Risk of fragility fracture among patients with sarcoidosis: a population-based study 1976-2013.

Incidence of fragility fracture of a population-based cohort of 345 patients with sarcoidosis was compared with age and sex-matched comparators. The incidence of fragility fracture was higher among patients with sarcoidosis with hazard ratio (HR) of 2.18. INTRODUCTION: Several chronic inflammatory disorders increase the risk of fragility fracture. However, little is known about the risk of fragility fracture in patients with sarcoidosis. METHODS: This study was conducted using a previously identified population-based cohort of 345 patients with incident sarcoidosis from Olmsted County, Minnesota. Diagnosis of sarcoidosis required physician diagnosis supported by biopsy showing non-caseating granuloma, radiographic evidence of intrathoracic sarcoidosis, and compatible clinical presentations without evidence of other granulomatous diseases. Sex and age-matched subjects randomly selected from the same underlying population were used as comparators. Medical records of cases and comparators were reviewed for baseline characteristics and incident fragility fracture. RESULTS: Fragility fractures were observed in 34 patients with sarcoidosis, corresponding to a cumulative incidence of 5.6% at 10 years, while 18 fragility fractures were observed among comparators for a cumulative incidence of 2.4% at 10 years. The HR of fragility fractures among cases compared with comparators was 2.18 (95% confidence interval [CI], 1.23-3.88). The risk of fragility fracture by site was significantly higher among patients with sarcoidosis, and was due to a higher rate of distal forearm fracture (HR 3.58; 95% CI 1.53-8.40). Statistically non-significant increased risk was also observed in proximal femur (HR 1.66; 95% CI 0.45-6.06) and proximal humerus (HR 3.27; 95% CI 0.66-16.21). Risk of vertebral fracture was not increased (HR 1.00; 95% CI 0.32-3.11). CONCLUSION: Patients with sarcoidosis have an increased risk of fragility fracture which is primarily driven by the higher incidence of distal forearm fracture.

Epidemiology of cutaneous sarcoidosis, 1976-2013: a population-based study from Olmsted County, Minnesota.

BACKGROUND: The epidemiology of cutaneous sarcoidosis is not well-characterized as only referral-based studies are available. OBJECTIVES: To characterize the epidemiology of cutaneous sarcoidosis, with emphasis on annual incidence and clinical characteristics, from 1976 to 2013. METHODS: Inception cohorts of patients with incident isolated cutaneous sarcoidosis and incident systemic sarcoidosis with cutaneous involvement in 1976-2013 in Olmsted County, Minnesota, United States were identified based on comprehensive individual medical record review. Inclusion in the isolated cutaneous sarcoidosis cohort required physician diagnosis and skin biopsy showing non-necrotizing granuloma. Inclusion in the systemic sarcoidosis with cutaneous involvement cohort required presence of systemic sarcoidosis and cutaneous lesions. Presence of systemic sarcoidosis was determined by physician diagnosis supported by histopathology of non-necrotizing granuloma, characteristic radiologic features of intrathoracic sarcoidosis and exclusion of other granulomatous diseases. Cutaneous lesions were defined as either sarcoidosis-specific or non-specific. RESULTS: There were 62 cases with sarcoidosis-specific cutaneous lesions (36 cases of sarcoidosis-specific cutaneous lesions and 26 cases of isolated cutaneous sarcoidosis) which corresponded to an incidence of 1.9 per 100 000 population. The female to male ratio was 2.1 : 1. Plaques, papules and subcutaneous nodules were the most commonly observed cutaneous lesions. There was no significant difference in cutaneous presentation between those who had isolated skin disease and those who had skin disease in association with systemic sarcoidosis. Prognosis of cutaneous sarcoidosis was favourable, as over 90% of patients had a good response to either glucocorticoids, hydroxychloroquine or tetracycline antibiotics. This study has a significant limitation, in that the studied population was predominantly Caucasians who generally have a lower prevalence of skin disease. CONCLUSIONS: The incidence of sarcoidosis-specific cutaneous lesions was about 1.9 per 100 000 population with female predominance. The cutaneous presentations were similar among those with and without systemic sarcoidosis.

