Modifying RA disease course with novel DMARDs
Treatment with disease-modifying antirheumatic drugs (DMARDs) continues to be the centre of expert recommendations for rheumatoid arthritis (RA), with particular focus on treat-to-target rather than agent-specific strategy. In an interview with MIMS Doctor, Dr Ho SO, Specialist in Rheumatology and Assistant Professor at the Chinese University of Hong Kong, provided an overview of current RA management principles and how newer therapies, including targeted synthetic DMARDs (tsDMARDs) such as Janus kinase (JAK) inhibitors, may benefit patients with active RA.
Treat to target: Achieving remission or low disease activity
As more effective RA therapies, such as newer biological DMARDs (bDMARDs) and tsDMARDs, have become available, the management strategy has shifted from symptomatic relief to a treat-to-target approach, where clinical remission is the ultimate goal and low disease activity (LDA) is viewed as an acceptable compromise. [Adv Ther 2022;39:75-93; Arthritis Rheumatol 2014;66:775-782]
“Achieving clinical remission in RA is crucial because it helps slow down radiologic damage and prevent disability, enhancing long-term structural and quality-of-life outcomes,” explained So. [Ann Rheum Dis 2010;69:631-637; Adv Ther 2022;39:75-93; Arthritis Rheumatol 2014;66:775-782]
Since a treat-to-target approach helps yield superior outcomes in RA, professional organizations including the European Alliance of Associations for Rheumatology (EULAR) and Hong Kong Society of Rheumatology (HKSR) have endorsed it as a fundamental management strategy. [Nat Rev Rheumatol 2019;15:180-186; Ann Rheum Dis 2020;79:685-699; Clin Rheumatol 2019;38:3331-3350]
“Validated tools used for RA clinical remission or disease activity assessment include the disease activity score in 28 joints [DAS28], the more stringent simplified or clinical disease activity index [SDAI or CDAI], or the strictest American College of Rheumatology [ACR]-EULAR Boolean criteria,” said So. “Although widely used in clinical trials and in clinical practice in Hong Kong, DAS-based remission may be less reliable than other assessment tools.” [Adv Ther 2022;39:75-93; Clin Rheumatol 2019;38:3331-3350; Ann Rheum Dis 2020;79:685-699; Ther Adv Musculoskelet Dis 2022;14:1759720X221096363]
“The overarching principle of the treat-to-target approach is aiming for the best care based on shared decision between patients and rheumatologists,” stressed So. “Treatment should be individualized, taking into consideration prognostic factors, medical comorbidities, safety issues as well as cost and availability of newer b/tsDMARDs.” [Ann Rheum Dis 2020;79:685-699; Clin Rheumatol 2019;38:3331-3350]
Newer RA therapies
The treat-to-target approach also helps guide optimal sequencing of DMARDs to achieve tight disease control. [Clin Rheumatol 2019;38:3331-3350]
“The conventional synthetic DMARD, methotrexate [MTX], remains an effective first-line treatment option for most patients with RA,” said So. [Ann Rheum Dis 2020;79:685-699; Clin Rheumatol 2019;38:3331-3350] “Data from randomized controlled trials showed remission rates of up to 50 percent with MTX monotherapy in early RA [ie, <1 year]. MTX also remains the basis for combination therapy with glucocorticoids or other cs/b/ts-DMARDs.” [Ann Rheum Dis 2020;79:685-699; RMD Open 2019;5:e000993]
Despite MTX’s established role in RA, adding newer b/tsDMARDs in treatment of early or more established disease has consistently shown better efficacy vs MTX monotherapy. [RMD Open 2019;5:e000993] For instance, the phase III OPERA study demonstrated that adding subcutaneous injections of the bDMARD tumour necrosis factor inhibitor, adalimumab, to MTX and intraarticular triamcinolone as first-line treatment in DMARD-naïve patients with early RA significantly improved remission rates vs placebo (eg, DAS28 based on C-reactive protein [DAS28CRP] <2.6, 74 percent vs 49 percent). [Ann Rheum Dis 2014;73:654-661]
