Prioritization and Management of Comorbidities in Rheumatoid Arthritis

Clinicians who treat rheumatoid arthritis are aware of the many complications that can arise in patients, from cardiovascular disease to infections associated with joint replacement. Translating that general information into specific treatment strategies remains a challenge, particularly given rheumatoid arthritis itself requires so much attention.

For Laure Gossec, MD, PhD, of the Department of Rheumatology at Pitié Salpêtrière Hospital in Paris, early detection is critical.

“These patients often need more screening procedures than the general population, but they are getting fewer screenings,” she said. “In some cases, they have more comorbidities. But it is also about screening for those comorbidities. They are not screened as often as healthier patients and rheumatologists should be concerned.”

Many experts, including Howard Amital, MD, professor of Medicine at the Sackler Faculty of Medicine of the Tel-Aviv University and head of the Department of Medicine ‘B’ at the Sheba Medical Center at the Sheba Medical Center in Tel-Hashomer, warned there is a tipping point.

“I do not necessarily think all [rheumatoid arthritis] RA patients need more cancer screenings than the general population,” he said. “We should not be performing unnecessary exams or procedures that are not recommended, but we should certainly be extra cautious with them. It is worth noting that, overall, the percent of patients — even in the general population — who are screened for cancers according to consensus recommendations is too low.”

Janet E. Pope, MD, MPH, professor of medicine in the Departments of Medicine and Epidemiology and Biostatistics, and division head of Rheumatology at Western University, Schulich School of Medicine and Dentistry in Ontario, has done research in cardiovascular disease, which is among the most prevalent complications found in patients with RA.

“The traditional risk factors are increased on average compared to age- and sex-matched controls,” she said. “[There is] more smoking, high blood pressure, elevated lipids, high BMI and slightly more type 2 diabetes. Also, inflammation uncontrolled for years is an increase for vascular dysfunction or accelerated atherosclerosis. Someone needs to identify and work on treatable risks. But there is no agreement if it should be the rheumatologist, the primary care physician and/or another specialist.”

Healio Rheumatology addresses comorbidities in RA and looks at datasets that involve atherosclerosis and gout, joint replacement infections and hypertension in this Cover Story. Sources weighed in on the drugs that may be associated with comorbidities, addressed the optimal timing for cancer screenings and offered insight into the role of other health care professionals.

Screening Procedures

Gossec and colleagues followed 776 patients with RA for 2 years to 4 years. Eligible participants underwent an intervention that consisted of a single 1-hour visit with a nurse for comorbidity counseling. The researchers developed a comorbidity screening score to assess the conditions for which the patients had undergone screening according to national recommendations (0 to100 where full screening is 0). At baseline, the score was 36.6 ±19.9. At 3 years, the score improved to 24.3 ±17.8, for a relative improvement of 33%. The results showed cardiovascular risk screening, vaccination status and bone densitometry performance improved during the study period, while cancer screening showed less of an improvement.

Gossec acknowledged it was difficult to prove causality between the nurse-driven intervention and the improvements.

“The initial trial was a crossover trial, so everyone received the intervention at different time points,” she said. “The patients may have improved because rheumatologists are more aware of these complications, but it may also be because patients are better at self-managing them. Between baseline and 3-year follow-up, many patients have improved a bit, particularly about cardiovascular measures, bone density and vaccination rates.”

The benefit was not as clear for cancer screenings, including colonoscopy and mammography, according to Gossec.

“It may be that patients are ready to do a blood test for blood sugar, but are still not ready to take the test for prostate cancer because the consequences are more serious,” she said.

The researchers understood that busy rheumatologists with competing priorities will not have time to address every potential comorbidity their patients might face.

“We asked ourselves, ‘Can doctors do this or can nurses do this?’” Gossec said. “We had nurses asking these questions about Pap smears, mammography, bone density screening. It took a full hour, which is a long time and raises questions about feasibility. We know rheumatologists cannot spend an hour asking a patient if his father had heart disease.”

