69.4% of subsequent episodes occurred in the same eye affected previously (95% CI 59.3%, 78.3%, p=0.0001). In subjects with recurrent AAU, the probability of being disease-free for one year was 38.9% (95% CI 29.1%, 52.0%) using Kaplan-Meier estimates. Univariate analyses showed that male gender (p=0.03) and AAU which recurred in the same eye (p=0.04) was associated with a shorter time interval between episodes. Multivariate analysis by the Cox proportional hazards model showed similar results. CONCLUSIONS: The initial episode of unilateral AAU associated with HLA-B27 or axial SpA randomly affects either eye. Subsequent episodes occur more often in the same eye previously affected. Male gender and history of unilateral AAU in the same eye are associated with a shortened time interval between relapses.

Rituximab for treatment of ocular inflammatory disease: a series of four cases.

Rituximab may be effective in the treatment of ocular inflammatory disease. Dosing is less frequent than many medications currently available. Four cases are reported, each of which appeared to have responded well to treatment with rituximab, although patient 2 was able to remain on a low dose of prednisone for only 2 months. The ongoing pilot study will hopefully provide additional insight into the benefit of rituximab for treatment of scleritis and idiopathic orbital inflammatory disease.

Activation of nucleotide oligomerization domain 2 exacerbates a murine model of proteoglycan-induced arthritis.

In addition to its role in innate immunity, nucleotide oligomerization domain 2 (NOD2) has been shown to play a suppressive role in models of colitis. Notably, mutations in NOD2 cause the inherited granulomatous disease of the joints called Blau syndrome, thereby linking NOD2 with joint disease as well. However, the role of NOD2 in joint inflammation has not been clarified. We demonstrate here that NOD2 is functional within the mouse joint and promotes inflammation, as locally or systemically administered muramyl dipeptide (MDP; the NOD2 agonist) resulted in significant joint inflammation that was abolished in NOD2-deficient mice. We then sought to investigate the role of NOD2 in a mouse model of inflammatory arthritis dependent on adaptive immunity using TCR-transgenic mice whose T cells recognized the dominant epitope of proteoglycan (PG). Mice immunized with PG in the presence of MDP developed a more severe inflammatory arthritis and histopathology within the joints. Antigen-specific activation of splenocytes was enhanced by MDP with respect to IFN-gamma production, which would be consistent with the Th1-mediated disease in vivo. Intriguingly, NOD2 deficiency did not alter the PG-induced arthritis, indicating that NOD2 does not play an essential role in this model of joint disease when it is not activated by MDP. In conclusion, we demonstrate that in a model of inflammatory arthritis dependent on T and B cell priming, NOD2 activation potentiates disease. However, the absence of NOD2 does not alter the course of inflammatory arthritis, in contrast to models of intestinal inflammation.

Invasion of human retinal vascular endothelial cells by Toxoplasma gondii tachyzoites.

BACKGROUND: Toxoplasma gondii infection is a leading cause of posterior uveitis. Human retinal endothelial cells (HREC) are more susceptible to infection with T gondii tachyzoites than other subpopulations of endothelial cells. It is hypothesised that this phenomenon reflects differences in invasion efficiency. METHODS: YFP-expressing RH strain T gondii tachyzoites were added to confluent HREC or human dermal endothelial cells (HDEC) (MOI = 50:1). Tachyzoite invasion after 1 h was determined by microplate reading of fluorescence intensity or parasite counts obtained using image analysis software. Selected cultures were incubated for three subsequent days, at which time fluorescence intensity indicated intracellular tachyzoite proliferation. RESULTS: HREC-tachyzoite cultures were more fluorescent than HDEC-tachyzoite cultures after 1 h (p = 0.020, paired t test, 3 experiments). Parasite counts also indicated that more tachyzoites invaded HREC than HDEC (p = 0.042, paired t test, 5 experiments). At 3 days, fluorescence intensity remained higher in HREC-tachyzoite cultures (p< or =0.002, t test, 3 experiments). CONCLUSION: In culture, T gondii tachyzoites invade HREC with greater efficiency than they invade HDEC. This observation suggests that the relative susceptibility of HREC to infection may reflect a high efficiency of tachyzoite invasion which may be relevant to understanding how T gondii infects human retina.

