Autoantibodies Targeting Ficolin‐2 in Systemic Lupus Erythematosus Patients With Active Nephritis

Objective

Systemic lupus erythematosus (SLE) is a multisystem inflammatory disease characterized by the production of various autoantibodies. The aim of this study was to investigate the presence of anti–ficolin‐2 antibodies in SLE patients and to evaluate the association between the levels of these autoantibodies, clinical manifestations, and disease activity.

Methods

This is a comparative study using a cohort of 165 SLE patients and 48 healthy subjects. SLE patients were further divided into 2 groups (low disease activity [SLE Disease Activity Index (SLEDAI) score ≤4, n = 88] and high disease activity [SLEDAI score >4, n = 77]). Clinical manifestations were defined according to the physician in charge. Active lupus nephritis (LN) was documented by kidney biopsy. Detection of anti–ficolin‐2 antibodies was performed by enzyme‐linked immunosorbent assay.

Results

Levels of anti–ficolin‐2 autoantibodies were significantly higher in SLE patients as compared to healthy subjects and associated with SLEDAI score. They were found to be positive in 61 of 165 SLE patients (37%). The presence of anti–ficolin‐2 antibodies was significantly related only to renal involvement, with a very high prevalence (86%) of anti–ficolin‐2 antibodies in SLE patients with active LN. Patients with active proliferative LN had significantly more positive anti–ficolin‐2 antibodies than those with nonproliferative LN. The combination of anti–ficolin‐2, anti–ficolin‐3, and anti‐C1q demonstrated a very high specificity (98%) for the diagnosis of active LN.

Conclusion

Our results support the usefulness of anti–ficolin‐2 as a complementary serologic biomarker for the diagnosis of active lupus with renal manifestations.

     

Association Between Anti–Citrullinated Fibrinogen Antibodies and Coronary Artery Disease in Rheumatoid Arthritis

Objective

Antibodies against citrullinated fibrinogen (anti–Cit‐fibrinogen) have been implicated in rheumatoid arthritis (RA) and associated with cardiovascular risk in RA. The objective of this study was to examine the association between anti–Cit‐fibrinogens and coronary artery disease (CAD) outcomes.

Methods

We performed the study in an RA cohort based in a large academic institution linked with electronic medical record data containing information on CAD outcomes from medical record review. Using a published bead‐based assay method, we measured 10 types of anti–Cit‐fibrinogens. We applied a score test to determine the association between the anti–Cit‐fibrinogens as a group with CAD outcomes. Principal components analysis (PCA) was performed to assess whether the anti–Cit‐fibrinogens clustered into groups. Each group was then additionally tested for association with CAD. Sensitivity analyses were also performed using a published International Classification of Disease, Ninth Revision code group for ischemic heart disease (IHD) as the outcome.

Results

We studied 1,006 RA subjects (mean ± SD age 61.0 ± 13.0 years; 72.2% anti–cyclic citrullinated peptide positive). As a group, anti–Cit‐fibrinogen was associated with CAD (P = 1.1 × 10^?4). From the PCA analysis, we observed 3 main groups, of which only 1 group, containing 7 of the 10 anti–Cit‐fibrinogens, was significantly associated with CAD outcomes (P = 0.015). In the sensitivity analysis, all anti–Cit‐fibrinogens as a group remained significantly associated with IHD (P = 2.9 × 10^?4).

Conclusion

Anti–Cit‐fibrinogen antibodies as a group were associated with CAD outcomes in our RA cohort, with the strongest signal for association arising from a subset of the autoantibodies.

     

Chronic relapsing homologous collagen‐induced arthritis in DBA/1 mice as a model for testing disease‐modifying and remission‐inducing therapies

Objective

To test whether the chronic relapsing arthritis induced by immunizing DBA/1 mice with homologous type II collagen is a valuable model for testing disease‐modifying antiarthritic drugs.

