Does Sildenafil Improve Endothelial Dysfunction in Rheumatoid Arthritis?

Rheumatoid arthritis (RA) is associated with a 2-fold increased risk of cardiovascular
disease (CVD), which is not explained by traditional cardiovascular (CV) risk factors alone;
this risk is likely mediated in part through systemic inflammation. Indeed, RA itself is
deemed to impart a CV risk equivalent to diabetes mellitus (DM). However, unlike in DM,
optimal CV management strategies in RA are lacking. Despite improved anti-inflammatory
therapies for RA, the mortality gap in RA compared to the general population is still
widening, in part due to suboptimal primary and secondary CV preventive care in RA. To date,
there have been no published controlled intervention trials for primary CV prevention in RA,
despite this clearly urgent unmet need.

One of the early stages of atherogenesis is endothelial dysfunction, and drugs that target
improvement in this are promising novel strategies for CVD prevention. The fundamental
feature of endothelial dysfunction is impaired nitric oxide (NO) bioavailability. Sildenafil
improves endothelial function by increasing NO signaling by inhibition of phosphodiesterase-5
(PDE5). PDE5 inhibitors improve endothelial function in pulmonary hypertension and DM, and
were safe and well tolerated in patients with erectile dysfunction and other CV
comorbidities. Furthermore, PDE inhibitors have immunomodulatory properties that may be
utilized to treat autoimmune conditions like RA. The investigators' central hypothesis is
that sildenafil is a uniquely suited agent targeting endothelial dysfunction as a novel
adjunctive CV prevention strategy and immunomodulatory agent in RA. Specifically, their goal
is to determine if sildenafil use in RA improves endothelial dysfunction and atherosclerosis
biomarkers.

The proposed study is a phase II, randomized double-blind placebo-controlled crossover
efficacy trial of 60 RA patients, with no known history of CVD but at least one traditional
CV risk factor, on stable baseline doses of RA medications; randomized 1:1 to receive either
sildenafil 50 mg or placebo orally once daily for 3 months, with a 2-week washout before the
crossover phase for another 3 months. Vascular studies validated in assessing endothelial
dysfunction and laboratory studies for selected atherosclerosis biomarkers will be performed
at baseline, 3 months pre- and post-washout, and 6 months. Adverse events will be collected
to assess safety. The Specific Aims are:

1. To determine whether sildenafil use in RA leads to improvement in parameters of vascular
function; and to confirm its safety profile.

2. To determine whether sildenafil use in RA is associated with improvement in
atherosclerosis biomarkers.

The results of this study will serve as preliminary data for future larger trials evaluating
sildenafil as a CV prevention strategy by reducing endothelial dysfunction in RA. It will
provide needed data on potential benefits of sildenafil for immunomodulation and CV
prevention in this high-risk population.

Inclusion Criteria:

- Meets 2010 American College of Rheumatology (ACR) classification criteria for
diagnosis of RA

- Aged 18 years or older

- No known history of CVD (see Exclusion Criteria)

- At least one traditional CV risk factor (i.e., older age [men ≥45 years, women ≥55
years], obesity [defined as body mass index (BMI) >30 kg/m2], smoking, hypertension,
hyperlipidemia, diabetes mellitus, family history of premature [defined as diagnosed
at <65 years old] CVD in first-degree relative)

- On stable baseline doses of RA medications, defined as no change in dose within past 4
weeks and no anticipated changes over the next 6 months

- On no higher than 10 mg per day of prednisone or prednisone-equivalent within past 4
weeks

- RA disease duration (from symptom onset) of more than 6 months

- Having clinical disease activity index (CDAI) of >2.8 but ≤22 (i.e., either low or
moderate disease activity), within 30 days of study enrollment

Exclusion Criteria:

- Aged <18 years

- Pregnant women

- Known personal history of CVD (clinical diagnoses of stroke, transient ischemic
attack, myocardial infarction, acute coronary syndrome, peripheral arterial disease,
percutaneous coronary intervention or coronary bypass graft surgery)

- Use of high-dose statins (e.g., atorvastatin 40-80 mg/day or rosuvastatin 20-40
mg/day) currently or within past 3 months, or any dose changes of statins or of blood
pressure medications that may affect endothelial function (i.e.,
angiotensin-converting-enzyme [ACE] inhibitors or angiotensin receptor blockers
[ARBs]) within past 3 months. If on statin or an ACE-I or ARB, there should be no
anticipated dose changes over the next 6 months.

- Persons with intra-cardiac and intra-pulmonary shunts, unstable cardiopulmonary
conditions, or anyone on chronic oxygen therapy

- Persons taking nitric oxide donors, organic nitrites and nitrates, such as glyceryl
trinitrate (nitroglycerin), sodium nitroprusside, amyl nitrite ("poppers")

- Severe hepatic impairment (liver function tests >1.5 times upper limit of normal)
within past 4 weeks

- Severe impairment in renal function (serum creatinine ≥1.5 mg/dL) within past 4 weeks

- Hypotension (defined as blood pressure [BP] <90/60)

- Hereditary degenerative retinal disorders (including genetic disorders of retinal
phosphodiesterases)

- Persons already taking (or taken within 3 months) sildenafil or other PDE inhibitors
(i.e., tadalafil, vardenafil)

- Persons unable to provide voluntary written informed consent

- Severe hypertension (BP >170/110)

- Persons with HIV/AIDS