In the Literature - April 2016

VBCR - April 2016, Vol 5, No 2 - In the Literature

In This Article

Growing Burden of Arthritis

The public health burden of arthritis and other rheumatic conditions is increasing and appears to be increasing disproportionately in nonurban areas, in women, and in older people. Moreover, it appears that gout and other crystal arthropathies account for a major proportion of the increase. These were the findings of a retrospective study involving urban and rural communities in the state of Nebraska from 2007 to 2012.

Annual emergency department visits for arthritis and related rheumatic conditions increased by 34%, hospitalizations increased by 22%, and mean charges increased by 30% to 70% in Nebraska over the study period. “This study provides an up-to-date assessment of the societal burden of arthritis and other rheumatic conditions….These results suggest that the burden of AORC [arthritis and other rheumatic conditions]-related mortality differs based on urban-rural residence, with the highest mortality rates observed in smaller rural communities,” wrote the authors. They also found that gout and other crystal arthropathies increased disproportionately compared with other related conditions involved in emergency department visits and hospitalizations over the previous 6 years.

According to current estimates, the prevalence of arthritis and related conditions will increase to 67 million by 2030, and 25 million people will have activity limitations due to these conditions. The data from this study can inform the potential need for future healthcare and other public health resources.

The study quantified annual rates of emergency department visits, hospitalizations, and mortality, plus medical charges involving arthritis and other rheumatic conditions in 4 urban and rural communities in Nebraska from 2007 to 2012. Ten diagnostic categories were included: rheumatoid arthritis; osteoarthritis and related disorders; gout and other crystal arthropathies; spondylosis/spondylitis and allied disorders; diffuse connective tissue disease; fibromyalgia; carpal tunnel syndrome; soft tissue disorders; joint pain, effusion, and other unspecified joint disorders; and other specified rheumatic conditions.

Emergency department visits related to arthritis and other rheumatic conditions were higher for women than men and higher for those who were older. Overall, emergency department visits increased by 34% between 2007 and 2012. Arthritis and other rheumatic conditions accounted for 17.3% of all-cause hospitalizations in Nebraska from 2007 to 2012. Hospitalizations significantly increased regardless of age or sex, except for females aged 0 to 9 years and males aged 0 to 19 years. Women had higher rates of hospitalizations than men, and hospitalizations increased with older age.

Analysis of patients’ disease profiles showed that emergency department visits for gout and other crystal arthropathies increased by 93%, whereas hospitalizations for these conditions increased by 76% over the study period.

Arthritis and other rheumatic conditions accounted for 3.1% of the 91,387 all-cause deaths reported for the study period. Female sex and older age were associated with mortality, but overall there was no significant change in mortality rate from these diseases over the study period.

Mean charges per emergency department visit for arthritis and other rheumatic conditions increased by 56.5%, and hospitalization-related charges increased by 15.7% during the study period. Total hospital charges for all emergency department visits involving arthritis and other rheumatic conditions increased by 120% over the study period, and total inpatient charges increased by 48% over the same period.

These findings suggest that arthritis and its comorbidities will continue to pose a significant economic burden to patients, their families, and society.

Han G-M, Michaud K, Yu F, et al. Arthritis Care Res (Hoboken). Published online February 11, 2016.

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Pregnancy Outcomes in Systemic Lupus Erythematosus

Adverse pregnancy outcomes for both mother and fetus are more common in women with systemic lupus erythematosus (SLE) than in the general population, according to a recent Swedish population-based study that seeks to characterize these differences more fully. Moreover, unfavorable outcomes were observed in pregnancies that occurred prior to the diagnosis of SLE.

The study “confirms previous findings of maternal and fetal risks in SLE pregnancy, such as preterm birth and preeclampsia.” These findings also suggest that “the underlying immunologic profile of SLE and alterations preceding clinical SLE may contribute to [the] pregnancy complications identified in this study,” the authors wrote.

The prospective cohort study identified 13,598 women with first singleton pregnancies in the Swedish Med­ical Birth Register: 551 pregnancies in women with prevalent SLE, 65 with pre-SLE pregnancies within 0 to 2 years, 133 with pre-SLE pregnancies within 2 to 5 years, and 12,847 pregnancies in the general population.