Methods

Six‐week‐old male DBA/1 mice were immunized with murine type II collagen in Freund's complete adjuvant, resulting in a chronic relapsing polyarthritis in >80% of the mice 4 weeks after immunization. At the onset of clinical arthritis, mice were treated for 4 weeks with different treatments, including anti–tumor necrosis factor (anti‐TNF) and anti–interleukin‐12 (anti–IL‐12) antibodies, salbutamol, or indomethacin. Alternatively, treatment was administered as a pulse at the beginning of clinical arthritis. Pulse treatments tested included anti‐CD3 in combination with anti‐TNF, anti‐TNF alone, and anti‐CD4, either alone or in combination with anti‐TNF. After 4 weeks of arthritis, mice were killed and hind paws were assessed histologically for joint damage.

Results

Anti‐TNF and salbutamol both suppressed clinical arthritis more effectively than indomethacin and, moreover, protected the joints from damage, whereas indomethacin did not. Anti–IL‐12 treatment initiated after the onset of clinical symptoms accelerated disease. Pulse therapy with anti‐CD3 plus anti‐TNF was found to induce remission, clinically as well as histologically, whereas a pulse with either anti‐CD4, anti‐TNF, or the combination of anti‐CD4 plus anti‐TNF was less effective.

Conclusion

Chronic relapsing homologous collagen‐induced arthritis is a valuable model for identifying remission‐inducing antiarthritic drugs and has predictive value with respect to their joint‐protective potency.

     

Tuberculosis Risk in Ankylosing Spondylitis,Other Spondyloarthritis,and Psoriatic Arthritis in Sweden: A Population‐Based Cohort Study

Objective

Rheumatoid arthritis is a risk factor for tuberculosis (TB), particularly following treatment with biologic agents. Since these therapies are increasingly used in ankylosing spondylitis (AS), other types of spondyloarthritis (SpA), and psoriatic arthritis (PsA), we investigated the corresponding TB risks in these patients.

Methods

We identified individuals with AS/SpA/PsA, and non‐AS/SpA/PsA comparators by linking Swedish national patient, population, TB, and rheumatology registers, and followed them for TB occurrence. Incidence rates were estimated for biologic‐naive and biologic‐exposed patients and the comparators. We calculated hazard ratios (HRs), adjusted for age, sex, and country of birth.

Results

Included in this study were 38,702 patients with AS/SpA/PsA, and 200,417 persons from the general population. Among the patients, 11 active TB cases were identified, with an incidence rate (per 10⁵) of 22 (95% confidence interval [95% CI] 8.3–59.2) for biologic‐exposed patients, 2.7 (95% CI 1.3–5.6) for biologic‐naive patients, and 2.4 (95% CI 1.8–3.3) for non‐AS/SpA/PsA comparators. The adjusted HR comparing biologic‐naive patients to the general population was 1.2 (95% CI 0.5–2.7), and 7.5 (95% CI 1.9–29) comparing biologic‐exposed to biologic‐naive patients.

Conclusion

Biologic‐naive AS/SpA/PsA patients are not at an increased TB risk in Sweden. Following treatment with biologic agents, the risk increased, but the absolute TB risk was low.

     

Medical Care Costs Associated With Rheumatoid Arthritis in the US: A Systematic Literature Review and Meta‐Analysis

Objective

Rheumatoid arthritis (RA) is a morbid, mortal, and costly condition without a cure. Treatments for RA have expanded over the last 2 decades, and direct medical costs may differ by types of treatments. There has not been a systematic literature review since the introduction of new RA treatments, including biologic disease‐modifying antirheumatic drugs (bDMARDs).

Methods

We conducted a systematic literature review with meta‐analysis of direct medical costs associated with RA patients cared for in the US since the marketing of the first bDMARD. Standard search strategies and sources were used, and data were extracted independently by 2 reviewers. The methods and quality of included studies were assessed. Total direct medical costs as well as RA‐specific costs were calculated using random‐effects meta‐analysis. Subgroups of interest included Medicare patients and those using bDMARDs.