Cardiovascular risk profile at the onset of psoriatic arthritis: a population-based cohort study.

OBJECTIVE: The role of cardiovascular disease (CVD) risk factors in psoriatic arthritis (PsA) is poorly understood. We examined the prevalence of CVD risk factors at initial onset of PsA and compared the observed incidence of CVD events with that predicted by the Framingham Risk Score (FRS) to determine its applicability in this patient population. METHODS: A population-based incidence cohort of 158 patients with PsA who fulfilled Classification of Psoriatic Arthritis criteria for PsA in 1989-2008 was assembled. Medical records were reviewed to ascertain CVD risk factors and CVD events. Future risk of CVD was estimated using the FRS algorithm. RESULTS: Mean age was 43.4 years (range 19-74 years), 61% were men, and 44% were obese (body mass index ≥30 kg/m(2) ). Fifty-four patients (34%) presented with ≥2 CVD risk factors at PsA incidence. Among 126 patients ages ≥30 years at PsA incidence with no prior history of CVD, 33% had an FRS ≥10%, with 11% having an FRS ≥20%, and 18 experienced a CVD event in the first 10 years of disease duration. The 10-year cumulative incidence of CVD events was 17% (95% confidence interval [95% CI] 10%-24%), almost twice as high as the predicted incidence based on the FRS (standardized incidence ratio 1.80, 95% CI 1.14-2.86; P = 0.012). CONCLUSION: The majority of newly diagnosed PsA patients have a >10% risk of CVD within 10 years of PsA incidence. The CVD risk in these patients is higher than expected and underestimated by the FRS.

The incidence of giant cell arteritis in Olmsted County, Minnesota, over a 60-year period 1950-2009.

OBJECTIVE: To assess the incidence of giant cell arteritis (GCA) in the era from 2000 to 2009. METHOD: We extended the previously identified population-based cohort of Olmsted County, Minnesota residents who fulfilled 1990 American College of Rheumatology (ACR) criteria for GCA for earlier decades during 1950-1999. RESULTS: In 2000-2009, 74 cases of GCA were identified (mean age 78.1 years; 80% women; 79% temporal artery biopsy positive; seven included based on radiological criteria). The incidence of GCA was 19.8 per 100,000 population. CONCLUSIONS: The GCA incidence rates have remained steady since 1970 and the age at incidence, which was progressively increasing, seems to have reached a plateau.

Safety of biological therapies following rituximab treatment in rheumatoid arthritis patients.

OBJECTIVE: To assess the safety of biological disease-modifying antirheumatic drugs (DMARD) in rheumatoid arthritis (RA) patients following rituximab. METHODS: RA patients who participated in an international rituximab clinical trial programme were included. Patients who had received one or more rituximab courses and entered safety follow-up (SFU) were permitted additional biological DMARD. Serious infection events (SIE) were collected. RESULTS: Of 185 of 2578 patients who entered SFU and received another biological DMARD, 88.6% had peripheral B-cell depletion at the time of initiation of another biological agent. Thirteen SIE (6.99 events/100 patient-years) occurred following rituximab but before another biological DMARD and 10 SIE (5.49 events/100 patient-years) occurred following another biological DMARD. SIE were of typical type and severity for RA patients. 153 had received one or more tumour necrosis factor inhibitor(s). No fatal or opportunistic infections occurred. CONCLUSIONS: In this analysis, treatment with biological DMARD after rituximab was not associated with an increased serious infection rate. Sample size with limited follow-up restricts definitive conclusions.

Etanercept therapy in rheumatoid arthritis and the risk of malignancies: a systematic review and individual patient data meta-analysis of randomised controlled trials.