The authors examined outcomes among women presenting with SLE up to 5 years postpartum from 1987 onward and compared them with outcomes in the general population. Maternal outcomes including preeclampsia, hypothyroid disease, stroke, and serious infection were more common among women with SLE and with women diagnosed with SLE soon after their first pregnancy. Women diagnosed with SLE 2 to 5 years after pregnancy tended to have lower maternal risks than these groups, but higher risks compared with the general population.

Preeclampsia occurred in 26% of women diagnosed with SLE 0 to 2 years postpartum, 13% for women diagnosed 2 to 5 years postpartum, and 16% for women with prevalent SLE compared with 5% of women without SLE. A similar pattern was observed for serious infections during pregnancy and in the first year postpartum.

Fetal outcomes followed a similar pattern for nonaverage size for gestational age, low birth weight, low 1-minute Apgar scores, infant mortality, and other clinical outcomes. During the first year of life, infections occurred in 21% of infants born to mothers with SLE during pregnancy compared with nearly 29% of infants whose mothers were diagnosed with SLE 0 to 2 years postpartum and 25% of infants with mothers diagnosed 2 to 5 years postpartum versus 14% of infants born to mothers in the general population. A similar pattern was observed for infections in the first 5 years of life. Numbers were too small to compare groups for congenital malformation or infant mortality.

The authors suggest that underlying disease activity, inflammation, and other immunologic features may explain some of the pregnancy outcomes in SLE. “These women with pre-SLE represent a group who may have immune dysregulation, autoimmunity, and increases in systemic inflammation during pregnancy. Not only will this knowledge inform and advance the understanding of clinical drivers of maternal and fetal outcomes, but it may also inform clinical care, prenatal counseling, and decision-making,” the authors wrote.

Arkema EV, Palmsten K, Sjöwall C, et al. Arthritis Care Res (Hoboken). Published online February 1, 2016.

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NSAIDs Safe for Axial Spondyloarthritis

High-quality evidence from a Cochrane Review supports the use of both traditional and COX-2 non­steroidal anti-inflammatory drugs (NSAIDs) in treating axial spondyloarthritis (axSpA), with similar harms as placebo over the short-term. There were no differences in efficacy or safety among the various NSAIDs, according to the review.

Moreover, NSAIDs may have other benefits. Two studies comparing continuous versus on-demand use included in the review suggest that NSAIDs “may be effective in retarding radiographic progression in the spine in axSpA, especially in certain subgroups of patients: e.g., patients with high CRP [C-reactive protein], and that this may be best achieved by continuous rather than on-demand use of NSAID,” wrote the authors.

“The results of our review are in keeping with current recommendations that NSAID are appropriate first-line treatments of patients with axSpA with active disease before tumor necrosis factor inhibitor biologicals are applied. They are effective and safe in the short term,” they wrote.

The Cochrane systematic review was performed to evaluate current evidence regarding the “benefits and harms” of NSAIDs used to manage symptoms, disease activity, and radiographic progression in patients with axSpA; it included 35 randomized controlled trials, 2 quasi-randomized controlled trials, and 2 cohort studies. The pooled analysis was based on 29 randomized controlled trials and 2 quasi-randomized controlled trials with a total of 4356 patients. These trials included comparisons of NSAID versus placebo (n = 5), COX-2 versus placebo (n = 3), COX-2 versus traditional NSAID (n = 4), NSAID versus NSAID (n = 24), naproxen versus other NSAID (n = 3), and low-dose versus high-dose NSAID (n = 5).

When compared with placebo, both traditional and COX-2 NSAIDs were consistently more efficacious than placebo at 6 weeks, and equally safe after 12 weeks of treatment. There were no differences found in benefits or harms or withdrawals due to adverse events among the various NSAIDs or between traditional and COX-2 NSAIDs.

“Surprisingly, we could not confirm in our review the safety concerns associated with both traditional NSAID and COX-2 NSAID that have been reported [in previous reviews] as well as in studies in other rheumatic diseases,” the authors wrote.

They suggested the absence of clear differences in short-term adverse events between traditional NSAIDs and COX-2 NSAIDs could be due to the fact that most patients with ankylosing spondylitis are younger and have fewer comorbidities than patients with other rheumatic diseases.