Results

We found 541 potentially relevant studies, and 12 articles met the selection criteria. The quality of studies varied: one‐third were poor, one‐third were fair, and one‐third were good. Total direct medical costs were estimated at $12,509 (95% confidence interval [95% CI] 7,451–21,001) for all RA patients using any treatment regimen and $36,053 (95% CI 32,138–40,445) for bDMARD users. RA‐specific costs were $3,723 (95% CI 2,408–5,762) for all RA patients using any treatment regimen and $20,262 (95% CI 17,480–23,487) for bDMARD users.

Conclusion

The total and disease‐specific direct medical costs for patients with RA is substantial. Among bDMARD users, the cost of RA care is more than half of all direct medical costs.

     

Depression Risk in Young Adults With Juvenile‐ and Adult‐Onset Lupus: Twelve Years of Followup

Objective

To compare major depression risk among young adults with juvenile‐onset and adult‐onset systemic lupus erythematosus (SLE), and to determine demographic and health‐related predictors of depression.

Methods

Young adults with SLE ages 18–45 years (n = 546) in the Lupus Outcomes Study completed annual telephone surveys from 2002–2015, including assessment of depression using the Center for Epidemiologic Studies Depression Scale (CES‐D), and self‐report measures of sociodemographics and health characteristics. Juvenile‐onset SLE was defined as age <18 years at diagnosis (n = 115). Repeated‐measures analysis was performed to assess the risk for major depression (CES‐D ≥24) at any point in study, and logistic regression was used to assess for recurrent (present on ≥2 assessments) major depression.

Results

Major depression was experienced by 47% of the cohort at least once during the 12‐year study period. In adjusted analyses, juvenile‐onset SLE patients had an increased risk of having a major depressive episode (odds ratio [OR] 1.7 [95% confidence interval (95% CI) 1.0–2.7]) and recurrent episodes (OR 2.2 [95% CI 1.2–4.3]), compared to participants with adult‐onset SLE. Older age, lower educational attainment, and physical function, higher disease activity, and a history of smoking were associated with an increased depression risk. Juvenile‐onset SLE patients had a higher risk of major depression across all educational groups.

Conclusion

Young adults with SLE, particularly those with juvenile‐onset disease, are at high risk for major depression, which is associated with increased disease activity, poorer physical functioning, and lower educational attainment. Early depression intervention in young adults with SLE has the potential to improve both medical and psychosocial outcomes.

     

Antinuclear Matrix Protein 2 Autoantibodies and Edema,Muscle Disease,and Malignancy Risk in Dermatomyositis Patients

Objective

Dermatomyositis (DM ) patients typically present with proximal weakness and autoantibodies that are associated with distinct clinical phenotypes. We observed that DM patients with autoantibodies recognizing the nuclear matrix protein NXP ‐2 often presented with especially severe weakness. The aim of this study was to characterize the clinical features associated with anti–NXP ‐2 autoantibodies.

Methods

There were 235 DM patients who underwent testing for anti–NXP ‐2 autoantibodies. Patient characteristics, including muscle strength, were compared between those with and without these autoantibodies. The number of cancer cases observed in anti–NXP ‐2‐positive subjects was compared with the number expected in the general population.

Results

Of the DM patients, 56 (23.8%) were anti–NXP ‐2‐positive. There was no significant difference in the prevalence of proximal extremity weakness in patients with and without anti–NXP ‐2. In contrast, anti–NXP ‐2‐positive patients had more prevalent weakness in the distal arms (35% versus 20%; P = 0.02), distal legs (25% versus 8%; P < 0.001), and neck (48% versus 23%; P < 0.001). Anti–NXP ‐2‐positive subjects were also more likely to have dysphagia (62% versus 35%; P < 0.001), myalgia (46% versus 25%; P = 0.002), calcinosis (30% versus 17%; P = 0.02), and subcutaneous edema (36% versus 19%; P = 0.01) than anti–NXP ‐2‐negative patients. Five anti–NXP ‐2‐positive subjects (9%) had cancer‐associated myositis, representing a 3.68‐fold increased risk (95% confidence interval 1.2–8.6) compared to the expected prevalence in the general population.

