Weighty Concerns: Tackling Obesity in Patients With Rheumatic Diseases

It is no secret that America has a weight problem. Likewise, it is well known among rheumatologists that overweight and obesity can worsen diseases like knee osteoarthritis — largely due to excessive mechanical load on the joint — and that inflammation present in both obesity and rheumatic diseases may be related.

In 2015, data from the CDC indicated that arthritis was observed in 16.4% of the underweight or normal weight population and in 27.7% of obese individuals. A mounting body of evidence shows worse outcomes for obese patients with a host of rheumatic and autoimmune diseases; these links are no secret. The questions pertain to how the average rheumatologist is supposed to manage their heavier patients. There are weight-based dosing issues to consider, treatment complications and increased comorbidities.

Rheumatologists must consider when to enlist the help of a weight management specialist and how to operate with a team approach that may also include a nutritionist or fitness instructor. With obesity putting a strain upwards of $150 billion on the U.S. health care system, the stakes couldn’t be higher.

There are plenty of available data on obesity and its impact on rheumatic diseases, according to Patricia P. Katz, PhD, of the division of rheumatology at the University of California, San Francisco. “A lot of research pertains to obesity and outcomes in various diseases, or reasons why there might be a link between obesity and disease status,” she said.

However, she highlighted a key shortcoming of the current body of knowledge: “Nobody has done the study to look at obesity as a risk factor for onset of disease.”

She noted that Jon T. Giles, MD, MPH, of the division of rheumatology at Columbia University, and colleagues, conducted a key study of obesity preceding rheumatoid arthritis. However, she expressed reservations about the result. “Causality is a touchy issue, and difficult to prove,” she said.

Giles agreed. “The associations are interesting in the studies I have done, particularly for RA and psoriatic arthritis, but the picture is still complicated and not well understood,” he said. “Obesity appears to be a contributor to RA development now that the population is heavier and people don’t smoke as much, but there are still questions surrounding adipose tissue and adiponectin that need to be answered.”

M. Elaine Husni, MD, MPH, vice chair of the department of rheumatic and immunologic diseases and director of the Arthritis Center at the Cleveland Clinic, noted that questions persist despite ongoing research to understand them. “There are studies that show that obesity worsens the course of RA, systemic lupus erythematosus, inflammatory bowel disease, psoriasis and PsA, while others show that obesity impairs the treatment response of RA, IBD, psoriasis and PsA,” she said.

Another query that requires further investigation surrounds response to various medications — namely TNF inhibitors — among heavier individuals. Other questions include the role of increased BMI as it pertains to poor outcomes in diseases ranging from SLE to gout. “I have done work in both RA and lupus, and in both conditions we have seen worse outcomes ranging from higher pain levels to increased rates of depression,” Katz said. “There is reason to suppose other quality of life factors may be impacted, but we are still trying to understand the associations.”

All of this begs the question of how rheumatologists can integrate weight management into a brief and busy visit, according to Joshua F. Baker, MD, MSCE, assistant professor of medicine and epidemiology in biostatistics and epidemiology at the Hospital of the University of Pennsylvania and the Philadelphia Veteran’s Affairs Medical Center. “This is a huge challenge in the clinic,” he said. “Rheumatologists and other providers do not get enough time to make good recommendations for physical activity for patients or to help with other approaches to weight loss.”

It is with this in mind that Healio Rheumatology aims to tackle some of these issues and offer actionable recommendations for practicing clinicians.

Role of Inflammation

A breakthrough study on the role of inflammation in obesity and rheumatic diseases was conducted by Hughes-Austin and colleagues. They analyzed samples from 144 first-degree relatives of individuals with RA to determine potential relationships between inflammation and markers such as adiponectin, cytokines, and high-sensitivity C-reactive protein. Results showed that 1% higher adiponectin was associated with a 26% reduction in both high-sensitivity C-reactive protein (P = .04) and IL-1B (P = .04). The researchers also observed interactions between high-sensitivity C-reactive protein and adiponectin that were associated with granulocyte-macrophage colony-stimulating factor, IL-6, and IL-9.

Christopher T. Ritchlin, MD, MPH, of the department of allergy, immunology and rheumatology at the University of Rochester Medical Center, dug into the subject of inflammation. “At the cellular level, inflammation and metabolic receptors converge on common pathways,” he said. “There are common organelles, and common gene transcription pathways in the nucleus. If you activate inflammation, you are probably activating metabolic pathways, and vice versa.”

Giles acknowledged that heavier patients tend to have more adipose mass and higher levels of circulating inflammatory markers. “Recently, we have seen studies that showed that adipose tissue has inflammatory properties,” he said. “Since RA patients tend to have more adipose tissue, it may be more inflamed and might be a driver of what is happening in the joints. This is what we are trying to understand a little more.”