The authors did not have sufficient data to draw conclusions about the long-term safety of NSAIDs for patients with axSpA.

Kroon FP, van der Burg LR, Ramiro S, et al. J Rheumatol. 2016;43:607-617.

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Rheumatic Problems with Chikungunya

The Centers for Disease Control and Prevention has reported that the first transmission of the chikungunya virus in the Americas was identified in late 2013 and beginning in 2014; cases of chikungunya virus disease were reported among travelers returning to the United States from the affected areas. A proportion of patients who become sick will have long-term painful symptoms that mimic rheumatoid arthritis. The findings of a recent study from the Bronx-Lebanon Hospital Center in New York, which serves a significant Caribbean population, suggests that up to one-third of patients will have muscle pain, joint pain, and joint swelling following chikungunya infection.

The study was based on 28 patients treated at the center in 2014. Data were available 13 months after diagnosis on 19 patients; of these, 37% had ongoing rheumatic problems; 32% reported joint pain, 32% reported joint swelling, and 26% reported muscle pain. These symptoms occurred in patients with and without preexisting rheumatic/musculoskeletal disease (RMD). Three patients without preexisting RMD had diffuse postchikungunya musculoskeletal disorders. Four patients with preexisting RMD reported worsening joint symptoms (n = 3) and more severe osteoarthritis of both knees (n = 1). This is the first known study of assessment of postchikungunya rheumatic disorders among individuals who contracted the virus while traveling to the Caribbean, the authors note.

“Patients seeking pre-travel health care in preparation for a trip to the Caribbean—as to any other chikungunya endemic region—need to be comprehensively counseled about the health risks related to the acute stage of the infection as well as...the risk for developing a potentially long-lasting rheumatic disorder,” the authors wrote.

Follow-up care with a primary care provider is important for patients diagnosed with the virus to identify those with postchikungunya rheumatic disorders and to manage their symptoms.

The initial report included 28 adults with a median age of 52 years with an average length of stay in the Caribbean of 30 days; 82% stayed in the Dominican Republic, 14% in Puerto Rico, and 4% in Guyana. Almost all were Hispanic (96%), and 54% were female. Follow-up on 19 patients was collected using a telephone questionnaire.

At the time of acute diagnosis, nearly all patients had fever (99%), joint pain (89%), myalgia (70%), and joint swelling (68%). Median pain level was 8 on a visual analog scale of 0 to 10. Fifty-nine percent had gastrointestinal problems, 48% had headache, and 48% had rash. Forty-six percent were hospitalized for inpatient care with complications that included hypotensive episodes, syncope, electrolyte imbalance, and thrombocytopenia.

Zeana C, Kelly P, Cifuentes WHA, et al. Travel Med Infect Dis. 2016;14:21-25.

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Seizures in Systemic Lupus Erythematosus

An estimated 5% to 7% of patients with systemic lupus erythematosus (SLE) develop seizures after diagnosis, and up to 12.5% can develop seizures over a mean of 5 years. In patients with SLE, seizures can be a primary event resulting from direct effects of SLE on the nervous system, or secondary due to other disorders. The results of previous studies have identified early disease onset, male sex, younger age, and African American ethnicity as risk factors for seizure. Studies have also found that those patients who develop seizure seem to have shorter disease duration, higher SLE disease activity, damage accrual, and a higher frequency of other neuropsychiatric disorders—especially psychosis and stroke.

A new study sought to characterize risk factors for seizure more fully, analyzing clinical and laboratory predictors associated with a first seizure. The authors found that risk of seizure after diagnosis of SLE is increased by prior psychosis, neuropathy, proteinuria, anti-Sm antibody, low C3, and use of corticosteroids.

Although seizures can occur at any time in patients with SLE, “before, at, or after SLE diagnosis, seizures have been a relatively early event in the disease course of SLE,” the authors wrote. “These results may help clinicians identify patients at highest risk for seizures and provide useful information for guiding the evaluation of disease and therapy,” they stated.

A total of 2203 SLE patients with no history of seizure prior to the SLE diagnosis in the Hopkins Lupus Cohort were followed for more than 5 years and analyzed. Incident seizures were examined at the time of diagnosis, more than 45 days postdiagnosis, and after cohort entry.