PURPOSE: Tumour necrosis factor (TNF) plays an important role in inflammation and may affect tumour growth control. To assess the risk of malignancy with etanercept, a fusion protein that inhibits TNF action, a meta-analysis was performed using individual patient data from randomised controlled trials (RCT) in patients with rheumatoid arthritis (RA). METHODS: A search was conducted of bibliographic databases, abstracts from annual meetings and any unpublished studies on file with manufacturers of etanercept to December 2006. Only RCT of etanercept used for 12 weeks or more in patients with RA were included. Nine trials met the inclusion criteria. To adjudicate endpoints, the case narratives of potential cases were reviewed. Patient-level data were extracted from the clinical trials databases. RESULTS: The nine trials included 3316 patients, 2244 who received etanercept (contributing 2484 person-years of follow-up) and 1072 who received control therapy (1051 person-years). Malignancies were diagnosed in 26 patients in the etanercept group (incidence rate (IR) 10.47/1000 person-years) and seven patients in the control group (IR 6.66/1000 person-years). A Cox's proportional hazards, fixed-effect model stratified by trial yielded a hazard ratio of 1.84 (95% CI 0.79 to 4.28) for the etanercept group compared with the control group. CONCLUSIONS: In this analysis, the point estimate of malignancy risk was higher in etanercept-treated patients, although the results were not statistically significant. The approach of obtaining individual patient data of RCT in cooperation with trial sponsors allowed important insights into the methodological advantages and challenges of sparse adverse event data meta-analysis.

Comparison of disease activity measures for anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis.

AIM: Currently, several different instruments are used to measure disease activity and extent in clinical trials of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, leading to division among investigative groups and difficulty comparing study results. An exercise comparing six different vasculitis instruments was performed. METHODS: A total of 10 experienced vasculitis investigators from 5 countries scored 20 cases in the literature of Wegener granulomatosis or microscopic polyangiitis using 6 disease assessment tools: the Birmingham Vasculitis Activity Score (BVAS), The BVAS for Wegener granulomatosis (BVAS/WG), BVAS 2003, a Physician Global Assessment (PGA), the Disease Extent Index (DEI) and the Five Factor Score (FFS). Five cases were rescored by all raters. RESULTS: Reliability of the measures was extremely high (intraclass correlations for the six measures all = 0.98). Within each instrument, there were no significant differences or outliers among the scores from the 10 investigators. Test/retest reliability was high for each measure: range = 0.77 to 0.95. The scores of the five acute activity measures correlated extremely well with one another. CONCLUSIONS: Currently available tools for measuring disease extent and activity in ANCA-associated vasculitis are highly correlated and reliable. These results provide investigators with confidence to compare different clinical trial data and helps form common ground as international research groups develop new, improved and universally accepted vasculitis disease assessment instruments.

Management guidelines and outcome measures in giant cell arteritis (GCA).

Giant cell arteritis (GCA) is a common form of vasculitis that predominantly affects the elderly. Cranial symptoms and elevated inflammatory markers are suggestive of the condition and the diagnosis is usually established by temporal artery biopsy. Corticosteroids are the mainstay of treatment for GCA and prolonged therapy is often necessary. Disease relapses and steroid-related adverse effects, however, are common. Serious complications of the disease may include visual loss, stroke, and aortic involvement with aneurysm formation.

Citrullination in extra-articular manifestations of rheumatoid arthritis.

BACKGROUND: Anti-citrullinated protein antibodies have been detected with high specificity in serum of patients with rheumatoid arthritis (RA), and citrullination of proteins may play a key role in the pathogenesis of RA. We therefore investigated the presence of citrullination in two extra-articular manifestations of RA, interstitial pneumonia (IP) and rheumatoid nodules. METHODS: Open-lung biopsy specimens from patients with RA-associated IP (n = 18), idiopathic IP (n = 20) and controls (n = 10), as well as specimens of rheumatoid nodules from 26 patients, were examined. All sections were incubated with an anti-modified citrulline antibody. Masked scoring of stained sections and analysis of results by stratification according to demographic and clinical characteristics was performed. RESULTS: Presence of citrulline could be detected in eight lung specimens of patients with RA-associated IP (44%) and nine patients with idiopathic IP (46%). Conversely, lung tissue from control patients showed weak extracellular citrullination in only two cases (20%). Citrullination did not show any significant associations with demographic or clinical characteristics such as age, gender, smoking habits, disease severity, histological subtype, degree of inflammation or steroid use. Rheumatoid nodules were citrulline positive in a majority of cases (70%). CONCLUSION: Citrullination is present in extra-articular manifestations of RA such as IP and nodules. In contrast to the high specificity of anti-citrulline antibodies in RA, citrullination is not only restricted to RA but can also be observed in idiopathic IP. Whether citrullination significantly contributes to the initiation or perpetuation of autoimmunity or merely reflects ongoing inflammation remains to be clarified.

