Low prevalence of antibodies to glucose‐6‐phosphate isomerase in patients with rheumatoid arthritis and a spectrum of other chronic autoimmune disorders

Objective

Arthritis in the K/BxN mouse model results from pathogenic immunoglobulins that recognize glucose‐6‐phosphate isomerase (GPI), a glycolytic enzyme residing in the cytoplasm of all cells. Antibodies directed against GPI can, alone, transfer arthritis to healthy recipients. Previous experiments have revealed significant titers of anti‐GPI antibodies in the serum of many patients with rheumatoid arthritis (RA). We evaluated the generality of these observations in cohorts of patients with 12 different arthritic and chronic autoimmune diseases and in population‐matched healthy control subjects.

Methods

Anti‐GPI antibodies were assayed in 811 individual serum samples by enzyme‐linked immunosorbent assay with 2 forms of GPI, recombinant and native. Results were confirmed by immunoblotting.

Results

Several patients had significantly elevated anti‐GPI antibody titers, but without the prevalence or the specificity reported previously. Only 15% of RA patients had anti‐GPI antibodies (range 12–29% in different cohorts), with a higher prevalence in patients with active disease. Psoriatic arthritis, undifferentiated arthritis, and spondylarthropathy patients also displayed anti‐GPI antibodies at similar frequencies (12–25%). Similar titers were detected in a proportion (5–10%) of control subjects or patients with Crohn's disease or sarcoidosis. Very high titers were found in rare cases of RA and systemic lupus erythematosus.

Conclusion

No disease‐specific pattern of antibody positivity to GPI was apparent. While the antibody‐mediated mechanism at play in the mouse model may exemplify a generic mechanism for some forms of arthritis in humans, GPI itself does not appear to be a target common to the majority of RA patients.

     

Neuro-ophthalmic manifestations of hemangiopericytoma

PURPOSE: To describe the neuro-ophthalmic presentations of a rare intracranial tumor, hemangiopericytoma. METHODS: Retrospective multicenter case series. RESULTS: The neuro-ophthalmic and radiographic features of hemangiopericytoma are reviewed. The clinical presentation may mimic meningioma and the pre-operative distinction between meningioma and hemangiopericytoma is important because the evaluation, management, treatment, and prognosis differ significantly for the two lesions. CONCLUSION: We report five cases of intracranial hemangiopericytoma and review the neuro-ophthalmic findings of this uncommon entity.     

Quality assurance study of the use of preventative therapies in glucocorticoid-induced osteoporosis in early inflammatory arthritis: results from the CATCH cohort

Objective. To characterize steroid use and compliance with glucocorticoid-induced osteoporosis (GIOP) guidelines within a large early inflammatory arthritis cohort. Methods. Using the Canadian Early Arthritis Cohort (CATCH) database, patients with inflammatory arthritis on glucocorticoids (oral, IA and i.m.) were identified. Consecutive steroid exposure was defined as using glucocorticoids for two consecutive clinic visits (at least 90 days apart). The primary outcome was the proportion of patients receiving calcium, vitamin D and a bisphosphonate among patients treated with consecutive oral glucocorticoids. Results. Six hundred and fifty-five patients were in the CATCH database, where 273 patients were identified as glucocorticoid users, of whom 48% were on oral prednisone, 38% received i.m. or IA and 13% both. The median oral daily dose of prednisone was 5?mg (interquartile range 2.5-10). Consecutive users (CUs, n?=?78) compared with non-consecutive users (NUs, n?=?532) showed that CUs were older (56 vs 50 years, P?=?0.001); females were fewer (63% vs 74%, P?=?0.04), but a similar proportion were RF positive (51% in CU vs 56% in NU, P?=?0.73). For the primary outcome, rates of prophylaxis for users of consecutive oral steroids were as follows: 53% were treated with calcium, 47% with vitamin D and 25% were on a bisphosphonate. For users of oral prednisone at doses ≥7.5?mg/day, rates of prophylaxis were as follows: 64% were treated with calcium, 57% with vitamin D and 21% were on a bisphosphonate. Conclusion. Glucocorticoid therapy is frequently used in early inflammatory arthritis. The use of calcium, vitamin D or a bisphosphonate was low among chronic glucocorticoid users and illustrates the need for more diligence in patients receiving glucocorticoids to prevent GIOP.     

