Relationship Between Disease Characteristics and Oral Radiologic Findings in Systemic Sclerosis: Results From a Canadian Oral Health Study.

OBJECTIVE: Systemic sclerosis (SSc; scleroderma) is associated with a wide periodontal ligament (PDL) and mandibular erosions. We investigated the clinical correlates of SSc with these radiologic abnormalities. METHODS: Subjects from the Canadian Scleroderma Research Group cohort underwent detailed radiologic examinations. Associations between radiologic abnormalities and clinical manifestations of SSc were examined with univariate and multivariate analyses. RESULTS: The study included 159 subjects; 90.6% were women, the mean ± SD age was 56 ± 10 years, diffuse disease was present in 28.3%, and mean ± SD disease duration was 13.7 ± 8.4 years. Widening of the PDL involving at least 1 tooth was present in 38% of subjects, and 14.5% had at least 1 site in the mandible with an erosion. In analyses adjusting for age, disease duration, sex, smoking, and education, we found significant associations between the number of teeth with widening of the PDL and disease severity assessed by the physician global assessment (PGA) (relative risk [RR] 1.19, 95% confidence interval [95% CI] 1.02-1.39, P = 0.028). Analyses replacing the PGA with the skin score, disease subset, or anti-topoisomerase I antibodies confirmed the relationship with indices of disease severity. There was no relationship between either the number of teeth with periodontal disease or the number of missing teeth, and the number of teeth with wide PDL. A smaller interdental distance (RR 0.89, 95% CI 0.82-0.97, P = 0.006), but not disease severity, facial skin score, or ischemia was associated with a larger number of erosions. CONCLUSION: In SSc, a wide PDL may reflect generalized overproduction of collagen, and mandibular erosions are related to local factors in the oral cavity.

The Canadian Systemic Sclerosis Oral Health Study IV: oral radiographic manifestations in systemic sclerosis compared with the general population.

OBJECTIVE: The aim of this study was to compare oral radiologic abnormalities associated with systemic sclerosis (SSc) against abnormalities in the general population. STUDY DESIGN: Patients with SSc and healthy controls were enrolled in a multi-site cross-sectional study. Included in the radiology examination were a panoramic radiograph, four bitewings, and an anterior mandibular periapical radiograph. Radiographs were evaluated by two oral and maxillofacial radiologists tested for interobserver and intraobserver reliability. Chi-squared tests, Fisher exact tests, and Mann Whitney U tests were used to summarize the radiologic manifestations of patients and controls. RESULTS: We assessed 163 SSc patients and 231 controls. Widening of the periodontal ligament space (PLS) (P < .001), with higher percentage of teeth with PLS widening (P < .001), was significantly more frequent in patients with SSc than in controls. The most significant differences between the two groups were found in the molars and premolars (P < .001). Moreover, 26% of the patients with SSc had a periapical PLS greater than 0.19 mm compared with 13% of the controls (P = .003). Patients with SSc had significantly more erosions compared with controls (14.5% vs. 3.6%; P < .001), mostly in the condyles (P = .022), coronoid processes (P = .005) and other locations (P = .012). CONCLUSION: Patients with SSc had more teeth with PLS widening and erosions of the mandible compared with controls.

The Canadian systemic sclerosis oral health study II: the relationship between oral and global health-related quality of life in systemic sclerosis.

OBJECTIVE: Both oral and global health-related quality of life (HRQoL) are markedly impaired in SSc. In this study we aimed to determine the degree of association between oral HRQoL and global HRQoL in SSc. METHODS: Subjects were recruited from the Canadian Scleroderma Research Group registry. Global HRQoL was measured using the Medical Outcomes Trust 36-item Short Form Health Survey (SF-36) and oral HRQoL with the Oral Health Impact Profile (OHIP). The Medsger Disease Severity Score was used to determine organ involvement. Multivariate regression models determined the independent association of the OHIP with the SF-36 after adjusting for confounders. RESULTS: This study included 156 SSc subjects. The majority (90%) were women, with a mean age of 56 years, mean disease duration 13.8 years (s.d. 8.5) and 29% of the subjects had dcSSc. Mean total OHIP score was 40.8 (s.d. 32.4). Mean SF-36 mental component summary (MCS) score was 49.7 (s.d. 11.1) and physical component summary (PCS) score was 37.0 (s.d. 10.7). In adjusted analyses, the total OHIP score was significantly associated with the SF-36 MCS and PCS, accounting for 9.7% and 5.6% of their respective variances. Measures of disease severity were not related to OHIP score. CONCLUSION: Oral HRQoL in SSc is independently associated with global HRQoL. Oral HRQoL, however, is not related to physician-assessed disease severity. This suggests that physicians may be disregarding issues related to oral health. HRQoL is an additional dimension of HRQoL not captured by generic instruments such as the SF-36.