SELECT-COMPARE: Upadacitinib vs adalimumab
Due to comparable efficacy and safety profiles, current EULAR and HKSR recommendations do not distinguish between bDMARDs and tsDMARDs in terms of treatment preference when remission or LDA is not achieved with first-line MTX and poor prognostic factors are present. [Ann Rheum Dis 2020;79:685-699; Clin Rheumatol 2019;38:3331-3350]
However, data from 3-year follow-up of the phase III SELECT-COMPARE study demonstrated significant efficacy advantages of the tsDMARD, upadacitinib, vs adalimumab in patients with active RA and inadequate response to MTX (n=1,629). At week 156, upadacitinib was associated with statistically significant improvements in clinical and functional outcomes of RA vs adalimumab. CDAI LDA/remission was achieved by 40 percent/24 percent of patients in the upadacitinib group vs 29 percent/17 percent of patients in the adalimumab group (p<0.01), while DAS28CRP ≤3.2/<2.6 was achieved by 37 percent/32 percent vs 26 percent/22 percent of patients (p<0.001). In addition, significantly more patients in the upadacitinib vs adalimumab group achieved the ACR-EULAR Boolean-based remission definition (20 percent vs 14 percent; nominal p=0.012). [RMD Open 2022;8:e002012]
“Upadacitinib was also associated with greater numerical improvements from baseline vs adalimumab in the Health Assessment Questionnaire-Disability Index [−0.75 vs −0.60 at week 156; nominal p<0.01] and greater reduction in pain [−39.8 vs −31.2 at week 156, nominal p<0.001],” noted So.
Adverse events (AEs), including AEs leading to discontinuation, serious infections and serious AEs, malignancies, adverse cardiovascular events and deaths, were generally comparable between upadacitinib and adalimumab. Consistent with earlier results, rates of herpes zoster (HZ) infection, lymphopenia, hepatic disorder and creatine phosphokinase elevation were higher with upadacitinib vs adalimumab.
“In general, DMARDs are associated with increased risks of opportunistic infections and reactivation of latent infections,” commented So. “Immunization against preventable infections [eg, pneumococcal infection, influenza, hepatitis B virus, human papilloma virus, and HZ] is therefore important in patients with RA.” [Clin Rheumatol 2019;38:3331-3350; Int J Rheum Dis 2019;22:357-375; Ann Rheum Dis 2020;79:39-52; Ann Rheum Dis 2020;79:685-699]
Furthermore, any active and serious infections should be managed before prescribing upadacitinib, and the agent should be avoided in patients with inadequately treated tuberculosis. It should also be used with caution in patients ≥75 years of age. [Rinvoq Hong Kong Prescribing Information]
“Importantly, although any RA treatment is associated with some risk of AEs, the alternative is uncontrolled disease, which is associated with a range of debilitating comorbidities, such as osteoporosis, fatigue, malignancy, and cardiovascular complications,” stressed So. [Front Med (Lausanne) 2020;doi:10.3389/fmed.2020.601618; Rheumatol Int 2020;40:2005-2012; Rheumatology (Oxford) 2019;58(Suppl 5):v1-v2; Rheumatol Ther 2017;4:333-347; Jt Bone Spine 2013;80:29-33]
Reversing structural damage
In SELECT-COMPARE, similar proportions of patients on continuous upadacitinib or continuous adalimumab for 2 years demonstrated no radiographic progression (82.0 percent vs 75.2 percent at 2 years). The rate of structural progression inhibition was also comparable based on mean change from baseline in modified Total Sharp Score, erosion score and joint space narrowing. [RMD Open 2022;8:e002012]
“Structural damage reversal remains the next big goal in RA therapy since it has yet to be demonstrated by any available DMARD,” said So.
“However, preliminary data from an open-label study at our centre involving 20 patients with active RA demonstrated that upadacitinib treatment may be associated with reduction in joint erosion size on high-resolution peripheral quantitative CT.”
(Figure) [So H, et al, unpublished data]