One of the most common clinical scenarios encountered by rheumatologists who have patients with inflammatory arthritis is also one for which no real useful management guidelines exist: monoarticular arthritis. When a patient's rheumatoid or psoriatic arthritis appears well-managed or in remission by traditional disease assessment indices, yet the person has one critical joint that remains painful, swollen, or inflamed, rheumatologists are forced to rely on experience, clinical judgment, and empiric treatment to determine the best treatment course, explained Francesco Ursini, MD, PhD, a professor of rheumatology at the University of Bologna and a rheumatologist at IRCCS Istituto Ortopedico Rizzoli in Bologna, Italy.

"We see this every day in our room, and it's something that is so normal that nobody thinks about it," Ursini told Medscape Medical News. "Then we need to manage it empirically." 

The core of the problem is that, considering the treat-to-target paradigm endorsed by guidelines, assessing the risk-benefit balance of escalating systemic therapy becomes more challenging when only one joint is the target. 

"The complexity starts when you have just one joint because you need to balance the potential harm of systemic escalation in which you cannot improve another joint," Ursini said. "The marginal benefit [to one joint] is less than systemic disease activity control, but the harm is the same, and we don't have any proper number to quantify this burden. A very small risk is acceptable for a patient that has maybe 10 swollen joints, but the same amount of risk may be less acceptable for a patient with one swollen joint." 

In a paper published this spring in The Lancet Rheumatology, Ursini and his colleagues described how the measurement systems intended to characterize a patient's disease state and the design of clinical trials aimed at identifying the safety and efficacy of various therapies both let monoarticular inflammatory arthritis to slip through the cracks of evidence-based guidance. They describe three monoarticular phenotypes: 

• A true monoarticular onset, where inflammatory markers and/or family history clearly identify the problem as inflammatory, but the actual inflammation is so far limited to one joint, which they note may account for nearly 40% of first presentations;
• Residual monoarticular synovitis, where patients are in remission or have low disease activity on background therapy based on formal definitions or disease indices, "but one persistently inflamed joint continues to disproportionately drive their symptoms and functional limitation"; and
• A new monoarticular flare that occurs despite otherwise well-controlled disease activity.

Inadequate Indices and Trial Data

They noted that many of the disease activity scores — including the Disease Activity Score in 28 joints (DAS28), Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI) in rheumatoid arthritis, and the Disease Activity index for PSoriatic Arthritis (DAPSA), Psoriatic Arthritis Disease Activity Score (PASDAS), or Minimal Disease Activity (MDA) criteria in psoriatic arthritis — "all tolerate a small number of residual swollen joints within low disease activity," even sometimes in their definitions of remission. 

And yet the appearance of remission or well-controlled disease by these measures then obscures "persistent inflammation in a single large joint" that "might drive pain, functional impairment, and future arthroplasty risk," the authors wrote. With rheumatoid arthritis, the problem is more commonly that weighted joint counts in these measures dilute the contribution of a particularly problematic, disabling joint — all joints are not created equal, but they are counted equally in the scoring. 

"You can have remission but still one swollen joint, and the index cannot make a distinction between a clinically important joint, such as a big joint like the knee" and less clinically important joints, Ursini said. "If you have a swollen knee, you cannot walk. You cannot work, and so on." If a patient has only a small finger with pain but is otherwise able to do all their usual daily activities, a single joint's recalcitrance may not be as concerning, but other single joints can be debilitating all on their own, he said. "This is not captured by the systemic complexity of the index." Those indices are conceived, he said, to capture systemic disease, and that's essential — measuring the impact of the overall disease — but that doesn't mean they're enough to cover all the actual clinical scenarios rheumatologists must manage in their patients. 

Even with psoriatic arthritis scores that capture a more global-level assessment, the contribution of a single joint may not be fully appreciated. 