Activation of NOD2 in vivo induces IL-1beta production in the eye via caspase-1 but results in ocular inflammation independently of IL-1 signaling.

Nucleotide-binding and oligomerization domain 2 (NOD2) belongs to the emerging Nod-like receptor (NLR) family considered important in innate immunity. Mutations in NOD2 cause Blau syndrome, an inherited inflammation of eye, joints, and skin. Mutations in a homologous region of another NLR member, NALP3, cause autoinflammation, wherein IL-1beta plays a critical role. Here, we tested the hypothesis that IL-1beta is a downstream mediator of NOD2-dependent ocular inflammation. We used a mouse model of NOD2-dependent ocular inflammation induced by muramyl dipeptide (MDP), the minimal bacterial motif sensed by NOD2. We report that MDP-induced ocular inflammation generates IL-1beta and IL-18 within the eye in a NOD2- and caspase-1-dependent manner. Surprisingly, two critical measures of ocular inflammation, leukocyte rolling and leukocyte intravascular adherence, appear to be completely independent of IL-1 signaling effects, as caspase-1 and IL-1R1-deficient mice still developed ocular inflammation in response to MDP. In contrast to the eye, a diminished neutrophil response was observed in an in vivo model of MDP-induced peritonitis in caspase-1-deficient mice, suggesting that IL-1beta is not essential in NOD2-dependent ocular inflammation, but it is involved, in part, in systemic inflammation triggered by NOD2 activation. This disparity may be influenced by IL-1R antagonist (IL-1Ra), as we observed differential IL-1Ra levels in the eye versus plasma at baseline levels and in response to MDP treatment. This report reveals a new in vivo function of NOD2 within the eye yet importantly, distinguishes NOD2-dependent from NALP3-dependent inflammation, as ocular inflammation in mice occurred independently of IL-1beta.

Anterior uveitis accompanies joint disease in a murine model resembling ankylosing spondylitis.

BACKGROUND: Uveitis is often associated with a systemic inflammatory disease such as ankylosing spondylitis. Our understanding of the eye's susceptibility to immune-mediated uveitis as in the apparent absence of infection has been limited by a relative lack of experimental models. Here we sought to assess whether ocular inflammation occurs in a previously described murine model of proteoglycan-induced spondylitis, wherein mice develop progressive spondylitis, sacroiliitis and peripheral arthritis--features common to the clinical presentations of ankylosing spondylitis. METHODS: Using intravital microscopy we examined the ocular inflammatory response after the onset of arthritis in mice that overexpressed the T cell receptor (TCR) specific for a dominant arthritogenic epitope of cartilage proteoglycan [TCR-Tg (transgenic) mice] or BALB/c controls. RESULTS: Immunized TCR-Tg mice showed a significant increase in the number of rolling and adhering cells within the iris vasculature compared to adjuvant control mice. Cellular infiltration within the iris tissue, as assessed by intravital microscopy and histology, was also increased. Our initial temporal analysis has revealed that immunized TCR-Tg mice show a significant increase in intravascular inflammation by 2 weeks after immunization, but it diminishes at 4 weeks after immunization. CONCLUSIONS: Although these data are preliminary, this model has the potential to clarify the mechanisms accounting for the coexistence of eye and sacroiliac inflammation as occurs in patients with ankylosing spondylitis.

Endotoxin upregulates CCR7 and its ligands in the lymphatic-free mouse iris.

