What's the next step for a patient with rheumatoid arthritis (RA) who has failed methotrexate (MTX) treatment and has a history of type 2 diabetes mellitus (T2DM), considering Upadacitinib (JAK inhibitor) as a potential treatment option?

Starting Upadacitinib After Methotrexate Failure in RA with Type 2 Diabetes

You can proceed with upadacitinib 15 mg once daily added to methotrexate (or as monotherapy if methotrexate must be discontinued), but you must carefully assess and counsel this patient about venous thromboembolism (VTE) risk given the diabetes history, which may be associated with other cardiovascular risk factors. 1

Risk Stratification for VTE Events

Before initiating upadacitinib, assess the following VTE risk factors that are specifically elevated with JAK inhibitors 1:

• Age ≥65 years (highest risk factor)
• Body mass index (obesity increases risk)
• Previous history of thromboembolic events (absolute contraindication if recent)
• Hormone replacement therapy use
• Cardiovascular risk factors (diabetes counts as one; assess for others including hypertension, dyslipidemia, smoking)

If this patient has multiple VTE risk factors (age ≥65 AND diabetes AND obesity, for example), strongly consider a TNF inhibitor instead as first-line biologic therapy. 1

Treatment Algorithm After MTX Failure

If Patient Has Poor Prognostic Factors:

Add a biologic DMARD (bDMARD) or targeted synthetic DMARD (tsDMARD) to methotrexate rather than switching to another conventional synthetic DMARD. 1

Poor prognostic factors include 1, 2:

• Positive rheumatoid factor or anti-CCP antibodies
• High disease activity (DAS28-CRP >5.1)
• Early erosions on imaging
• Failure of two or more csDMARDs

Upadacitinib Efficacy Data:

Upadacitinib 15 mg has demonstrated superior efficacy compared to both placebo and adalimumab in MTX-inadequate responders 3:

• ACR20 response at week 12: 71% vs 36% placebo (p≤0.001)
• DAS28-CRP <2.6 at week 12: 29% vs 6% placebo (p≤0.001)
• Superior to adalimumab for ACR50 response, DAS28-CRP ≤3.2, and functional outcomes 3

Combination vs Monotherapy Decision

Combine upadacitinib with methotrexate for optimal efficacy. 1 The EULAR guidelines state that bDMARDs and tsDMARDs should be combined with a csDMARD. 1

If methotrexate must be discontinued due to intolerance or contraindications (hepatotoxicity, renal impairment from diabetes), upadacitinib monotherapy is acceptable as JAK inhibitors have demonstrated good efficacy as monotherapy 1, 4:

• In the SELECT-MONOTHERAPY trial, upadacitinib 15 mg monotherapy achieved ACR20 in 68% vs 41% continuing methotrexate (p<0.0001) 4

Diabetes-Specific Considerations

Monitor closely for infections, particularly given the immunosuppressive effects combined with diabetes 1, 5:

• Herpes zoster rates are elevated with upadacitinib (1-3% in trials) 1, 3, 4
• Consider varicella zoster vaccination before starting if patient is seronegative
• Serious infection rates are comparable to adalimumab but may be numerically higher in patients with cardiovascular risk factors 6

Screen for latent tuberculosis and hepatitis B/C before initiation 7, 5

Cardiovascular Risk Assessment

Given the diabetes diagnosis, assess total cardiovascular risk 6:

• In patients with higher CV risk (age ≥65 and/or ≥1 CV risk factor including diabetes), rates of major adverse cardiovascular events (MACE) were numerically higher but comparable between upadacitinib and adalimumab over 5 years 6
• The benefit-risk profile of upadacitinib remained favorable even in higher CV risk patients, with consistently better clinical outcomes than adalimumab 6

Monitoring Requirements

Assess disease activity every 1-3 months using DAS28-CRP, SDAI, or CDAI 1, 7:

• If no improvement by 3 months, adjust therapy
• If treatment target (remission or low disease activity) not reached by 6 months, switch to another bDMARD or tsDMARD 1, 7

Laboratory monitoring 5:

• Baseline and periodic CBC (lymphopenia risk)
• Hepatic transaminases (elevations more common with upadacitinib than adalimumab) 3, 8
• Creatine phosphokinase (CPK elevations occur with upadacitinib) 3
• Lipid panel (JAK inhibitors can increase LDL cholesterol)

Critical Safety Warnings

Three specific safety signals require explicit counseling 1:

1. Venous thromboembolism (pulmonary embolism, deep vein thrombosis) - observed with all JAK inhibitors, particularly in high-risk patients
2. Malignancy risk - ongoing surveillance data from tofacitinib trials suggest possible increased risk in patients ≥65 with cardiovascular risk factors
3. Herpes zoster - consistently elevated across JAK inhibitor class

Alternative if VTE Risk Too High

If this patient has age ≥65 years plus diabetes plus additional VTE risk factors, initiate a TNF inhibitor (adalimumab, etanercept, certolizumab, golimumab, or infliximab biosimilar) instead 1. TNF inhibitors remain the most extensively studied biologics with the longest safety track record and lower VTE signal. 1

Dosing

Upadacitinib 15 mg orally once daily is the FDA-approved and recommended dose for rheumatoid arthritis 5, 9. The 30 mg dose showed higher efficacy but also higher adverse event rates and is not recommended for RA. 5, 4