2013 American College of Rheumatology/European League against rheumatism classification criteria for systemic sclerosis outperform the 1980 criteria: data from the Canadian Scleroderma Research Group.

OBJECTIVE: The goal of this study was to determine the sensitivity of the new 2013 classification criteria for systemic sclerosis (SSc; scleroderma) in an independent cohort of SSc subjects and to assess the contribution of individual items of the criteria to the overall sensitivity. METHODS: SSc subjects from the Canadian Scleroderma Research Group cohort were assessed. Sensitivity was determined in several subgroups of patients. In patients without the criterion of skin thickening proximal to the metacarpophalangeal (MCP) joints, we recalculated sensitivity after removing the individual criterion. RESULTS: A total of 724 SSc patients were included. Most were women (86%), mean age was 55.8 years, mean disease duration was 10.9 years, and 59% had limited cutaneous SSc (lcSSc). Overall, the sensitivity of the 2013 criteria was 98.3% compared to 88.3% for the 1980 criteria. This pattern was consistent among those with lcSSc (98.8% versus 85.6%), anticentromere antibodies (98.9% versus 79.8%), disease duration ≤3 years (98.7% versus 84.7%), and no skin involvement proximal to the MCP joints (97% versus 60%). In the latter subgroup, removing Raynaud's phenomenon and sclerodactyly from the criteria reduced the sensitivity to 77% and 79%, respectively. Removing both sclerodactyly and puffy fingers reduced the sensitivity to 62%. CONCLUSION: The 2013 SSc classification criteria classify more SSc patients than the 1980 criteria. The improvement in sensitivity is most striking in those with lcSSc, especially those without skin involvement proximal to the MCP joints. The addition of Raynaud's phenomenon and puffy fingers to the 2013 criteria accounts for important gains in sensitivity.

Relationship between disease characteristics and orofacial manifestations in systemic sclerosis: Canadian Systemic Sclerosis Oral Health Study III.

OBJECTIVE: Systemic sclerosis (SSc; scleroderma) is associated with decreased saliva production and interincisal distance, more missing teeth, and periodontal disease. We undertook this study to determine the clinical correlates of SSc with these oral abnormalities. METHODS: Subjects were recruited from the Canadian Scleroderma Research Group cohort. Detailed dental and clinical examinations were performed according to standardized protocols. Associations between dental abnormalities and selected clinical and serologic manifestations of SSc were examined. RESULTS: One hundred sixty-three SSc subjects were included: 90% women, mean ± SD age 56 ± 11 years, mean ± SD disease duration 14 ± 8 years, 72% with limited cutaneous disease, and 28% with diffuse cutaneous disease. Decreased saliva production was associated with Sjögren's syndrome-related autoantibodies (ß = -43.32; 95% confidence interval [95% CI] -80.89, -5.75), but not with disease severity (ß = -2.51; 95% CI -8.75, 3.73). Decreased interincisal distance was related to disease severity (ß = -1.02; 95% CI -1.63, -0.42) and the modified Rodnan skin thickness score (ß = -0.38; 95% CI -0.53, -0.23). The number of missing teeth was associated with decreased saliva production (relative risk [RR] 0.97; 95% CI 0.94, 0.99), worse hand function (RR 1.52; 95% CI 1.13, 2.02), and the presence of gastroesophageal reflux disease (GERD; RR 1.68 [95% CI 1.14, 2.46]). No clinical or serologic variables were correlated with periodontal disease. CONCLUSION: In SSc, diminished interincisal distance is related to overall disease severity. Decreased saliva production is related to concomitant Sjögren's syndrome antibodies. Tooth loss is associated with poor upper extremity function, GERD, and decreased saliva. The etiology of excess periodontal disease is likely multifactorial and remains unclear.