Conclusion

In DM , anti–NXP ‐2 autoantibodies are associated with subcutaneous edema, calcinosis, and a muscle phenotype characterized by myalgia, proximal and distal weakness, and dysphagia. As anti–NXP ‐2‐positive patients have an increased risk of cancer, we suggest that they undergo comprehensive cancer screening.

     

Comparative Effectiveness of Mycophenolate Mofetil for the Treatment of Juvenile‐Onset Proliferative Lupus Nephritis

Objective

Although juvenile‐onset proliferative lupus nephritis (PLN ) leads to significant morbidity and mortality, there is no clinical trials–based evidence to support the treatment effectiveness of any therapy for juvenile‐onset PLN . Marginal structural models enable us to estimate treatment effectiveness using observational data while accounting for confounding by indication.

Methods

We used prospectively collected data to examine the effect of mycophenolate mofetil (MMF ), compared to the use of other therapies, on the long‐term outcome of a juvenile‐onset PLN cohort (age at PLN onset <18 years). The major outcome variable was the estimated glomerular filtration rate (GFR ) using the revised Schwartz formula. Confounding by indication was corrected for marginal structural model.

Results

A total of 172 subjects with juvenile‐onset PLN , with a mean followup duration of approximately 4 years, were included. Overall, MMF was superior to other therapies, with a relative effect estimate for MMF of 1.06, i.e., 6% better estimated GFR on average (95% confidence interval 0.7, 11.3), corrected for potential confounding by indication. We found that beginning in year 4 there was a significant improvement in estimated GFR in the patients who were treated with MMF versus other therapies. This improvement was maintained until the end of the study.

Conclusion

MMF was more beneficial than other therapies in improving/maintaining long‐term renal function in patients with juvenile‐onset PLN up to a maximum followup of 7 years. This finding is consistent with evidence from adult PLN clinical trials.

     

Interleukin‐22 Reduces the Severity of Collagen‐Induced Arthritis in Association With Increased Levels of Interleukin‐10

Objective

The mechanism of action of interleukin‐ 22 (IL‐22) in inflammatory arthritis remains unknown. IL‐22–deficient mice exhibit an intact humoral and cellular immune response to collagen and yet have a reduced incidence of collagen‐induced arthritis (CIA). Further, administration of anti–IL‐22 does not reduce the severity of clinical arthritis but rather improves only certain aspects of joint inflammation as assessed histologically. This study was undertaken to investigate the mechanism of action and role of systemic IL‐22 in modulating target organ inflammation.

Methods

CIA was induced in DBA mice by immunization with collagen and Freund's complete adjuvant. Expression of IL‐22 and its receptor (IL‐22R) in lymphoid organ and target tissues was determined during various phases of arthritis. The effector functions of IL‐22 on induction/regulation of various cytokines in in vitro restimulation cultures were analyzed by enzyme‐linked immunosorbent assay (ELISA). Recombinant IL‐22 with or without anti–IL‐10 antibody was administered to mice following immunization with collagen and prior to the onset of arthritis, and the severity of arthritis was evaluated by clinical scoring and histopathologic assessment. Anticollagen antibodies in mouse sera were analyzed by ELISA.

Results

IL‐22 and IL‐22R were up‐regulated in lymphoid organs and joints during the course of arthritis. IL‐22 augmented IL‐10, IL‐17, and IL‐6 in lymphoid tissues in vitro. Administration of recombinant IL‐22 was associated with an increase in IL‐10 levels in vivo and a significant reduction in the progression of arthritis severity. Anti–IL‐10 antibody treatment was associated with the abrogation of this protective effect of IL‐22.

Conclusion

Our data demonstrate, for the first time, that IL‐22 has a protective role in inflammatory arthritis.

     

Treatment with a neutralizing anti‐murine interleukin‐17 antibody after the onset of collagen‐induced arthritis reduces joint inflammation,cartilage destruction,and bone erosion

Objective

Interleukin‐17 (IL‐17) is a proinflammatory cytokine that is expressed in the synovium of rheumatoid arthritis (RA) patients. This T cell cytokine is implicated in the initiation phase of arthritis. However, the role of IL‐17 during the effector phase of arthritis has still not been identified; this was the objective of the present study.