"These patient-reported outcomes capture overall disability well but might underrepresent the burden of a single functionally high-impact joint … especially when patients adapt activities, compensate, or recalibrate expectations," Ursini and colleagues wrote. 

Not only is this a problem if one joint is driving substantial disabilities or quality-of-life issues for the patient, but persistent inflammation in one joint may also contribute to long-term structural damage even in the presence of otherwise low disease activity. 

Ursini finds it frustrating that this status quo has existed for so long with such a common scenario. Inflammatory arthritis is not a rare disease where clinicians may be forced to accept greater risk with a therapy or accept the complexity of not having an answer to every major clinical question, he said. "We are talking about everyday, common, predominant joint diseases in the everyday life of a rheumatologist." 

It's not clear why these cases occur, Ursini said, but every rheumatologist is familiar with them. 

"We know that it is very common that you have maybe one, two, or three joints that escape the overall control of disease activity," something that may depend on the interaction between inflammation and biomechanics for joints used more often or with more load-bearing, he speculated. "It is possible that this joint escapes control because you have a persisting biomechanical trigger that makes it difficult to achieve the same status of wellness of other systemic joints that are maybe unloaded," he said. That could even result from micro-stress over time, but he acknowledged that these are only hypotheses — that we really don't know what allows a single joint to evade control. 

Whatever the reason and however common it is, another reason for the lack of clear evidence-based guidance on treatment plans for these cases is that clinical trials rarely enroll patients with only a single joint involvement. Most nearly always require a minimum number of tender or swollen joints for inclusion, often at least three joints. 

"We have virtually no trial-level evidence on the efficacy of DMARDs [disease-modifying antirheumatic drugs] specifically in monoarthritis either at onset or as residual activity," they wrote. That leaves unanswered the question of which monoarthritis phenotypes will benefit from systemic DMARD therapy escalation and how to integrate joint-specific outcomes into existing treat-to-target frameworks. Treatment recommendations are therefore extrapolated from polyarthritis populations without adequate knowledge about whether the risk-benefit balance still leans toward systemic therapy when only one joint remains inflamed. 

"The harms of systemic escalation do not conveniently scale down with joint count," they wrote. 

A Practical Framework for Monoarticular Inflammatory Arthritis

In their paper, Ursini and his colleague proposed a pragmatic approach to managing these cases in the absence of trial evidence. As with treating any other patient with inflammatory arthritis, the first step in these clinical situations, Ursini said, is asking the patient what the most bothersome or important joint is for them. 

A disease score could be low enough that guidelines would not recommend stepping up anti-inflammatory therapy, "but you have to do something else, as one joint is still hurting," said Bibi Ayesha, MBBS, associate professor of rheumatology and director of the Vasculitis Clinic at Montefiore Medical Center and Albert Einstein College of Medicine in the Bronx, New York. "That one joint could be the most important joint for the patient." The most common ones she sees are the knee, the hip, the shoulder, or the wrist, all major joints that can confer substantial disability even if the rest of a person's disease is in remission. 

Next, determine if the patient actually has monoarticular inflammatory arthritis by eliminating other possibilities, such as septic arthritis, crystal-induced arthritis, and mechanical and degenerative mimics. In short, clinicians need to determine whether a patient complaining of a pain in a single joint "has something else going on," said Neal Birnbaum, MD, a rheumatologist with MarinHealth in San Rafael, California, and a past president of the American College of Rheumatology.

"The fact that you have rheumatoid arthritis and your knee hurts doesn't mean it's from the rheumatoid arthritis necessarily," he said. "In this era of really very effective therapies, many times our patients with rheumatoid arthritis are living long enough and doing well enough that they start developing osteoarthritis." As therapies for inflammatory arthritis conditions have improved over the years, Birnbaum said he's actually seeing this clinical scenario more often, where the inflammatory disease truly is well-controlled but it's osteoarthritis that's the issue. In that case, the patient may need a referral to an orthopedist and/or surgeon if they need a hip or knee replacement. 