The results show nurses can handle these tasks. “We do not even have rheumatology nurses in France,” Gossec said. “This was performed by general nurses after a short training.”

Cardiovascular Disease

There is little debate patients with RA require ongoing attention for cardiovascular disease. A number of data sets provide the evidence. Pope and colleagues assessed the prevalence and progression of subclinical carotid artery atherosclerosis in a cohort of 31 patients with active RA. They found atherosclerotic plaque in 35% of the cohort and arterial wall hypertrophy in 86%. An abnormal lipid profile was reported in 68%. This condition was impacted by RA activity, according to the researchers. Regression analysis results suggested several factors that predicted plaque burden, including Framingham risk score and erythrocyte sedimentation. Higher baseline C-reactive protein, erythrocyte sedimentation and heavy smoking predicted progression of plaque in regression analysis. However, only high-sensitivity C-reactive protein predicted growth of plaque in the multivariable model.

“RA-related inflammation contributed to augmented [cardiovascular] burden in RA and might mediate its effect on atherosclerosis through [high-sensitivity C-reactive protein] and modulation of the traditional [cardiovascular] risk factors, such as dyslipidemia,” the researchers concluded.

Clinicians should consider avoiding steroids and using methotrexate (MTX) and biologics to decrease cardiovascular events, according to Pope. “Effective treatment of RA decreases the risks of heart attack and stroke,” she said. “Avoiding drugs that aggravate blood pressure, such as NSAIDs, is a good idea if patients have high blood pressure. However, pain also increases stress and blood pressure.”

Rantapää-Dahlqvist and colleagues conducted a case-control study that included 547 pre-symptomatic individuals and 1,641 controls. They aimed to elucidate signs of cardiovascular disease before the onset of RA. Results showed elevated ApoB/ApoA1 ratio smoking, BMI of at least 25 and diabetes were reported among individuals who went on to develop RA. For women, elevated ApoB/ApoA1, smoking and BMI of at least 25 carried the most significant associations with RA, while smoking and diabetes were the two most significant factors in men. Smoking remained the only significant factor in older patients, while elevated ApoB/ApoA1, smoking and BMI of at least 25 were factors associated with the development of RA in patients aged 50.2 years or younger. Three or more risk factors were found in 42% of individuals in the pre-symptomatic group compared with 30% found in the control group.

“Several of the [cardiovascular] risk factors were present in individuals already years before onset of symptoms of RA,” the researchers concluded. “These results urge an early [cardiovascular] prevention in patients with RA.”

Pope stressed that promotion of smoking cessation and the treatment of diabetes, cholesterol and hypertension are steps that should be taken to minimize these risks.

“Interestingly, the epidemic of cardiovascular events in RA is likely reducing, possibly because some patients are more mild than years ago or because disease control is better than before,” she said.

There have been temporal trends in the disease, including older age of onset, less damage and fewer extra-articular features than in years past, according to Pope.

Despite the association between smoking and a number of adverse health outcomes, Amital stressed data sets should be interpreted carefully.

“A number of different analyses have shown that RA contributes to excessive cardiovascular morbidity,” he said. “In a separate analysis, we have shown associations with myocardial disease. But once you remove cigarette smoking from the equation, you do not find any independent link. We need to understand the exact cause and effect of what we are looking at.”

Pope brought it back to basics. “We should all promote exercise and healthy diet,” she said. “We need to measure factors that are treatable as a rheumatologist or ask the primary care provider or others to do this.”

Kobayashi and colleagues investigated the hypothesis that myocardial abnormalities are associated with corrected QT interval in a cohort of 70 patients with RA. Thirty-three of those patients were treated with non-biologic disease-modifying antirheumatic drugs (DMARDs), while 37 received biologic DMARDs. The researchers assessed patients for myocardial late gadolinium enhancement, which they described as an indicator of myocardial fibrosis or myocarditis, and T2-weighted imaging. Results indicated 20 patients were positive for myocardial late gadolinium enhancement, while seven had T2-weighted imaging abnormalities.