Methods

Mice with collagen‐induced arthritis (CIA) were treated with polyclonal rabbit anti‐murine IL‐17 (anti–IL‐17) antibody–positive serum or normal rabbit serum after the first signs of arthritis. In addition, during a later stage of CIA mice were selected and treated with anti–IL‐17 antibody or control serum. Arthritis was monitored visually, and joint pathology was examined radiologically and histologically. Systemic IL‐6 levels were measured by enzyme‐linked immunosorbent assay, and local synovial IL‐1 and receptor activator of NF‐κB ligand (RANKL) expression was analyzed using specific immunohistochemistry.

Results

Treatment with a neutralizing anti–IL‐17 antibody after the onset of CIA significantly reduced the severity of CIA. Radiographic analysis revealed marked suppression of joint damage in the knee and ankle joints. Histologic analysis confirmed the suppression of joint inflammation and showed prevention of cartilage and bone destruction after anti–IL‐17 antibody therapy. Systemic IL‐6 levels were significantly reduced after anti–IL‐17 antibody treatment. Moreover, fewer IL‐1β–positive and RANKL‐positive cells were detected in the synovium after treatment with neutralizing IL‐17. Interestingly, initiation of anti–IL‐17 antibody therapy during a later stage of CIA, using mice with higher clinical arthritis scores, still significantly slowed the progression of the disease.

Conclusion

IL‐17 plays a role in early stages of arthritis, but also later during disease progression. Systemic IL‐6 was reduced and fewer synovial IL‐1–positive and RANKL‐positive cells were detected after neutralizing endogenous IL‐17 treatment, suggesting both IL‐1–dependent and IL‐1–independent mechanisms of action. Our data strongly indicate that IL‐17 neutralization could provide an additional therapeutic strategy for RA, particularly in situations in which elevated IL‐17 may attenuate the response to anti–tumor necrosis factor/anti–IL‐1 therapy.

     

Association of α‐actinin–binding anti–double‐stranded DNA antibodies with lupus nephritis

Objective

Anti–double‐stranded DNA (anti‐dsDNA) antibodies may contribute to the pathogenesis of glomerulonephritis (GN) by cross‐reacting with α‐actinin in murine models and in some patients with systemic lupus erythematosus (SLE). We therefore sought to determine possible disease associations with serologic and clinical features and to characterize this new autoantibody specificity.

Methods

One hundred patients with SLE were recruited into this multicenter study, as well as 100 rheumatic disease controls and 2,100 healthy blood donors. Clinical disease was evaluated by the SLE Disease Activity Index (SLEDAI; excluding the anti‐DNA component). Anti‐dsDNA antibodies were detected by conventional enzyme‐linked immunosorbent assay (ELISA) and by a commercial enzyme immunoassay (EIA). Anti–α‐actinin antibodies were detected by ELISA, and their specificity was confirmed by Western blotting and by indirect immunofluorescence using rat kidney sections and mesangial cells as substrates. Highly positive sera were selected for absorption experiments and were affinity‐purified for cross‐reactivity studies and measurement of antibody avidity.

Results

Sera from 62 of the SLE patients had anti‐dsDNA antibodies; 21 of these sera also had anti–α‐actinin antibodies, as compared with 1 of the 38 sera without anti‐dsDNA antibodies. Of the 22 patients with anti–α‐actinin antibodies, 10 had GN, as compared with 14 of the 78 without anti–α‐actinin antibodies (P < 0.01). In patients with GN, anti–α‐actinin, but not anti‐dsDNA, antibodies correlated with the SLEDAI score (minus the anti‐DNA component) and with treatment. The fraction of serum anti‐dsDNA antibodies that cross‐reacted with α‐actinin exhibited high avidity for dsDNA, as determined using a commercial EIA for high‐avidity anti‐dsDNA antibodies and an in‐house conventional ELISA.