The confounding aspect of these associations is that adiponectin may lead to joint damage, according to Giles. “Individuals with higher adiponectin levels tend to have more erosions in their joints,” he said. “People who are lean have less adipose tissue that produces abundant adiponectin. As they gain weight, the production of adiponectin declines. Adiponectin has an anti-inflammatory effect in the adipose tissue and arteries, but appears to have a different effect in the joints where it may turn on several processes that lead to erosive damage. We and others have shown that RA patients with higher adiponectin levels tend to have more erosions over time.”

It is worth noting that this phenomenon may not be the case in every tissue, noted Giles. “But it does present something of a dichotomy in weight management with RA,” he said. “If they lose weight, they may be less systemically inflamed and cardiovascular risk goes down, and perhaps the burden of synovitis goes down, but erosions may develop.”

For Katz, understanding that some of the inflammatory processes seen in obesity are also at play in RA is a good first step. “However, I don’t think we have good data for how those interact yet,” she said. “We haven’t teased out some of those relationships. All we have are observational studies showing worse outcomes.”

Husni also encouraged further investigation. “Studies to date, however, have not established adipocytokines as a direct link between obesity and the development of RA,” she said. “Vitamin D deficiency, sex hormone differences, and insulin resistance leading to increased inflammation have been proposed as other potential mechanisms. However, they are all currently hypothetical.”

Cause and Effect

Another key step that could be answered in the research arena is whether obesity actually causes rheumatic or autoimmune disease. Feng and colleagues conducted a meta-analysis of 13,562 RA cases among 400,609 participants across 13 studies to determine possible associations between BMI and RA risk. Obesity carried a risk for RA (RR = 1.21; 95% CI, 1.02-1.44), as did overweight (RR = 1.05; 95% CI, 0.97-1.13). For every 5 kg/m² increase in BMI, the researchers observed an increase in RA risk of 13% (RR = 1.13; 95% CI, 1.01-1.26). Subgroup analyses demonstrated that obese women were particularly at risk for RA (RR = 1.26; 95% CI, 1.12-1.40). Further, obese individuals who were seronegative for RA also were at risk for the disease (RR = 1.47; 95% CI, 1.11-1.96).

“What I find interesting about this study is that they show how the effect of obesity on RA is only observed for people who have seronegative disease and for women,” Baker said. “These observations should cause us to question whether the relationship between obesity and RA is related to misdiagnosis.”

However, there is a key shortcoming of retrospective studies, according to Katz. “The studies attempting to establish causality have really only involved people with disease,” she said. “To really find out if a factor like obesity precedes onset, we would have to do a prospective study, which would be different from the data we have, and difficult to conduct.”

Reduced Therapeutic Response

A growing body of data is showing that overweight or obesity leads to reduced response to therapy — except when it doesn’t.

Gremese and colleagues identified 641 obese patients with chronic RA who had been treated with TNF inhibitors during 2006 through 2009. The analysis included 260 patients treated with adalimumab (Humira, AbbVie), 227 with etanercept (Enbrel, Amgen), and 154 with infliximab (Remicade, Janssen). Baseline data showed a DAS28 score of 5.6 ± 1.4. At follow-up 12 months after treatment, DAS28 of less than 2.6 was reported in 15.2% of obese participants, 30.4% of those with a BMI of 25 kg/m² to 30 kg/m², and 32.9% of those with a BMI of less than 25 kg/m² (P = .01). Patients treated with infliximab carried the lowest likelihood of achieving remission compared with the other two therapies (P = .003).

“Studies have shown poor response to therapy and worsening of disability in obese patients,” Baker told Healio Rheumatology. “Some of this may be due to direct effects of the obesity that impact how we measure the impact of the arthritis. It seems clear that reducing obesity would have a direct beneficial effect on measures that are important to patients with arthritis.”

Similarly, Ottaviani and colleagues retrospectively reviewed 76 normal weight, overweight and obese patients treated with infliximab. Compared with patients with a higher BMI, those with a lower BMI were more likely to experience a decrease in DAS28 (OR = 0.88; P = .02) and a EULAR good response (OR = 0.87; P = .03). Lower BMI also demonstrated a non-significant trend toward EULAR remission (OR = 0.88; P = .14).

“The body of data is increasing, showing that anti-TNF agents are less effective in obese patients,” Ritchlin said. “This is why in patients with a higher BMI, we use a TNF agent with weight-based dosing.”

However, Ritchlin acknowledged that most biologic therapies are not weight-based. “We are starting to see trends that as patients’ weight goes up, efficacy can drop,” he said. “This should make us reconsider dosing.”