Patients who were positive for myocardial late gadolinium enhancement had higher disease activity than those who were negative for this outcome. Also, patients with positive myocardial late gadolinium enhancement had significantly higher corrected QT interval than those who were negative (431.1 ± 20.1 ms vs. 408.2 ± 10.5 ms). An association was also reported between myocardial abnormalities and corrected QT interval. Patients treated with biologic DMARDs had a significantly lower corrected QT interval than those treated with non-biologics. Analysis of receiver operating characteristics indicated the corrected QT interval was effective in detecting myocardial abnormalities, according to the results.

“We should consider the possibility of subclinical cardiac involvements in RA cases, even in those with normal [corrected QT] interval,” the researchers concluded.

“On average, RA patients die of cardiovascular events and cancer, just like the general population, but slightly earlier,” Pope said. “Non-standardized imaging, such carotid imaging or MRI of the heart, is not needed for routine care, but can be used as research tools.”

Joint Replacement-associated Infections

Joint replacement and associated infections present another group of comorbidities for rheumatologists to tackle. Michael D. George, MD, MSCE, an instructor in the Division of Rheumatology at the University of Pennsylvania, and colleagues assessed whether the timing of infliximab therapy before elective hip or knee arthroplasty was associated with an increase in infection risk in 4,288 surgeries performed in 3,867 patients. Specifically, they evaluated a stop time for the drug of less than 4 weeks compared with 8 weeks to 12 weeks. Adjusted analysis results indicated stopping at the shorter time period was not associated with an increase in 30-day infection risk. There was no difference in infection risk among patients who stopped infliximab (Remicade, Janssen) earlier or later than 4 weeks before surgery. However, oral glucocorticoid dose greater than 10 mg, age older than 80 years, higher Charlson comorbidity, previous hospitalization for infection, more outpatient visits and treatment from 2007 to 2009 vs. 2010 to 2013 were factors associated with increased infection risk.

“A number of previous studies have suggested that patients with RA have an increased risk of infection after joint replacement surgery, especially the risk of prosthetic joint infection,” George said in an interview with Healio Rheumatology. “Even though the risk of a serious prosthetic joint infection is higher in patients with RA than in patients with osteoarthritis (OA), the overall risk of serious infection still remains low and most patients do well with surgery.”

George said it is unclear whether the elevated risk of infection after surgery in patients with RA is related to medications, comorbidities or the disease itself. He suggested the infection risk may come from inflammation in the joint that renders surgery more difficult or interferes with the healing or rehabilitation process or from medications or other factors.

“This study looks at what to do when patients who are on infliximab undergo surgery,” he said. “There are concerns that being on these medications might increase the risk of infection after surgery. For this reason, physicians might decide to stop the medication before surgery in the hope that patients have a lower risk of infection after surgery. Stopping the medication has risks as well. Patients might have a flare requiring higher doses of glucocorticoids, either of which might increase their risk of infection after surgery.”

Waiting at least 1 week to 2 weeks after surgery and ensuring that the surgery site is healing well before restarting infliximab “is still a good idea,” according to George. “A big takeaway from our study is that higher doses of glucocorticoids, especially more than 10 mg per day, were associated with increased rates of infection,” he said. “The effect of glucocorticoids on infection seems to be stronger than any effect from stopping or continuing medications like infliximab. Trying to minimize the glucocorticoid dose before surgery is important.”

Controlling RA prior to surgery is also critical, according to George. “Having a surgeon who performs a lot of joint surgeries can lead to better outcomes, and surgeons who are experienced in operating in patients with RA may be helpful, as well,” he said.

Glucocorticoids are a major risk factor for infection, especially at higher doses, according to George.

“Finding a medication regimen that allows disease control with either no glucocorticoids or low doses may help prevent infections in general and after surgery,” he said. “Glucocorticoids seem to have a much greater impact on the risk of infection than any effect from stopping a medication like infliximab, so stopping infliximab but increasing glucocorticoids before surgery to control RA is not a good idea.”