Conclusion

The α‐actinin–binding antibodies are significantly associated with GN in SLE. Whether such autoantibodies may anticipate the development of this complication of SLE remains to be verified.

     

Risk of Hepatitis B Virus Reactivation in Patients With Inflammatory Arthritis Receiving Disease‐Modifying Antirheumatic Drugs: A Systematic Review and Meta‐Analysis

Objective

To assess hepatitis B virus (HBV) reactivation rates in patients with resolved or chronic HBV infection, receiving disease‐modifying antirheumatic drugs (DMARDs) and with or without antiviral prophylaxis.

Methods

We conducted a systematic review and meta‐analysis. Electronic searches were conducted in PubMed, Medline, and Embase using Ovid through December 31, 2015. A search strategy was developed for each database using the following inclusion criteria: for participants, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and resolved or chronic HBV infection; for intervention, tumor necrosis factor (TNF) inhibitors or non‐TNF biologic or nonbiologic DMARDs; and for outcome, HBV reactivation. Four reviewers independently extracted study data and assessed study quality using the Newcastle‐Ottawa Scale. To determine the pooled HBV reactivation rate, the variances of the raw proportions were stabilized using a Freeman‐Tukey‐type arcsine square root transformation, using a random‐effects model.

Results

Twenty‐five studies met the inclusion criteria. The overall pooled rate of HBV reactivation was 1.6% (95% confidence interval [95% CI] 0.8–2.6) in patients with resolved HBV. Similar rates were observed in resolved patients taking TNF inhibitors (1.4% [95% CI 0.5–2.6]), non‐TNF biologics (6.1% [95% CI 0.0–16.6]), and nonbiologic DMARDs (1.7% [95% CI 0.2–4.2]). We also found that the reactivation rate was lower in patients with chronic HBV infection who received antiviral prophylaxis (9.0% [95% CI 4.1–15.5]) than in those who did not (14.6% [95% CI 4.3–29.0]).

Conclusion

We found that the HBV reactivation rate in inflammatory arthritis patients receiving DMARDs was low in resolved patients and moderate in patients with chronic HBV infection. Further, lower rates were observed in patients with chronic HBV infection who were using antiviral prophylaxis.

     

Salmonella septicemia in rheumatoid arthritis patients receiving anti–tumor necrosis factor therapy: Association with decreased interferon‐γ production and toll‐like receptor 4 expression

Objective

Patients treated with antibodies to tumor necrosis factor α (TNFα) have an increased susceptibility to intracellular infections. We describe 2 patients with rheumatoid arthritis (RA) who developed Salmonella septicemia during anti‐TNF treatment. The aim of this study was to identify the mechanisms involved in the increased susceptibility of anti‐TNF–treated patients to intracellular microorganisms.

Methods

We evaluated an additional 6 RA patients receiving anti‐TNF antibodies, 5 RA patients not receiving anti‐TNF therapy, and 6 age‐ and sex‐matched healthy volunteers. The in vitro production of cytokines (interleukin‐1β [IL‐1β], IL‐6, interferon‐γ [IFNγ], and IL‐10) upon bacterial stimulation of whole blood and the expression of Toll‐like receptor 4 (TLR‐4) on dendritic cells from RA patients treated with infliximab, RA patients not treated with infliximab, and healthy controls were compared.

Results

Stimulation with heat‐killed Salmonella typhimurium or Candida albicans led to a significantly decreased production of IFNγ, but not to a decreased production of IL‐10, IL‐β, or IL‐6, in anti‐TNF–treated RA patients compared with RA patients who were not receiving anti‐TNF antibodies and compared with healthy controls. TNF‐blocking treatment ex vivo significantly inhibited TLR‐4 expression on dendritic cells from RA patients and healthy controls.

Conclusion

Since recognition of microorganisms by TLR‐4 and activation of phagocytes by IFNγ are essential mechanisms for the defense against intracellular and fungal pathogens, we propose that this pathway is crucial for the increased susceptibility to these microorganisms in patients receiving anti‐TNF therapy.

