There is no single best injection for rheumatoid arthritis. The most effective option depends on your specific blood markers, how your body responds to initial treatments, and whether you’ve already tried other medications. That said, TNF inhibitors are the most commonly prescribed first-line injectable therapy, and combining any biologic injection with methotrexate consistently produces better results than using either alone.
The American College of Rheumatology’s 2021 guidelines include 44 recommendations for RA treatment, and nearly all of them are conditional, meaning the “right” choice varies from person to person. Here’s what the evidence says about each major category of injectable treatment and how doctors decide which one to try first.
TNF Inhibitors: The Most Common Starting Point
TNF inhibitors block a protein called tumor necrosis factor that drives inflammation in RA joints. They’re the largest and most studied class of biologic injections, and they’re typically the first injectable a rheumatologist will prescribe after conventional pills like methotrexate haven’t provided enough relief. The major options in this class include adalimumab (Humira), etanercept (Enbrel), infliximab (Remicade), certolizumab (Cimzia), and golimumab (Simponi).
Head-to-head comparisons show no meaningful difference in effectiveness among these drugs. They all produce similar rates of symptom improvement. In clinical trials, about 59% of patients taking adalimumab plus methotrexate achieved at least a 50% improvement in symptoms after two years, compared with 43% on methotrexate alone. That gap is significant, but it also means roughly 4 in 10 patients on a TNF inhibitor still don’t reach that level of improvement, which is why alternative mechanisms exist.
Most TNF inhibitors are available as prefilled syringes or auto-injectors you use at home, typically every one to two weeks. Infliximab is the exception: it’s given as an intravenous infusion at a clinic every six to eight weeks, though a subcutaneous version given every two weeks is now available. Many patients prefer the at-home options for convenience, and studies confirm that subcutaneous versions work just as well while saving the time and hassle of regular hospital visits.
IL-6 Inhibitors: When TNF Blockers Aren’t Enough
Tocilizumab (Actemra) and sarilumab (Kevzara) work by blocking a different inflammatory signal called interleukin-6. These are commonly used when a TNF inhibitor hasn’t worked well or caused side effects. Tocilizumab is notable because it’s one of the few biologics that performs relatively well even without methotrexate, making it a strong option for patients who can’t tolerate that drug.
Research on synovial tissue (the lining inside joints) has identified biological signatures that may predict which patients respond best to which drug. Patients with a lymphoid-dominant pattern in their joints, reflected by higher levels of a blood marker called CXCL13, tend to have the largest response to tocilizumab. In contrast, patients with a myeloid-dominant pattern respond better to TNF inhibitors. This kind of testing isn’t yet routine, but it illustrates why the “best” injection is increasingly a personalized question.
A new biosimilar version of tocilizumab called Avtozma was approved by the FDA in January 2025 as interchangeable with the original Actemra. It’s available in both intravenous and subcutaneous forms. Biosimilars like this can lower costs substantially, which matters given that biologic injections often run thousands of dollars per month.
Other Biologic Options
Abatacept (Orencia)
Abatacept works by blocking the activation of T cells, a type of immune cell involved in the inflammatory cascade. It’s available as both a weekly subcutaneous injection and a monthly IV infusion. One consistent finding across multiple studies is that patients who test positive for anti-CCP antibodies (a common blood marker in RA) respond better to abatacept, with odds of a good response roughly 1.4 to 1.9 times higher than in patients without those antibodies. The strongest responses occur in people with the highest antibody levels.
Rituximab (Rituxan)
Rituximab targets B cells, another arm of the immune system. It’s given as an intravenous infusion, typically two doses spaced two weeks apart, repeated every six months or so. High levels of anti-CCP antibodies strongly predict a good response to rituximab, with one analysis showing 5.1 times greater odds of a good outcome. It’s often reserved for patients who haven’t responded to TNF inhibitors or other biologics.
Cortisone Shots for Flare-Ups
Corticosteroid injections directly into a joint serve a completely different purpose than biologics. They’re not a long-term disease management strategy. Instead, they provide localized relief during a flare, reducing pain and swelling in a single joint that’s particularly inflamed. Relief can last up to several months, but doctors limit the number of shots per joint per year because repeated injections can damage cartilage over time. Think of cortisone shots as a bridge or rescue tool, not as a replacement for systemic treatment.
Why Combination Therapy Matters
One of the strongest findings in RA research is that combining a biologic injection with methotrexate works significantly better than either treatment alone. A meta-analysis of seven randomized trials found that combination therapy was 74% more likely to produce clinical remission at one year compared to methotrexate by itself. It also slowed joint damage more effectively, though the benefit for preventing physical erosion was less dramatic than the improvement in symptoms.
This is why most rheumatologists will keep you on methotrexate (or another conventional DMARD) even after adding an injectable biologic. Stopping the background medication often means losing some of the benefit you gained.
Infection Risk With Biologic Injections
All biologic injections suppress part of the immune system, which means a higher risk of serious infections. On traditional DMARDs alone, about 20 out of every 1,000 patients per year develop a serious infection. Adding a standard-dose biologic increases that number by roughly 6 additional cases per 1,000 patients annually. That’s a modest increase in absolute terms, though it’s not trivial. High-dose biologics raise the risk more, adding about 17 extra cases per 1,000, and combining two biologics together (which is rarely done for this reason) pushes it to 55 additional cases per 1,000.
Before starting any biologic, you’ll be screened for tuberculosis and hepatitis B, since these drugs can reactivate dormant infections. Recent guidelines have become stricter about excluding patients with positive TB tests from biologic therapy without treatment first.
How Doctors Choose Your First Injection
The decision typically follows a sequence. Most patients start with methotrexate or another conventional DMARD. If that doesn’t control the disease adequately after three to six months, an injectable biologic gets added. TNF inhibitors are the default first choice simply because they have the longest track record and the most safety data. If the first TNF inhibitor doesn’t work, your rheumatologist may try a second one or switch to a different mechanism entirely, like an IL-6 inhibitor or abatacept.
Your antibody profile can influence this choice. If you’re strongly positive for anti-CCP antibodies, abatacept or rituximab may be especially effective. If you can’t take methotrexate, tocilizumab becomes more attractive because it holds up better as a standalone treatment. Practical factors matter too: if you prefer self-injecting at home over sitting in an infusion chair for two hours, that narrows the options. Cost and insurance coverage also play a major role, which is where newer biosimilars are starting to open doors that were previously closed.