In another study, Namrata Singh, MD, of the Department of Internal Medicine at the University of Iowa Hospitals and Clinics and of the Iowa City VA (UIHC-VA), and colleagues aimed to evaluate the risk for recurrence of prosthetic joint infections in patients with RA compared to patients without RA. The retrospective cohort study included 731 veterans accrued between 2003 and 2010. There were 91 patients with RA assessed in the analysis. No difference was reported between the RA and non-RA groups in terms of time to the first infection after arthroplasty. However, patients with RA trended toward a lower risk for recurrent infection compared with the OA group. Patients with MRSA were more likely to have recurrent infections compared to those with methicillin-susceptible Staphylococcus aureus.

“What needs to be kept in mind is that our study was evaluating RA as a predictor of recurrent prosthetic joint infection and not the incident prosthetic joint infection,” Singh said. “To our knowledge, only two other studies have looked at the outcome of first prosthetic joint infection in RA patients.”

She noted that this is the first study to the investigator’s knowledge to look at the recurrence of PJIs in the VA rheumatoid arthritis patients.

“The results of our study show that patients with RA do not have higher risk of recurrent S. aureus infection compared to OA,” she said. “This perhaps can be explained by the fact that if a patient’s inflammatory arthritis is controlled, then they tend to have a favorable prognosis. This is a VA study and so a mostly male population contributed to the data set. Results should be generalized to the appropriate population.”

Adequate control of the underlying inflammatory arthritis is critical in minimizing these risks, as is working closely with other specialists, including infectious diseases and orthopedic clinicians, Singh suggested. “This will help develop the best management plan for an individual patient,” she said.

A two-stage exchange surgery process for joint replacement may also be beneficial. “If [the] patient is a candidate for this surgery, it is the surgery that should be recommended to them,” Singh said. “At UIHC-VA, my coauthors are involved in a large study to reduce infections in this population where we screen patients for S. aureus colonization. If they are carriers, we give them nasal ointment and an antimicrobial body wash to get the S. aureus off of their nose and skin. We then give them antibiotics during surgery that are directed at the bacteria that we find.”

Infectious Diseases

Pretorius and colleagues reviewed the extent to which infectious agents, including those that become dormant within the host, impact the etiology of RA. Infectious agents produce auto-antigens. These cross-reactive antigens, along with inflammatory agents, such as lipopolysaccharide, can lead to fibrin amyloid formation. Iron dysregulation, hypercoagulability, anomalous morphologies of host erythrocytes and microparticle formation occur in chronic inflammatory diseases and may contribute to the hypothesis that dormant bacteria are also involved in RA disease etiology and development.

Douglas Kell, MA, DPhil, DSc, of the University of Manchester, was a collaborator on this study.

“The evidence for a role of bacteria in RA is overwhelming,” he said. “What has made it hard for folks to recognize this fact is that the bacteria are typically in a latent or dormant state, in which they do not replicate easily and thus, are invisible to conventional culture-based microbiology.”

“However, the presence of these bacteria also provides a stress,” Kell said. “That means the immune system may not be able to fend off other bacteria that either come in again as genuine infection or which were already there and dormant and also happen to wake up.”

Kell added the cell wall is the most inflammatory component of a bacterial cell.

“The kinds of bacteria most implicated in RA — namely Proteus species — are Gram-negative,” he said. “The cell wall component is known as lipopolysaccharide, which is extremely potent at causing inflammation. It induces the production of inflammatory cytokines such as [tumor necrosis factor] TNF-alpha that are well-known to be raised in RA, especially during flares.”

He also said the molecules involved in this process may cause inflammation in other inflammatory conditions, which could provide a simple explanation for the comorbidities.

“In addition, we recently found lipopolysaccharide caused blood to clot into an anomalous and so-called amyloid form,” he said. “That is much harder to remove than normal blood clots.”