     

Therapeutic effects of interleukin‐6 blockade in a murine model of polymyositis that does not require interleukin‐17A

Objective

To explore new molecular targets in the treatment of polymyositis (PM) by examining a recently established murine model of PM, C protein–induced myositis (CIM), for involvement of an interleukin‐6 (IL‐6)/IL‐17A pathway.

Methods

CIM was induced by immunizing wild‐type mice as well as IL‐6–null and IL‐17A–null C57BL/6 mice with recombinant mouse skeletal C protein fragments. Some mice were treated with anti–IL‐6 receptor (anti–IL‐6R) monoclonal antibodies or control antibodies. Muscle tissue samples were examined histologically and immunohistochemically.

Results

The syngeneic C protein fragments successfully induced inflammation in the skeletal muscles of wild‐type mice. IL‐6 was expressed by mononuclear cells, especially in macrophages, infiltrating in the muscles. IL‐6–null mice developed myositis with significantly lower incidence and milder severity than wild‐type mice. In contrast, IL‐17A–null mice were as susceptible to CIM as wild‐type mice. Intraperitoneal administration of anti–IL‐6R monoclonal antibodies, but not of control monoclonal antibodies, ameliorated CIM both preventively and therapeutically.

Conclusion

Our findings indicate that IL‐6 is critically involved in the development of CIM. Although many other autoimmune models require IL‐6 for differentiation of pathogenic T cells producing IL‐17A, IL‐17A was dispensable in CIM. Nevertheless, treatment with anti–IL‐6R antibodies was effective. IL‐6 blockade is potentially a new approach to the treatment of autoimmune myositis, via processes distinct from interference in the IL‐6/IL‐17A pathway.

     

Evaluation of a Methodologic Approach to Define an Inception Cohort of Rheumatoid Arthritis Patients Using Administrative Data

Objective

Identifying incident rheumatoid arthritis (RA) is desirable in order to create inception cohorts. We evaluated an approach to identify incident RA in health plan claims data.

Methods

Both Medicare and commercial claims data were linked to Corrona, a US RA registry. We evaluated the accuracy of year of RA onset in the registry (gold standard) versus different claims algorithms, varying International Classification of Diseases, Ninth Revision codes for RA/arthritis, duration of health plan enrollment preceding diagnosis (minimum of 1 versus 2 years), and use of RA medications. Results were reported as positive predictive values (PPVs) of the claims‐based algorithm for incident RA.

Results

Depending on the algorithm tested and whether patients were enrolled in Medicare or the commercial health plan, the PPVs for incident RA ranged from 68–81%. A 2‐year clean period free of all RA‐related diagnoses and medications was somewhat more optimal although, by comparison, a 1‐year clean period yielded similar PPVs and retained approximately 90% more RA patients for analysis.

Conclusion

Claims‐based algorithms can accurately identify incident RA.

     

Disparities in Total Knee Replacement: Population Losses in Quality‐Adjusted Life‐Years Due to Differential Offer,Acceptance, and Complication Rates for African Americans

Objective

Total knee replacement (TKR) is an effective treatment for end‐stage knee osteoarthritis (OA). American racial minorities undergo fewer TKRs than whites. We estimated quality‐adjusted life‐years (QALYs) lost for African American knee OA patients due to differences in TKR offer, acceptance, and complication rates.

Methods

We used the Osteoarthritis Policy Model, a computer simulation of knee OA, to predict QALY outcomes for African American and white knee OA patients with and without TKR. We estimated per‐person QALYs gained from TKR as the difference between QALYs with current TKR use and QALYs when no TKR was performed. We estimated average, per‐person QALY losses in African Americans as the difference between QALYs gained with white rates of TKR and QALYs gained with African American rates of TKR. We calculated population‐level QALY losses by multiplying per‐person QALY losses by the number of persons with advanced knee OA. Finally, we estimated QALYs lost specifically due to lower TKR offer and acceptance rates and higher rates of complications among African American knee OA patients.