In their meta-analysis of 19,372 patients from 54 cohorts, Singh and colleagues found that obese patients were 60% more likely to fail therapy (OR = 1.6; 95% CI,1.39-1.83). The researchers also reported a dose-response relationship, with both obese vs. normal BMI individuals (OR = 1.87; 95% CI, 1.39-2.52) and overweight vs. normal BMI individuals (OR = 1.38; 95% CI, 1.11-1.74) demonstrating an increased likelihood of poor response. The researchers saw this effect in all diseases except IBD.

Conversely, Gardette and colleagues conducted a multicenter retrospective study that included 64 normal weight patients, 38 who were overweight, and 39 who were obese. Results of the univariable analysis showed that BMI did not impact response or non-response in terms of DAS28 decrease (P = .95), EULAR good response (P = .96), or remission (P = .83).

Baker addressed the conflicting data for dose-response in obese patients with RA. “This is an interesting area of debate for which there is not a good answer,” he said. “There are a number of studies in RA that have shown poor response in obese patients to a number of drugs. However, without head-to-head studies, it is very unclear whether one drug is better than another in this group. Currently, most rheumatologists would not alter therapy based on weight, with the exception of dosing medications differently.”

Associations Beyond RA

To evaluate the impact of obesity on patients with SLE, Rizk and colleagues examined quality of life (QoL) outcomes, along with functional capacity and the risk of carotid atherosclerotic plaque formation, in a cohort of 60 patients with SLE. The researchers observed a significant association between increased BMI and both lupus nephritis and hypertension. Obese SLE patients also were more likely to have lower QoL parameters, poorer functional capacity, and obvious dyslipidemia, according to the results. Other findings showed a correlation between increased waist circumference and atherosclerosis risk.

“There are some studies suggesting that obesity is a risk factor for the development of both RA and lupus,” Baker said. “The results of these studies are not consistent. There is also concern that people who are obese are simply more likely to come to attention and to be diagnosed with these conditions, as opposed to a true causal relationship. The relationships are also fairly modest.”

Katz added that there may be an additional component to the lupus story. “In lupus, we also saw obesity associated with higher probability of cognitive impairment,” she said.

Larsson and colleagues studied whether overall obesity as assessed by BMI and waist-to-hip ratio adjusted for BMI increased gout risk in 2,115 cases of the disease, 67,259 controls, and serum urate concentrations in 110,347 individuals culled from the Global Urate Genetics Consortium. Increased BMI, but not waist-to-hip ratio adjusted for BMI, carried an association with both gout risk and serum urate concentrations, according to the results. An increase of about 4.6 kg/m² in BMI yielded more than a two-fold risk of gout (OR = 2.24; 95% CI 1.7-2.95) and a 0.3 mg/dL (95% CI, 0.25-0.35) increase in serum urate concentrations, according to the findings.

“The associations between weight gain and gout are most likely related to risk factors related to metabolic syndrome and hypertension,” Giles said. “In these cases, unlike with the adiponectin association, losing weight doesn’t have a down side.”

Considering PsA in their study published in Arthritis Care & Research, diMinno and colleagues assessed whether obesity could impact minimal disease activity as an endpoint in 135 obese patients and 135 with normal weight. Results indicated that the prevalence of obesity was 64% in patients who failed to reach minimal disease activity and 25.5% in those who reached this outcome (P < .001). The association persisted through adjusted multivariable analysis (HR = 4.9; 95% CI, 3.04-7.87).

“The psoriasis story is interesting in that we have known for a long time that people with psoriasis and PsA are more likely to be overweight or obese,” Giles said. “It’s cleaner than the RA story. As people gain weight, risk for psoriasis increases, and as they increase weight further, risk for PsA increases.”

Giles added that the severity of PsA also increases as patients with this disease gain weight.

Conversations on Weight Loss

Underlying all of these associations and potential associations is the need for rheumatologists to address weight loss with their patients in some way. The age-old recommendations for diet and exercise are as difficult to drive home as they have ever been, according to Katz. “It’s really hard — in general, dealing with obesity requires lifestyle changes,” she said. “You have to change the way you eat and change the way you move. I’m more familiar with the move aspect than the food aspect, but I know that changing what people eat is extremely difficult, and that it is probably easier to change people’s physical activity levels.”

Ritchlin stressed the importance of using data as a tool. “If we can show our patients compelling studies showing that reducing BMI can lead to a dramatic improvement in treatment response, it can be easier to get them to make those changes,” he said.

Katz agreed. “Many patients believe that moving or doing exercise might make their disease worse, or might make their joints hurt more,” she said. “However, the data actually show the exact opposite of that, that people who are more active have better outcomes, across the board, including for pain and quality of life. This is a key message.”

For Giles, the most common association pertains to a reduction in mechanical load as a way of relieving pain and stress in knee OA. “We can show our patients these studies,” he said.