It is important to acknowledge treatments that target microbial proliferation may be beneficial in patients with RA, according to Kell. “These can include iron withholding or certain antibiotics,” he said. “It is worth noting that several DMARDs in common use are in fact antibiotic. Finally, we think molecules that defend against excess or anomalous coagulation may also be of value.”

Vaccination Rates

In a study presented at the American College of Rheumatology Annual Meeting, Park and colleagues wrote that influenza vaccination is critical in patient populations with RA. They aimed to investigate whether a temporary discontinuation of MTX improves the effectiveness of seasonal influenza vaccination in a single-center, randomized, single-blind, open-label, prospective, parallel group intervention study that involved 219 patients. There were four study groups. In the first group, 54 patients with a stable MTX dose continued that dose; in the second, 44 patients ceased MTX for 4 weeks before influenza vaccination; in the third, 49 patients ceased MTX for 2 weeks before vaccination and 2 weeks after vaccination; and in the fourth, 52 patients ceased MTX for 4 weeks after vaccination.

Four weeks after vaccination, the third and fourth groups demonstrated higher increases in antibody titers against H1N1, H3N2 and B-Yamagata antigens than patients in the first group. The first and second groups demonstrated comparable increases in antibody titers and satisfactory vaccine responses, according to the results. While all groups responded well to H3N2, the third and fourth groups showed notable improvements in protective titers against H1N1 and B-Yamagata.

“Temporary discontinuation of MTX improves the immunogenicity of seasonal influenza vaccination in RA patients,” the researchers concluded. “Further studies are needed to determine the duration of MTX discontinuation.”

Gossec underscored an earlier point. “RA patients also need more vaccinations than the general population, but they are not getting them,” she said.

Other Complications

Merdler-Rabinowicz and colleagues, including Amital, suggested the coexistence of RA and gout is rare. However, in an analysis of 11,540 patients with RA and 56,763 controls, the proportion of gout was significantly higher among patients with RA than controls (1.61% vs. 0.92%). The association persisted in multivariable analysis. “The proportion of gout in RA patients is not lower than in the general population,” the researchers concluded.

Amital noted the comprehensive nature of the database in Israel from which this information was drawn. “Every clinical encounter from the last 15 years is included in this database,” he said. “This allows us to find interesting aspects of diseases, including comorbidities. This is real-life data.”

In this particular study, the researchers wanted to see whether any association existed between the two diseases, according to Amital.

“It is a well-known concept that patients with gout also frequently have RA, but there are different explanations for it,” he said. “It may have to do with the fact that uric acid has antioxidants that impact the joints, or it may have to do with the drugs used to treat inflammation in RA patients. These concepts still have not been validated.”

Regarding other conditions, Garip and colleagues investigated comorbidities in a cohort of 160 patients with RA in Turkey and how those comorbidities impact quality of life (QOL). The overall comorbidity rate was 67%. Peptic ulcers were reported in 31.3% of the group. Osteoporosis occurred in more than 20% of patients, while dyslipidemia, depression, hypertension and diabetes mellitus were reported in 10% to 15% of patients. Thyroid disorders, lung diseases, cardiovascular diseases and cancers also were present. Patients with comorbidities scored significantly higher in a number of QOL measures.

“Patients should be engaged in their care and responsible for diet, exercise, taking their medications, weight loss and an overall healthy lifestyle,” Pope said. “We all know this is not easy and even more of a problem if there are swollen, painful joints.”

Ozen and colleagues followed 13,669 patients with RA for a median of 4.6 years to determine diabetes mellitus incidence. They found 1,139 incident cases, for a standardized incidence ratio of 1.37 compared to the general U.S. population. Adjusted analysis results showed factors contributing to diabetes mellitus in patients with RA, including hydroxychloroquine, abatacept vs. MTX monotherapy, glucocorticoids and statins. “Hydroxychloroquine and abatacept were associated with decreased risk of [diabetes mellitus], and glucocorticoids and statins with increased risk,” the researchers concluded.