PURPOSE: Using time lapse intravital microscopy and histology, we previously reported that we could not detect migration of antigen-presenting cells from the iris to the regional lymph node. Dendritic cells (DC) in other peripheral tissues migrate to lymph nodes in response to chemokines, CCL19 (ELC) and CCL21b (SLC), that activate the CCR7 receptor. We hypothesized that DCs in an inflamed iris might show a different chemokine receptor and ligand profile, thus explaining the DC's inability to migrate. METHODS: Eyes of 35 BALB/c mice were injected intravitreally with 2 mul of 250 ng E. coli lipopolysaccharide (LPS) or phosphate buffered saline (PBS). Five mice served as naïve controls. After 3 and 6 h, the iris-ciliary bodies were dissected and pooled in groups of five. Total RNA was isolated, and reverse-transcriptase polymerase chain reaction (RT-PCR) for chemokine receptor and ligand mRNA was performed. In addition, one eye from each of the three animals was taken 6 h after LPS injection for immunohistology (IHC). RESULTS: The naïve iris, the iris after PBS injection, and the iris after LPS injection contained CCR5 mRNA at approximately equal levels and did not have detectable CCR6 mRNA. No CCR7 mRNA expression was found in the naïve iris, but it was weakly expressed in PBS-injected eyes and was approximately 3.4 fold upregulated after LPS injection. This was confirmed by IHC with no staining for CCR7 in the control iris but positive staining in the inflamed eyes. Transcripts for the CCR7 ligands, CCL19 and CCL21b, were found after LPS or PBS injection but not in naïve iris-ciliary bodies. CONCLUSIONS: The clear upregulation of CCR7 and its ligands in the inflamed iris suggests that another mechanism prevents iris DCs from migrating. Other possibilities include the absence of co-factors, inhibitory substances, the lack of lymphatics inside the eye, or inadequate biologicAL activity of these chemotactic factors and ligands.

Alterations in peripheral blood lymphocyte cytokine expression in obesity.

Obesity is characterized by alterations in immune and inflammatory function. In order to evaluate the potential role of cytokine expression by peripheral blood mononuclear cells (PBMC) in obesity-associated inflammation, we studied serum protein levels and mRNA levels in PBMC of interleukin (IL)-6, IL-1beta, tumour necrosis factor (TNF)-alpha and IL-1Ra in nine lean and 10 obese subjects. Serum IL-1beta was undetectable, IL-1Ra serum levels were elevated, serum levels of TNF-alpha were decreased and serum levels of IL-6 were similar in obese subjects compared to lean subjects, while transcript levels of IL-6, IL-1beta and TNF-alpha, but not IL-1Ra, were decreased in PBMC from obese subjects. PBMC from obese subjects did, however, up-regulate cytokine expression in response to leptin. Thus, obesity-associated changes in IL-1Ra serum levels and IL-6 mRNA levels were not correlated with changes in cognate mRNA and serum levels, respectively, while TNF-alpha serum levels and PBMC mRNA levels were both decreased in obese patients. While immune alterations in obesity are manifest in peripheral blood lymphocytes, the general lack of correlation between altered serum levels and altered PBMC gene expression suggests that PBMC may not be the source of aberrant serum cytokine levels in obesity.

Retention time for corticosteroid-sparing systemic immunosuppressive agents in patients with inflammatory eye disease.

BACKGROUND: Multiple immunosuppressive drugs have been used to manage inflammatory eye disease when control cannot be achieved by corticosteroid alone. However, although clinical studies support the effectiveness of most of these agents, comparative studies have not been undertaken. Retention time, a measure of the duration of treatment with any given drug, is a crude indicator of drug effectiveness and tolerability that facilitates such a comparison. The retention time was compared for corticosteroid-sparing immunosuppressive agents in patients attending our tertiary referral inflammatory eye disease clinic. METHODS: The clinical records of all patients attending an inflammatory eye disease clinic at the Casey Eye Institute over a 1-year period (2003) were reviewed. From these records, we collected the following clinical data: age; sex; ocular diagnosis; and use of steroid-sparing systemic immunosuppression, including drugs, duration of treatment and, if ceased, reasons for cessation. Cox regression analysis, adjusted for clustering, was used to compare other drugs against methotrexate. RESULTS: 107 of 302 (35%) patients seen at the inflammatory eye disease clinic in 2003 had a total of 193 current or past prescriptions for systemic steroid-sparing immunosuppressive agents. The treated group, most of whom had uveitis, included 32 men and 75 women, aged 5-86 years. Most commonly prescribed were methotrexate (66 uses, 34%), ciclosporin (37 uses, 19%), azathioprine (26 uses, 13%), mycophenolate mofetil (22 uses, 11%) and cyclophosphamide (15 uses, 8%). Patients were retained significantly less on ciclosporin (p = 0.004), azathioprine (p = 0.04), mycophenolate mofetil (p = 0.04) and cyclophosphamide (p<0.001) compared with methotrexate. Reasons for cessation included adverse events, lack of effectiveness, success or remission, cost and desire for fertility. CONCLUSIONS: In patients with inflammatory eye disease, methotrexate may offer a superior combination of effectiveness and tolerability over other commonly used corticosteroid-sparing immunosuppressive agents. In this study, there was a twofold risk of not being retained on azathioprine, mycophenolate mofetil and ciclosporin and a fourfold risk of not being retained on cyclophosphamide compared with methotrexate.