But sometimes the messages simply don’t compute, Giles noted. “As with many people in our field, I have patients with whom I have been discussing strategies for weight loss for years, even decades, and it never seems to translate,” he said. “There still seems to be a disconnect between what patients understand intellectually and what they do at home.”

Giles said that clinicians should do whatever it takes to push the weight loss message. “I have shown patients who were participants in a body composition study the result of a specialized body scan where they can visually see how much fat, muscle and bone they have,” he said. “When they saw their tiny skeleton surrounded by so much adipose tissue, two of my patients said it was a wakeup call.”

Like most experts, Husni recommends starting small. “Just as with other patients without immune-mediated diseases, it would be more beneficial to lose pounds over time rather than large decreases in shorter periods of time,” she said. “Also, we recommend having a buddy. It is always easier to stay on target with a buddy than without a buddy.”

On the subject of targets, Katz suggested reasonable goals. “We don’t tell patients they have to join a gym or walk 10,000 steps a day,” she said. “We tell them that if they can take a walk for 15 or 20 minutes, they may start to get over the hump of simply being tired all the time.”

It is generally understood that while exercise can lead to a healthier lifestyle overall, the true way to lose is through a combination of diet and exercise. “You have to engage in an extraordinary amount of exercise in order to lose fat in the absence of decreasing dietary caloric intake” Giles said.

“What we emphasize is caloric restriction,” Ritchlin added. “It doesn’t matter how you do it, whether you get your patients on the Mediterranean diet, or Atkins. You just have to get them to reduce the number of calories they take in per day.”

Giles put a number on that reduction: 300. “Reducing caloric intake by 300 to 350 calories a day — approximately the number of calories in a bagel — results in about a pound of weight loss per week, which is a good way to approach sustained weight loss,” he said.

Ritchlin prefers Weight Watchers, specifically the component of the program where patients go to actual meetings rather than simply tracking their calories online or through a mobile app. “We have found that a supervised environment is more effective,” he said.

Baker feels that there are few resources to provide to patients to help them accomplish weight loss goals and physical activity goals. “Referral to physical therapy can sometimes be helpful,” he said. “For those with means, personal trainers with expertise in joint conditions can be highly valuable. There are no pharmacologic therapies for obesity that are currently in regular use in this population.”

Regardless of the approach, Ritchlin stressed ongoing communication between doctor and patient. “It is difficult to find the time and the right way to have this discussion, but it is an important discussion to have,” he said. “Many patients want to know what they can do for their disease. We just have to keep telling them that losing weight is a good place to start.” – by Rob Volansky

• References:
• diMinno MN, et al. Arthritis Care Res (Hoboken). 2013;doi: 10.1002/acr.21711.
• Feng J, et al. Medicine (Baltimore). 2016;doi:10.1097/MD.0000000000002859.
• Gardette A, et al. Eur J Clin Invest. 2016;doi:10.1111/eci.12691.
• Gremese E, et al. Arthritis Care Res (Hoboken). 2013;doi:10.1002/acr.21768.
• Hughes-Austin JM, et al. PLoS One. 2018;doi: 10.1371/journal.pone.0199578.
• Larsson SC, et al. Rheumatology (Oxford). 2018;doi:10.1093/rheumatology/key229.
• Ottaviani S, et al. Clin Exp Rheumatol. 2015:478-483.
• Rizk A, et al. Int J Rheum Dis. 2012;doi: 10.1111/j.1756-185X.2011.01698.x.
• Singh S, et al. PLoS One. 2018;doi:10.1371/journal.pone.0195123.

• For more information:
• Joshua F. Baker, MD, MSCE, can be reached at 3400 Spruce St, Philadelphia, PA 19104; email: holly.auer@uphs.upenn.edu.
• Jon T. Giles, MD, MPH, can be reached at 630 W 168th St, New York, NY 10032; email: jtg2122@cumc.columbia.edu.
• M. Elaine Husni, MD, MPH, can be reached at 9500 Euclid Ave A50, Cleveland, OH 44195; email: husnie@ccf.org.
• Patricia P. Katz, PhD, can be reached at 3333 California St., Suite 270, San Francisco, CA 94143-0920; email: patti.katz@ucsf.edu.
• Christopher Ritchlin, MD, MPH, can be reached at Calkins Corporate Park, 400 Red Creek Drive, Suite 240, Rochester, NY 14623; email: susanne_pallo@URMC.Rochester.edu.

Disclosures: Baker reports consulting for Bristol-Myers Squibb. Ritchlin reports research grants from Abbvie, Amgen and UCB, as well as consulting fees from Abbvie, Amgen, Lilly, Novartis, Pfizer and UCB. Giles, Katz and Husni report no relevant financial disclosures.