The first seizure occurred at the time of SLE diagnosis in 37 (1.68%) patients or after diagnosis (120 patients, 5.45%). The risk of having a seizure at the time of diagnosis was significantly higher in patients with a history of malar rash (P = .002), proteinuria (P = .004), and psychosis (P <.001). In a multivariate analysis of the first seizure occurring after diagnosis, history of low C3 (P = .0078), psychosis (P <.0001), cranial or peripheral neuropathy (P = .0043), anti-Sm antibody (P = .0551), renal involvement (P = .0177), and current corticosteroid use (P <.0001) were independently associated with a higher incidence of seizure. After adjusting for corticosteroid use, disease activity did not predict for a first seizure.

Huang X, Magder LS, Petri M. J Rheumatol. 2016;43:565-575.

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Link Between TNFi Therapy and Breast Cancer Not Found in New Study

People with a history of breast cancer who then begin tumor necrosis factor inhibitor (TNFi) therapy for rheumatoid arthritis are not at increased risk of breast cancer recurrence, according to a paper published in Annals of Rheumatic Diseases.

Pauline Raaschou, MD, and her colleagues from the Karolinska Institute in Stockholm, Sweden, sought to examine concerns about a link between TNFi and cancer development. They compared the outcomes of 143 women who had had rheumatoid arthritis and at least 1 breast cancer diagnosis before starting TNFi therapy between 1999 and 2010, and 143 women who were biologics-naive.

There were a total of 592 person-years of follow-up among those with TNFi treatment and 550 person-years of follow-up in the control group. Nine women in each group developed a breast cancer recurrence. The investigators calculated the adjusted hazard ratio for recurrence to be a non–statistically significant 1.1 with TNFi treatment.

These findings corroborate those of some studies and contradict those of others. The investigators note that, in another study, low levels of TNF were associated with a lower rate of tumor progression in women with locally advanced breast cancer. Furthermore, clinicians may be less inclined to give TNFi to women with recent, larger or high-grade breast cancer, and this may affect study results, the authors noted.

“Our results offer support to clinical guidelines which state that TNFi may be initiated in patients with a history of breast cancer >5 years ago. Although overall reassuring, whether our findings are generalisable to women with active, poor prognosis and/or recently diagnosed breast cancer, remains unclear,” the researchers concluded.

Raaschou P, et al. Ann Rheum Dis. 2015;74:2137-2143.

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Bipolar Disorder and Rheumatoid Arthritis Not Significantly Associated

Although the rate of bipolar disorder is higher among people with rheumatoid arthritis (RA) than those without this inflammatory disorder, that association is likely due to other factors such as smoking, according to a paper recently published in the Journal of Affective Disorders.

The team parsed data from a large Israeli healthcare provider organization, focusing on 11,782 patients with RA and 57,973 people without RA. Their multivariate analysis found that there was not a significant association between the 2 conditions.

“Our findings emphasize the need for additional studies to examine the relationship between RA and bipolar disorder,” wrote lead author Adir Farhi, MD, from the Sheba Medical Center, Tel-Hashomer, Israel, and coauthors.

Farhi A, et al. J Affect Disord. 2016;189:287-289.

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International Team Drafts List of Infections Associated with Biologic Therapy for Inflammatory Conditions

An expert panel has grappled with the issue of opportunistic infections in people being treated with biologics for rheumatoid arthritis and other immune-mediated inflammatory diseases. The results of their work were published in the Annals of Rheumatic Diseases.

The group of rheumatologists and infectious disease specialists from the United States, the United Kingdom, Italy, France, and Austria pored over the literature. Based on the studies they found, they arrived at an exhaustive list of pathogens that should be considered to be ‘indicator’ infections. Their definition of indicator infections is the presence or specific presentation of a pathogen that suggests a high likelihood of an alteration in host immunity.

Among the organisms they included in the list were oral Candida, invasive forms of Salmonella and other bacterial diarrheal pathogens, and herpes zoster. The consensus panel members expressed the hope that their work will help accurately categorize and classify infections that occur during clinical trials, including helping guide data collection in studies of biologics that are in the pipeline.

Winthrop KL, et al. Ann Rheum Dis. 2015;74:2107-2116.

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