The Canadian systemic sclerosis oral health study: orofacial manifestations and oral health-related quality of life in systemic sclerosis compared with the general population.

OBJECTIVE: The aim of this study was to compare oral abnormalities and oral health-related quality of life (HRQoL) of patients with SSc with the general population. METHODS: SSc patients and healthy controls were enrolled in a multisite cross-sectional study. A standardized oral examination was performed. Oral HRQoL was measured with the Oral Health Impact Profile (OHIP). Multivariate regression analyses were performed to identify associations between SSc, oral abnormalities and oral HRQoL. RESULTS: We assessed 163 SSc patients and 231 controls. SSc patients had more decayed teeth (SSc 0.88, controls 0.59, P = 0.0465) and periodontal disease [number of teeth with pocket depth (PD) >3 mm or clinical attachment level (CAL) ≥5.5 mm; SSc 5.23, controls 2.94, P < 0.0001]. SSc patients produced less saliva (SSc 147.52 mg/min, controls 163.19 mg/min, P = 0.0259) and their interincisal distance was smaller (SSc 37.68 mm, controls 44.30 mm, P < 0.0001). SSc patients had significantly reduced oral HRQoL compared with controls (mean OHIP score: SSc 41.58, controls 26.67, P < 0.0001). Multivariate regression analyses confirmed that SSc was a significant independent predictor of missing teeth, periodontal disease, interincisal distance, saliva production and OHIP scores. CONCLUSION: Subjects with SSc have impaired oral health and oral HRQoL compared with the general population. These data can be used to develop targeted interventions to improve oral health and HRQoL in SSc.

Vitamin D status is associated with disease activity among rheumatology outpatients.

UNLABELLED: The co-existence of high prevalence of vitamin D inadequacy among Canadians and high prevalence of systematic autoimmune rheumatic diseases (SARDs) raise the question on relationship between the two situations. OBJECTIVE: To determine vitamin D status in known cases of common SARDs and compare to those with non-autoimmune diseases; further, to evaluate the impact of vitamin D on disease activity in rheumatoid arthritis (RA) cases. METHODS: In a retrospective case-control study design, we evaluated 116 patients in a community clinic classified in two groups, CONTROL GROUP: patients with non-rheumatic disease (n = 56), and Case group: those with rheumatic diseases (n = 60). We compared plasma vitamin D status (25(OH)D), indicators of disease activity and other potential confounders. Further, we determined factors associated with disease activity in RA cases. RESULTS: The plasma 25(OH)D was significantly lower in Case group (64.8 ± 29.8) compared to CONTROL GROUP (86.8 ± 37.7). High number of SARDs outpatients 56%) had considerably low plasma 25(OH)D concentration. RA cases with low plasma 25(OH)D had over five times higher risk of disease activity (OR = 5.15 95% CI 1.16, 22.9; p = 0.031). CONCLUSION: Inadequate vitamin D status in SARDs cases, along with considerably strong association with disease activity in RA cases, indicate the need for proper evaluation of vitamin D status in this clinical population. Moreover, appropriate training should be given to the patients to ensure the intake of the recommended amount of vitamin D per day through diet or supplement.

Antibodies to porphyromonas gingivalis are associated with anticitrullinated protein antibodies in patients with rheumatoid arthritis and their relatives.