Results

African American men and women gain 64,100 QALYs from current TKR use. With white offer and complications rates, they would gain an additional 72,000 QALYs. Because these additional gains are unrealized, we call this a loss of 72,000 QALYs. African Americans lose 67,500 QALYs because of lower offer rates, 15,800 QALYs because of lower acceptance rates, and 2,600 QALYs because of higher complication rates.

Conclusion

African Americans lose 72,000 QALYs due to disparities in TKR offer and complication rates. Programs to decrease disparities in TKR use are urgently needed.

     

Occupation and Risk of Developing Rheumatoid Arthritis: Results From a Population‐Based Case–Control Study

Objective

Environmental factors are of importance for the etiology of rheumatoid arthritis (RA), but much remains unknown concerning the contributions from distinct occupational hazards. We explored the association between occupation and the risk of anti–citrullinated protein antibody (ACPA)+ RA or ACPA? RA.

Methods

We analyzed 3,522 cases and 5,580 controls from the Swedish population–based Epidemiological Investigation of Rheumatoid Arthritis case–control study. A questionnaire was used to obtain information on work history and lifestyle factors. Blood samples were drawn for serologic analyses. Unconditional logistic regression was used to calculate the odds ratio (OR) of RA associated with the last occupation before study inclusion. Analyses were performed with adjustments for known environmental exposures and lifestyle factors, including pack‐years of cigarette smoking, alcohol use, body mass index, and education.

Results

Among men, bricklayers and concrete workers (OR 2.9, 95% confidence interval [95% CI] 1.4–5.7), material handling operators (OR 2.4, 95% CI 1.3–4.4), and electrical and electronics workers (OR 2.1, 95% CI 1.1–3.8) had an increased risk of ACPA+ RA. For ACPA? RA, bricklayers and concrete workers (OR 2.4, 95% CI 1.0–5.7) and electrical and electronics workers (OR 2.6, 95% CI 1.3–5.0) had an increased risk. Among women, assistant nurses and attendants had a moderately increased risk of ACPA+ RA (OR 1.3, 95% CI 1.1–1.6). No occupations were significantly associated with ACPA? RA among women.

Conclusion

Mainly occupations related to potential noxious airborne agents were associated with an increased risk of ACPA+ or ACPA? RA, after adjustments for previously known confounders.

     

Comparable Rates of Glucocorticoid‐Associated Adverse Events in Patients With Polymyalgia Rheumatica and Comorbidities in the General Population

Objective

To investigate the use of glucocorticoids (GCs) and related adverse events (AEs) in a long‐term, geographically defined cohort of patients with polymyalgia rheumatica (PMR).

Methods

Using a population‐based inception cohort, details of GC therapy were abstracted from medical records of all patients diagnosed with PMR in 2000–2014. Age‐ and sex‐matched comparators without PMR were identified from the same underlying population. Cumulative and daily dosage of GC, rate of disease relapse, occurrence of GC‐related AEs, and rate of GC discontinuation were analyzed.

Results

The study included 359 patients with PMR and 359 comparators. The median time to taper below 5 mg/day for 6 months was 1.44 years (95% confidence interval [95% CI] 1.36–1.62), while the median time to permanent discontinuation was 5.95 years (95% CI 3.37–8.88). The mean ± SD cumulative dose of GC at 2 and 5 years was 4.0 ± 3.5 grams and 6.3 ± 9.8 grams, respectively. The mean ± SD daily dose of GC at 2 and 5 years was 6.1 ± 7.6 mg/day and 7.2 ± 9.5 mg/day, respectively. There were no differences in rates of AEs between patients with PMR and comparators for diabetes mellitus, hypertension, hyperlipidemia, or hip, vertebral, or Colles fractures (P > 0.2 for all). Cataracts were more common in patients with PMR than comparators (hazard ratio 1.72 [95% CI 1.23–2.41]).

Conclusion

Relapse rates in PMR are highest in the early stages of therapy. Despite often protracted therapy, with the exception of cataracts, the rates of studied morbidities linked to GC are not more common in PMR than comparators.