I had a new patient, LO, come to me following a referral from urgent care in March 2017. Her urgent care visit was prompted by joint swelling and pain in her hands and wrists, certainly not an unusual combination in our new patients. Among LO’s issues was the fact that she was obese, with a body mass index (BMI) of 37.1.

The initial workup showed that LO’s labs were negative for rheumatoid factor and anti-citric citrullinated protein antibodies. Her uric acid level was borderline high, at 6.0 mg/dL, while her C-reactive protein (CRP) levels were clearly elevated at 7.1 mg/dL. This presentation was consistent with seronegative rheumatoid arthritis (RA), and we initiated a prednisone dose pack to get LO’s symptoms under short-term control. One unrelated yet important finding during our workup was the identification of a previously undiagnosed heart murmur, which led to a referral to cardiology for an echocardiogram.

After our initial exam, I ordered a multi-biomarker disease activity (MBDA) panel to gauge the severity of LO’s RA. Results showed highly active disease, with 22/28 swollen and tender joints. Recent research has shown that patients with seronegative RA often have more severe early-stage disease, so this finding was not surprising.1

Due to LO’s high CRP, I immediately started her on methotrexate while continuing the prednisone at 10 mg daily. Six weeks later, LO returned for her initial follow-up and expressed modest improvements in her morning stiffness and overall joint pain. We began weaning her off of prednisone at this time. We also reviewed LO’s echocardiogram results, which showed elevated right ventricular systolic pressure of 33 mm Hg, qualifying LO for mild pulmonary hypertension.2 We again encouraged LO to see a cardiologist to help manage this issue.

By July 2017, LO’s symptoms continued to improve on 8 tablets of MTX weekly, and she had successfully been weaned off prednisone. With this progress, our team encouraged LO to start exercising more regularly, and we discussed with her the potential benefits of an anti-inflammatory diet to help with disease control and weight loss. LO initially had some success with the Whole30® program – losing 6 pounds in a 4-week span – but she found the diet too restrictive and decided to enroll in a Weight Watchers plan instead.

LO’s RA symptoms continued to improve. By October, her MBDA score had fallen from 35 to 29, showing marked improvement. However, the objective improvements were not matched by LO’s subjective improvements – she was still not happy. She felt burdened by persistent daily fatigue and said she “just didn’t feel like my old self.” Based on her feelings, we decided to add daily tofacitinib 11 mg to her MTX.

Six months later, there was mild improvement, but the fatigue and joint pain persisted. This time, LO’s MBDA score was back up near baseline levels. Her BMI was creeping up as well. LO reported feeling “exhausted all the time” and relied on sweets to give her the energy to get her through the workday.

By mid-May, LO’s BMI had shot up to 39.0. She came into my office in tears, fearing that she was going to lose to her job due to fatigue and an inability to concentrate. Our team again brought up the possibility of initiating an anti-inflammatory diet and began discussing another possible modification to LO’s treatment regimen. We also decided to look deeper into her MBDA to see if there were any clues within the results that may be of use. The one significant outlier we found was in LO’s serum leptin level. It was sky high at 110 ng/ mL (even in obese women, mean serum leptin levels are only approximately 65.0 ng/mL or less).3-4 Leptin is a fat hormone known to play a role in autoimmunity and inflammation. It also plays a role in the development of metabolic syndrome.5

Several recent studies have explored the efficacy of TNF inhibitors in RA patients with high leptin levels and a poor clinical response to traditional disease modifying anti-rheumatic drugs such as MTX. In general, these studies showed that TNF inhibitors have, at best, limited impact on lowering leptin levels and BMI, irrespective of their potential beneficial impact on RA disease activity.6-8

After perusing through the literature, I suggested to LO that she might fare better on weight-based intravenous therapy and suggested a trial of IV abatacept, a T-cell inhibitor. I also suggested to LO that she likely wouldn’t start feeling significantly better until she started taking care of her whole self. LO re-committed to Weight Watchers and told me she would begin taking walks on her breaks at work.

After this visit, LO went back to her cardiologist for another follow-up. Interestingly, since starting MTX, LO’s right ventricular systolic pressure had decreased to 20 mm Hg, putting her out of
immediate concern for pulmonary hypertension.

And then another roadblock.

LO’s insurance company denied the initiation of abatacept, insisting that she be put on a TNF inhibitor first. Bruised and disheartened, my practice manager and I called LO and explained that she would have to try golimumab first because we couldn’t get access to the medication we felt would work best for her.

I haven’t yet given up hope, and neither has LO. We continue to wait for the day—hopefully in the not-too-distant future—when we will be able to utilize biomarker tests that show us which patients will respond to which medications and allow us to avoid the messiness of jumping from treatment to treatment and pleading our case to insurance companies for hours each week.

AUTHOR BIO
Iris Zink, MSN, NP, RN-BC is a nurse practitioner at Lansing Rheumatology in Lansing, Michigan.

References

1. Choi S, Lee KH. Correction: Clinical management of seronegative and seropositive rheumatoid arthritis: A comparative study. PLoS One. 2018;13(6):e0199468.

2. American Heart Association. Pulmonary hypertension – high blood pressure in the heart-to-lung system. Available at www.heart.org/HEARTORG/Conditions/HighBloodPressure/
GettheFactsAboutHighBloodPressure/Pulmonary-Hypertension—High-Blood-Pressure-in-the-Heart-to-Lung-System_UCM_301792_Article.jsp#.
Wzp-1tJKjIU. Accessed July 2, 2018.

3. Kazmi A, Sattar A, Hashim R, Khan SP, Younus M, Khan FA. Serum leptin values in the healthy obese and non-obese subjects of Rawalpindi. J Pak Med Assoc. 2013;63(2):245-8.

4. Gijón-Conde T, Graciani A, Guallar-Castillón P, et al. Leptin reference values and cutoffs for identifying cardiometabolic abnormalities in the Spanish population. Rev Esp Cardiol (Engl Ed). 2015;68(8):672-9.

5. Patel SB, Reams GP, Spear RM, Freeman RH, Villarreal D. Leptin: linking obesity, the metabolic syndrome, and cardiovascular disease. Curr Hypertens Rep. 2008;10(2):131-7.

6. Engvall IL, Tengstrand B, Brismar K, Hafstrom I. Infliximab therapy increases body fat mass in early rheumatoid arthritis independently of changes in disease activity and levels of leptin and adiponectin: a randomized study over 21 months. Arthritis Res Ther. 2010;12:R197.

7. Gonzalez-Gay MA, Garcia-Unzueta MT, Berja A, et al. Anti-TNF-alpha therapy does not modulate leptin in patients with severe rheumatoid arthritis. Clin Exp Rheumatol. 2009;27:222–228.

8. Gonzalez-Gay MA, Garcia-Unzueta MT, Berja A, et al. Anti-TNF-alpha therapy does not modulate leptin in patients with severe rheumatoid arthritis. Clin Exp Rheumatol. 2009;27:222–228.