Gelatinase expression and activity in the synovium and skin of patients with erosive psoriatic arthritis

OBJECTIVE: Matrix metalloproteinases (MMP), especially the gelatinases (MMP2, MMP9), have been implicated in several features of inflammatory arthritis including angiogenesis and bone erosions. We examined the expression and activity of the gelatinases and their regulators in psoriatic skin and synovium using tissue immunohistochemistry and a sensitive tissue based zymographic technique. METHODS: Lesional and perilesional skin biopsies and synovial samples obtained by closed needle biopsy from 15 patients with erosive psoriatic arthritis (PsA) were analyzed by immunohistochemistry for the expression of the gelatinases and their regulators, tissue inhibitor of metalloproteinase 1 and 2 (TIMP-1, TIMP-2) and membrane type metalloproteinases (MTI-MMP. MT2-MMP), using immunohistochemistry. Synovial tissue from 8 patients with erosive rheumatoid arthritis (RA) was used as a comparison. MMP tissue expression was quantified by 2 blinded independent observers. Immunohistochemical data are reported as the mean percentage positive cells per total nucleated cells in 10 high power fields +/- SD. Functional activity of the gelatinases was measured using a sensitive tissue based zymography technique and corrected for protein content. Zymography data are presented as ng/mg +/- SE. RESULTS: MMP expression was greater in the synovial lining layer (LL) than in the synovial sublining layer (SL) in both PsA and RA tissue for most MMP except collagenase I (MMPI), which was equally distributed between the LL and SL. Expression of MMP or their regulators did not differ between PsA synovial membrane (SM) and RA SM in LL. Moreover, although latent gelatinase A (MMP2) staining in PsA SM was equivalent to RA SM, increased gelatinase A activity was found in PsA SM over RA SM using zymography L82.4 (SD 62.8) vs 10.1 (SD 1.7); p = 0.02]. Compared to PsA SM, lesional skin had lower levels of MT1-MMP (MMP14) (1.4 +/- 1.7 vs 15.7 +/- 8.4; p = 0.009) and MT2-MMP (MMP15) (12.1 +/- 8.7 vs 21.6 +/- 9.9; p = 0.001). CONCLUSION: We characterized the expression and activity of gelatinases in PsA and demonstrate that gelatinase activity in SM of PsA patients with erosive disease is comparable to if not greater than that in RA synovium.     

Familial seropositive rheumatoid arthritis in North American Native families: effects of shared epitope and cytokine genotypes

OBJECTIVE: A number of North American native (NAN) populations have high prevalence rates of both rheumatoid arthritis (RA) and the shared epitope (SE). We examined the phenotype and familial incidence of RA in a NAN population, and investigated how the SE and cytokine genes may affect disease risk within affected families. METHODS: NAN patients with seropositive RA or polyarthritis rheumatoid factor (RF) positive juvenile idiopathic arthritis (JIA) were identified from clinical databases. Patients were recruited consecutively as they presented for clinic visits. Family pedigrees were constructed and consenting relatives were interviewed and examined. The risk of RA within families was calculated by multiple logistic regression. Input variables were the SE and cytokine genotypes. Probands and affected relatives were entered as the affected group, and unaffected relatives within families as the unaffected group. Results were confirmed among unrelated subjects, i.e., unrelated patients and unaffected relatives of other probands. RESULTS: The familial prevalence of RA was 0.50 (95% confidence intervals 0.30, 0.70) among 28 families studied. The interleukin 10 (IL-10) promoter -1082 G/A genotype decreased the odds of RA relative to the A/A genotype in affected families (OR 0.247, 95% CI 0.081, 0.751; p = 0.014) and among unrelated subjects (OR 0.203, 95% CI 0.064, 0.640; p = 0.006). The G/G genotype yielded an OR of 0.093 (95% 0.013, 0.676; p = 0.019) among unrelated subjects. The SE had no effect in these calculations. CONCLUSION: There was a high familial prevalence of RA in this NAN cohort. In susceptible NAN families, the risk of RA was reduced by IL-10 genotypes, whereas the SE did not affect risk. Study of healthy NAN controls is required to determine if these conclusions apply to this NAN population as a whole.     