OBJECTIVE: Anticitrullinated protein antibodies (ACPA) are relatively specific for rheumatoid arthritis (RA), and predate disease. The oral pathogen Porphyromonas gingivalis may play a role in breaking immune tolerance to citrullinated antigens. We studied a cohort of patients with RA and their relatives looking for associations between anti-P. gingivalis antibodies and ACPA. METHODS: Patients with RA (n = 82) and their relatives (n = 205) from a North American Native (NAN) population were studied, along with 47 NAN and 60 non-NAN controls. IgM and IgA rheumatoid factor (RF) were tested by nephelometry and ELISA. Second-generation anticyclic citrullinated peptide (anti-CCP2) isotypes and IgG anti-P. gingivalis lipopolysaccharides were tested by ELISA. HLA-DRB1 typing was performed by sequencing. Oral hygiene and smoking habits were assessed by questionnaires. RESULTS: Autoantibody frequency in patients with RA and relatives: ACPA 91% vs 19%, respectively; IgM RF 82% vs 17%; IgA RF 48% vs 22%. Anti-P. gingivalis levels were higher in patients with RA compared to relatives and controls (p = 0.005) and higher in ACPA-positive patients with RA than in ACPA-negative patients with RA (p = 0.04) and relatives (p < 0.001), but comparable in RF-positive and RF-negative patients and relatives. Poor oral hygiene and smoking were prevalent, but with no clear association with autoantibodies. Relatives with 2 shared-epitope alleles were more likely to be ACPA-positive (OR 2.5, p = 0.02). CONCLUSION: In a genetically predisposed population of NAN patients with RA and their relatives, anti-P. gingivalis antibodies were associated with ACPA. These findings suggest that immune responses to P. gingivalis may be involved in breaking immune tolerance to citrullinated antigens.

Immunogenetic risks of anti-cyclical citrullinated peptide antibodies in a North American Native population with rheumatoid arthritis and their first-degree relatives.

OBJECTIVE: To determine the prevalence of anti-cyclic citrullinated peptide (anti-CCP) antibodies in unaffected relatives of North American Native probands with rheumatoid arthritis (RA); and the associations of the shared epitope (SE) and HLA-DRB1*0901 with RA and anti-CCP antibodies. METHODS: The subjects were RA probands, affected relatives, unaffected first-degree (FDR) and more distant relatives, and unaffected controls from the same population. HLA-DRB1 typing was determined by DNA sequencing and anti-CCP antibodies were determined by ELISA. RESULTS: DRB1*0901, SE, and SE/DRB1*0901 genotypes were all associated with RA. SE/DRB1*0901, but not other SE genotypes, was associated with disease onset at age<16 years. The frequency of anti-CCP antibodies was 82% in RA probands, 17% in FDR, 11% in more distant relatives, and 3% in controls. Among unaffected relatives, a significant increased risk of anti-CCP was associated with SE/DRB1*0901 genotype, but not with SE. CONCLUSION: An independent association of the non-SE allele DRB1*0901 with RA was confirmed in this population, and this allele in combination with a SE allele was associated with younger age at disease onset. FDR of RA probands have a higher prevalence of anti-CCP antibodies than more distant relatives and unrelated controls, suggesting a gradient of risk for disease development. Immunogenetic risks may act early in disease pathogenesis at the level of initiation of RA autoantibody formation; however, it is not clear what additional genetic and environmental risks are involved in progression to clinical disease.

Demographic and clinical factors associated with physician service use in systemic sclerosis.

OBJECTIVE: To assess physician service use in a large sample of patients with systemic sclerosis (SSc), and to determine factors associated with physician use. METHODS: Our sample was a national SSc registry maintaining data on demographics (age, sex, race/ethnicity, education, income) and clinical factors (disease onset, organ involvement, etc.). Registry cohort members completed detailed questionnaires, and rheumatologists provided clinical assessments. We examined cross-sectional data from 397 patients who provided information on physician visits in the past 12 months. Patients were classified as high physician-users if they reported more than the median number (6) of physician visits in the past year. In multivariate logistic regressions, we assessed the independent effects of race/ethnicity, education, degree of skin involvement, comorbidity, and SF-36 scores on physician use. RESULTS: On average, subjects reported 3.8 visits per year to specialty physicians (SD 4.2) and 3.5 visits per year to family physicians (SD 4.3). Regression models suggested the following factors as independently associated with number of physician visits: high skin scores, greater comorbidity, and low physical component summary scores on the SF-36. CONCLUSION: There is evidence of independent relationships between clinical characteristics and physician use by patients with SSc.

Assessment of reproductive history in systemic sclerosis.