Severe extra-articular disease manifestations are associated with an increased risk of first ever cardiovascular events in patients with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis is associated with increased cardiovascular mortality and morbidity. OBJECTIVE: To assess the effect of severe extra-articular rheumatoid arthritis (ExRA) manifestations on the risk of cardiovascular disease (CVD) in patients with rheumatoid arthritis. METHODS: Patients with ExRA (n = 81) according to predefined criteria and controls (n = 184) without evidence of extra-articular disease were identified from a large research database of patients with rheumatoid arthritis. In a structured review of the medical records, the occurrence and the date of onset of clinically diagnosed CVD events were noted. Cox proportional hazards models were used to estimate the effect of ExRA on the risk of first ever CVD events after the diagnosis of rheumatoid arthritis. ExRA manifestations were modelled as time-dependent covariates, with adjustment for age, sex and smoking at the diagnosis of rheumatoid arthritis. Onset of erosive disease and rheumatoid factor seropositivity were entered as time-dependent variables. Patients were followed until onset of CVD, death or loss to follow-up. RESULTS: ExRA was associated with a significantly increased risk of first ever CVD events (p<0.001), and also with an increased risk of new-onset coronary artery disease, adjusted for age, sex and smoking (hazard ratio (HR): 3.16; 95% confidence interval (95% CI: 1.58 to 6.33). The association between ExRA and any first ever CVD event remained significant when controlling for age, sex, smoking, rheumatoid factor and erosive disease (HR: 3.25; 95% CI: 1.59 to 6.64). CONCLUSION: Severe ExRA manifestations are associated with an increased risk of CVD events in patients with rheumatoid arthritis. This association is not due to differences in age, sex, smoking, rheumatoid factor or erosive joint damage. It is suggested that systemic extra-articular disease is a major determinant of cardiovascular morbidity in rheumatoid arthritis.

Morphological and quantitative assessment of mast cells in rheumatoid arthritis associated non-specific interstitial pneumonia and usual interstitial pneumonia.

BACKGROUND: The role of mast cells in extra-articular manifestations of rheumatoid arthritis (RA) has not been studied so far. OBJECTIVE: To characterise and quantify mast cells in RA associated interstitial pneumonia (IP) by an immunohistological study. METHODS: Lung biopsy specimens from 15 patients with RA associated IP, 12 patients with idiopathic IP, and 5 control patients were stained with antibodies directed against tryptase (mast cell marker). Morphological characterisation of stained specimens was carried out and staining was quantified by computer assisted image analysis. RESULTS: Tryptase staining showed the marked presence of mast cells in idiopathic IP and in RA associated IP. A significant difference in stained tissue area was found between RA associated IP (2.6%, IQR 2.0-3.2%, p = 0.015) and idiopathic IP (3.1%, IQR 1.8-3.7%, p = 0.003) compared with control tissue specimens (1.0%, IQR 0.7-1.5%). The extent of mast cell infiltration correlated well and inversely with pulmonary function variables. CONCLUSIONS: Mast cell infiltrates are present in RA associated IP and idiopathic IP. The observed correlation of pulmonary function and mast cell numbers would be consistent with the proposed role of mast cell mediators in the promotion of fibrogenesis. The findings provide a rationale for studying functional aspects of mast cell involvement in the pathogenesis of RA associated lung disease.