Shen and colleagues found the rate of sleep apnea was 75% higher in patients with RA than patients without RA.

“The more data sets we see, the more tools we are going to have to understand the linkages between RA and different diseases,” Amital said. “Clinicians should be open-minded about all of these conditions. Often, you can find data sets that state different findings or concepts, but when you drill down and find the evidence you find they are not valid. But this does not mean that these complications do not exist.”

For Amital, it simply comes down to awareness.

“Physicians should understand the primary and secondary prevention procedures for the comorbidities that may arise in their RA patients,” he said.

Pope agreed.

“Rheumatologists should be interested in comorbidities,” she said. “They should be concerned.” – by Rob Volansky

• References:
• Garip Y, et al. Acta Reumatol Port. 2016. [Epub ahead of print].
• George MD, et al. Abstract #2052. Presented at: American College of Rheumatology Annual Meeting; Nov. 11-16, 2016; Washington.
• Gossec L, et al. Abstract #2050. Presented at: American College of Rheumatology Annual Meeting; Nov. 11-16, 2016; Washington.
• Kell DB, et al. Progr Biophys Mol Biol. 2016;doi:http://dx.doi.org/10.1016/j.pbiomolbio.2016.1008.1006.
• Kobayashi Y, et al. Abstract #2055. Presented at: American College of Rheumatology Annual Meeting; Nov. 11-16, 2016; Washington.
• Ozen G, et al. Ann Rheum Dis. 2016;doi:10.1136/annrheumdis-2016-209954.
• Park JK, et al. Abstract #2054. Presented at: American College of Rheumatology Annual Meeting; Nov. 11-16, 2016; Washington.
• Pretorius E, et al. J R Soc Interface. 2016;123:20160539.
• Pretorius E, et al. Exp Biol Med (Maywood). 2016;pii:1535370216681549.
• wRantapaa-Dahlqvist S, et al. Abstract #2051. Presented at: American College of Rheumatology Annual Meeting; Nov. 11-16, 2016; Washington.
• Pope JE, et al. Open Rheumatol J. 2016;10:49-59.
• Shen TC. BMJ Open. 2016; doi:10.1136/bmjopen-2016-013151.
• Singh N, et al. Abstract #2053. Presented at: American College of Rheumatology Annual Meeting; Nov. 11-16, 2016; Washington.

• For more information:
• Howard Amital, MD, can be reached at ­­­­­­­­­Sheba Medical Center Hospital-Tel Hashomer, 52621 Ramat Gan, Israel; email: howard.amital@sheba.health.gov.il.
• Michael D. George, MD, MSCE, can be reached at 3400 Spruce St; 5 White Building, Philadelphia, PA 19104; email: michael.george@uphs.upenn.edu.
• Laure Gossec, MD, PhD, can be reached at Pitié Salpétriere Hospital, 47 Bd Hopital, 75013 Paris, France; email: laure.gossec@psl.aphp.fr.
• Douglas Kell, MA, DPhil, DSc, can be reached at School of Chemistry and Manchester Institute of Biotechnology, The University of Manchester, 131 Princess St, Manchester M1 7DN, Lancs, United Kingdom; email: dbk@manchester.ac.uk.
• Janet E. Pope, MD, can be reached at St. Joseph’s Hospital 268 Grosvenor St., London, Ontario, N6A 4V2, Canada; email: janet.pope@sjhc.london.on.ca.
• Namrata Singh, MD, can be reached at 200 Hawkins Dr., C42 E10, Iowa City, IA 52242; email: namrata-singh@uiowa.edu.

Disclosures: Amital, George, Gossec, Kell and Singh report no relevant financial disclosures. Pope reports she is a consultant for AbbVie, Amgen, Bristol-Myers Squibb, Genzyme, Hospira, Janssen, Eli Lilly, Merck, Novartis, Pfizer, Regeneron, Roche, Sandofi and UCB.