Modification of the Woodruff-Stamper assay demonstrates binding of Toxoplasma gondii tachyzoites to retinal vascular endothelium.

In the human host, infection with the protozoan parasite, Toxoplasma gondii, most commonly involves the eye and/or the brain. Previous work indicates a relative susceptibility of the human retinal vascular endothelium to infection with the T. gondii tachyzoite, which may contribute to this tissue localization. To facilitate the investigation of potential adhesive interactions between parasite and endothelium in the retina, we have modified the Woodruff-Stamper assay, originally described to study lymphocytic-endothelial binding. Vascular endothelium was identified in sections of human retina by Alexa Fluor 594-tagged anti-von Willebrand factor antibody. Binding of yellow fluorescent protein-expressing tachyzoites to endothelium under conditions of flow, simulated by rotation on an orbital shaker, was quantified in a masked fashion using imaging software. We observed multiple yellow spots in contact with Alexa Fluor 594-positive retina, indicating binding of T. gondii tachyzoites to retinal vascular endothelium. This modification of the Woodruff-Stamper assay provides an opportunity to evaluate potential host receptors for T. gondii on the retinal vascular endothelium. In addition, the assay suggests a methodology that could be used to examine adhesion of other microbes to microvasculature in different tissues.

Lack of association of matrix metalloproteinase 3 (MMP3) genotypes with ankylosing spondylitis susceptibility and severity.

OBJECTIVE: To study the linkage and association of ankylosing spondylitis (AS) with genotypes for matrix metalloproteinase 3 (MMP3), a gene located at chromosome 11q22.3 and lying within the 101-124 cM region observed in a recent genome-wide scan as a region associated with AS susceptibility. METHODS: MMP3 genotypes were examined in 229 pedigrees with AS, 131 sporadic AS cases and 87 Caucasian controls. Eight single-nucleotide polymorphisms (SNPs) were selected and genotyped using Taqman. Non-parametric linkage (NPL) analysis was conducted between the eight MMP3 SNPs and AS using the NPL-all statistic and two-point parametric linkage analysis using GeneHunter Plus. Unrelated AS cases and controls were compared using chi2 statistics, and family-based controls using the transmission disequilibrium test and pedigree disequilibrium test. RESULTS: None of the eight MMP3 SNPs were significantly associated with AS, either using the 131 sporadic cases alone or in analyses which combined these cases with the 226 unrelated affected AS patients derived from the pedigrees. Analysis of linkage disequilibrium (LD) demonstrated that seven of the eight SNPs studied were in strong LD except for rs626750, which is about 6 kb upstream of the 5' end of the gene. No significant linkage was observed using NPL and LODs in the families. No association was seen of any of the MMP3 SNPs with disease severity (defined by patient functioning), as measured either by the Bath Ankylosing Spondylitis Functional Index or the modified Health Assessment Questionnaire. CONCLUSION: These data suggest that MMP3 genotypes are not involved in AS susceptibility or severity.

Neurological concomitants of uveitis.

AIM: To describe the prevalence and types of neurological disease that occur in association with uveitis. METHODS: Retrospective review of medical records of patients attending a tertiary referral uveitis service over a 15 year period. RESULTS: Of 1450 patients with uveitis, 115 (7.9%) had neurological disease that was considered to be causally related to the eye inflammation. The most frequent neurological associations were Vogt-Koyanagi-Harada disease, primary central nervous system lymphoma, multiple sclerosis, and herpes virus infections. CONCLUSIONS: Neurological disease is common among patients attending a uveitis service. The distinctive characteristics of the uveal inflammation may be useful in diagnosing the neurological disease.