OBJECTIVE: To assess the number of live births in women whose systemic sclerosis (SSc) onset occurred during their reproductive years, and to compare this with general population rates. METHODS: Within the Canadian Scleroderma Research Group cohort, we identified 320 women whose SSc symptoms began prior to age 50 years. We determined the number of children born in the years following first onset of symptoms. We summed the years of followup from the time of first symptoms in subjects up to age 50 years (or oldest age attained, if the subject was age <49 years). We applied age-specific birth rates for Canadian women to these years of followup in order to determine the expected number of live births for the period. We then calculated the standardized incidence ratio (SIR) of observed to expected live births. RESULTS: In the 320 women studied, the number of live births over the interval since symptom onset was below the expected number (111 live births observed versus 140 expected; SIR 0.79, 95% confidence interval [95% CI] 0.65-0.95). This finding was more prominent in women with diffuse cutaneous disease versus limited cutaneous disease. The mean and median numbers of live births were similar across SSc subgroups based on organ involvement or cyclophosphamide exposure. In repeat analyses, including the reproductive period before SSc symptom onset, the ratio of observed to expected births was 1.23 (95% CI 1.13-1.33). CONCLUSION: Compared with the general population, fewer live births were noted in women with SSc, but this phenomenon was only apparent in the period after symptom onset.

Marked differences in fine specificity and isotype usage of the anti-citrullinated protein antibody in health and disease.

OBJECTIVE: Anti-citrullinated protein antibodies (ACPAs) display high association with rheumatoid arthritis (RA) and are implicated in its pathogenesis. The presence of ACPAs is known to precede the onset of RA. In order to identify the features that could confer its pathogenicity, we extensively characterized this antibody response in a unique North American native population of patients with RA and their unaffected relatives. METHODS: The levels of IgA, IgM, and IgG ACPAs, as well as IgM and IgA rheumatoid factor (RF), were measured in serum samples obtained from 81 patients with RA and 195 of their unaffected relatives. The isotype distribution, the fine specificity of the ACPA response, and its association with RF were compared in health and disease. RESULTS: ACPA positivity was observed in 19% of the healthy relatives and approximately 91% of the patients with RA. ACPA isotype usage was strikingly lower in unaffected relatives than in patients with RA (1-2 versus 5-6 isotypes). Fine specificity studies showed that reactivity to citrullinated fibrinogen and vimentin was present in sera from patients with RA, while it was virtually absent in their unaffected relatives. Finally, the ACPA and RF responses were associated in patients with RA but were discordant in their healthy relatives. Extended analyses revealed that the presence of ACPAs was associated with RA irrespective of RF status, while the association of RF with disease relied on its interaction with ACPAs. CONCLUSION: The fine specificity and isotype usage of the ACPA response are qualitatively different in health and disease. Epitope spreading and expansion of the isotype repertoire might be necessary for development of RA, and this could be facilitated by the presence of RF antibodies.

Smoldering rheumatoid arthritis: is the Canadian healthcare system neglecting a significant disease population?

OBJECTIVE: To investigate rheumatology practice in Canada with regard to evaluating disease activity status and treatment regimens in patients with rheumatoid arthritis (RA). It was hypothesized that patients with "smoldering" disease activity were not being adequately treated. METHODS: Rheumatologists were invited to participate by the Canadian Rheumatology Association in an audit entitled the Assessment in Rheumatology (AIR) program. From across Canada, 65 rheumatologists participated. One thousand five hundred ninety-six consecutive patients with RA seen in regular clinics were classified according to 4 states of disease activity: remission, controlled adequately, smoldering, and uncontrolled. Demographics (age, sex, geographic region), therapy (nonsteroidal antiinflammatory drugs, disease modifying antirheumatic drugs, biologicals, steroids), joint counts (tender/swollen), comorbidity, and treatment decisions at the time of the visit were recorded. Data were collected at the time of the visit with personal digital assistants (PDA) and aggregated, without personal identifiers, for analysis in SPSS. RESULTS: The majority of patients had "smoldering" (29%) or "uncontrolled" disease (23%), with the remainder in "remission" (15%) or "controlled adequately" (33%) at the time of their visit. Following the appointment, the uncontrolled group had a 100% increase (from 10.4% to 23.4%) in the addition of biological agents; however, there was no significant increase in the rates for those with smoldering disease (19.4% to 20.5%). CONCLUSION: Despite Canada's universal healthcare system, current treatment regimens may not be optimized on the basis of disease activity. A large proportion of patients with RA (29%) seen in Canadian rheumatology practices may be experiencing unnecessary disease for a variety of reasons.