Testicular involvement in rheumatoid vasculitis.

We report the case of an adult with rheumatoid arthritis (RA) who developed biopsy-confirmed testicular involvement of vasculitis in the setting of mononeuritis multiplex. This unusual presentation of rheumatoid vasculitis was successfully treated with a combination of corticosteroids and cyclophosphamide.

Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years.

OBJECTIVE: To investigate the trends in incidence of extra-articular rheumatoid arthritis (ExRA) in a well defined community based cohort of patients with rheumatoid arthritis (RA), and to examine possible predictors of ExRA occurrence. METHODS: Using the resources of the Rochester Epidemiology Project, a retrospective medical record review was conducted of a cohort of 609 cases of RA in Olmsted County, MN, diagnosed during 1955-94. These cases had been previously classified using the ACR 1987 criteria for RA. Patients were followed up from 1955 to 2000 (median follow up 11.8 years; range 0.1-42.8), and incident ExRA manifestations were recorded according to predefined criteria. Time to first presentation of ExRA was compared in patients with RA by decade of diagnosis. Possible ExRA risk factors were identified in case record reviews. RESULTS: ExRA occurred in 247 patients (40.6%). A subgroup of 78 patients (12.8%) had ExRA manifestations considered to be severe in a previous study from Malmö, Sweden. The incidence of severe ExRA did not change significantly over the decades (p=0.165). In a multivariate analysis the main predictors of severe ExRA were smoking at RA diagnosis (risk ratio (RR)=2.94; 95% confidence interval (95% CI) 1.68 to 5.13) and early disability (Steinbrocker class III-IV at diagnosis) (RR=2.45; 95% CI 1.51 to 4.00). The effect of smoking overwhelmed the weaker effect of rheumatoid factor seropositivity. CONCLUSION: There was no decrease in the incidence of extra-articular manifestations in patients with RA diagnosed up to 1995. Smoking and early disability are independent risk factors for extra-articular RA.

Fatal sepsis in a patient with rheumatoid arthritis treated with etanercept.

Patients with long-standing, severe, erosive rheumatoid arthritis who have extra-articular manifestations and have undergone joint replacement surgery are at increased risk for serious infection and premature mortality. New therapies, including cytokine antagonists, hold great promise for improving the course of rheumatoid arthritis. However, they have powerful anti-inflammatory effects that may mask symptoms of serious infection. We report a case of fatal pneumococcal sepsis occurring in a 37-year-old woman with rheumatoid arthritis treated with the tumor necrosis factor antagonist etanercept and suggest management strategies for early detection and management of this complication.

Survivorship in a population based cohort of patients with Sjögren's syndrome, 1976-1992.

OBJECTIVE: Sjögren's syndrome (SS) has been associated with development of lymphoid malignancies and other significant medical complications, but the effect of SS on survival in a population based sample has not been reported. We analyzed survival in an incidence cohort of patients diagnosed with SS in residents of Olmsted County, Minnesota, USA, between 1976 and 1992. METHODS: All records of physician diagnosed SS were reviewed, as well as all records from patients diagnosed with xerostomia and keratoconjunctivitis sicca, and records of patients with rheumatoid arthritis (RA) and systemic lupus erythematosus. The case definition for SS required 2 of 3 criteria: keratoconjunctivitis sicca, xerostomia, or serologic abnormality. Confounding illnesses were excluded. All patients were white. RESULTS: Of the 74 cases of SS identified, 50 (67%) had primary SS and 24 (33%) secondary SS. An average of 7.2 years of followup was available for patients with primary SS and 9.9 years for patients with secondary SS. Compared with the general population, patients with SS had increased mortality (p = 0.04). When patients with primary and secondary SS were studied separately, increased mortality was found in patients with secondary SS (p < 0.005) but not primary SS (p = 0.86). CONCLUSION: In this population based cohort, patients with primary SS did not have increased mortality. However, mortality may have been increased in patients with secondary SS, the majority of whom had RA.