High Adherence to System‐Level Performance Measures for Rheumatoid Arthritis in a National Early Arthritis Cohort Over Eight Years

Objective

To assess adherence to 3 system‐level performance measures in a national early rheumatoid arthritis (RA) cohort.

Methods

Patients enrolled in the Canadian Early Arthritis Cohort (2007–2015) who met 1987 or 2010 American College of Rheumatology/European League Against Rheumatism criteria with <1 year of symptom duration and ≥1 year of followup after enrollment were included. Performance measures assessed were the percentage of RA patients seen in yearly followup, and the number of gaps between visits of >12 or >14 months, the percentage of RA patients treated with a disease‐modifying antirheumatic drug (DMARD), and days from RA diagnosis to initiation of a DMARD. Results are shown stratified by enrollment year to assess for temporal changes in performance.

Results

A total of 1,763 early RA patients were included (mean age 54 years, 73% female, and 82% white). At enrollment, mean ± SD disease duration was 6 ± 3 months, and Disease Activity Score in 28 joints was 5.1 ± 1.5. Over 8 years, the proportion of patients seen in annual followup declined from 100% to 91%. Over followup, 42% of patients had 0 gaps in care of >12 months, and 64% had 0 gaps >14 months. The percentage of DMARD‐treated early RA patients was and remained high (95–87%), and the percentage receiving DMARDs within 14 days of diagnosis was 75%. Median time‐to‐DMARD therapy was 1 day, indicating DMARDs were initiated at diagnosis (90th percentile 93 days).

Conclusion

There was evidence of high adherence to system‐level performance measures in this early RA cohort following a protocol. Small declines in performance were noted with increasing length of patient followup. Our findings are useful for performance measure benchmarking.     

A distinct multicytokine profile is associated with anti-cyclical citrullinated peptide antibodies in patients with early untreated inflammatory arthritis

OBJECTIVE: Early inflammatory arthritis is clinically heterogenous and biologically-based indicators are needed to distinguish severe from self-limited disease. Anti-cyclical citrullinated peptides (CCP) have been identified as potential prognostic markers in early arthritis cohorts. Since cytokine networks are known to play a critical role in the pathogenesis of rheumatoid arthritis (RA) and other forms of inflammatory arthritis, a panel of pro- and antiinflammatory cytokines was measured to identify biologically-based subsets of early arthritis, relating cytokine profiles to clinical measures and to the presence of RA-associated autoantibodies. METHODS: Plasma concentrations of cytokines [interleukin 1beta (IL-1beta), IL-2, IL-4, IL-5, IL-6, IL-7, CXCL8 (IL-8), IL-10, IL-12p70, IL-13, IL-17, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-g (IFN-g), CCL2 (monocyte chemoattractant protein-1, MCP-1), CCL4 (MIP-1beta), and tumor necrosis factor-a (TNF-a)] were measured in patients with early, untreated inflammatory arthritis [symptom duration < or = 12 months; > or = 1 swollen joint; RA, n = 41; undifferentiated arthritis (UA), n = 23]. Cytokine expression patterns were determined using cluster analysis. RESULTS: Both pro- and antiinflammatory cytokines were elevated in patients over controls (n = 21). RA clustered into subgroups based solely on cytokine profiles. The "mild" RA subgroup (n = 23) had higher CCL4 (MIP-1beta), CXCL8 (IL-8), IL-2, IL-12, IL-17, IL-5, and IL-10 levels, lower IL-6, IFN-g, GM-CSF, and IL-4 levels, less CCP positivity (52% vs 82%; p < 0.05), and lower CCP titers [71 (78) vs 153 (94); p < 0.01], but similar erythrocyte sedimentation rate, C-reactive protein, and joint counts compared to the "severe" RA groups. CCL4 (MIP-1beta), IL-13, IL-12, TNF-a, and IL-4 best distinguished the groups. Combining UA with RA samples preserved cytokine subgroups and strengthened the autoantibody associations. Fewer UA patients in the "mild" cluster (n = 16) were RF-positive (24% vs 100%; p < 0.002) or CCP-positive (24% vs 66%; p < 0.08) compared to the "severe" group. CONCLUSION: Early untreated inflammatory arthritis can be categorized into distinct subgroups based on cytokine profiles. These subgroups are associated with CCP and RF autoantibodies. Integration of cytokine profiles with autoantibody status may assist prognostication and treatment decisions in these patients.