"If enough damage has occurred that they develop post-inflammatory degenerative arthritis, no medicine is going to fix that if the cartilage is gone, and we have to start thinking about some kind of surgical option," Birnbaum said. 

Another example of a mimic, he said, is a patient with psoriatic arthritis who has developed gout, for which people with psoriatic arthritis have up to five times greater risk of developing, according to a recent meta-analysis. 

"You don't want to give up on what they're doing for the psoriatic arthritis if they're otherwise doing well," Birnbaum said. "You want to diagnose and treat the gout." 

Other differentials to exclude besides osteoarthritis and crystalline arthritis include trauma or a joint infection, such as staph or even extrapulmonary tuberculosis, Birnbaum said. 

If other possibilities have been eliminated, it's next important to identify whether the issue is pain alone that needs to be addressed or whether there is continuing inflammation. 

"Even after treating the inflammation, the nerve endings are active, and [the patient] still tends to perceive the pain," Ayesha said. The medications may address the inflammation, redness, and swelling in a joint, but if neuropathic pain remains, or there's cartilage damage or bone erosion, the patient may need a referral to physical therapy or another supportive treatment. 

When Inflammation Is Involved

Once other possibilities have been removed from the equation, it's important to establish whether the inflammation is truly confined to one joint since that could influence the risk-benefit analysis of stepping up therapy. 

"We need to assess if that patient really has only monoarticular involvement because sometimes it happens that a patient complains of a swollen ankle because they cannot walk or do their job, but if you assess other joints, maybe with ultrasound, you recognize that maybe a wrist or knee is also inflamed, but the ankle is so much more important" that the patient may not even realize other joints are affected, Ursini said. 

Through imaging, a rheumatologist can look to see what the actual inflammation levels are in the patient even if they're only reporting problems with one joint. Such an approach may reveal subclinical inflammation, allowing an opportunity for early intervention that could prevent worsening disease later. 

"Then we can discuss with the patient the possibility that the benefit of escalating to systemic treatment is probably beyond the benefit on that single problematic joint because we may also protect the wrist from progressive damage associated with subclinical involvement," Ursini said.

Ayesha also considers markers of inflammation in determining whether to discuss stepping up therapy is the right call. 

"If the inflammatory markers are very high and the clinical examination reveals a swollen joint with fluid or redness, and there is tenderness, that means there is active, ongoing inflammation there, so you definitely need to consider stepping up the therapy," she said. "If the inflammatory markers are stone cold, and if there's no swelling, no effusion, no tenderness, and the patient just complains of pain, that is the point you don't step up." 

If the inflammation is limited to a single joint, Ursini and colleagues advise characterizing joint-level impact, including whether the joint is a dominant or weight-bearing one, such as a knee or hip; what functional limitations can be attributed to the index joint; and the structural risk in the joint. 

If global disease activity truly is otherwise controlled, the inflammation is truly confined to a single joint, no subclinical inflammation in other joints would reclassify their phenotype, and the functional disability from that joint is substantial enough to need treatment, the only next step available is shared clinical decision-making regarding the options. 

A conversation with the patient that involves shared clinical decision-making is, "at the moment, the best option because we don't have clinical trial-level evidence that one approach is better than another," Ursini said. "It's completely empirical." 

One of the easiest, most common tools to reach for in these cases is an intra-articular corticosteroid injection, "the plain vanilla solution for monoarthritis," Ursini said. 

Birnbaum agreed, saying that his first go-to would be a cortisone injection into the joint to see if that quiets it down. However, multiple steroid injections can worsen the cartilage metabolism and increase later surgical risk, so it's not a long-term solution if the pain, swelling, and inflammation return, Ursini said.

Other potential interventional options, though their access varies by payer coverage, clinic, and geography, are radiosynovectomy, synovectomy, or, possibly soon, transarterial embolization, an emerging therapy for osteoarthritis that has been receiving more attention in research and may be a promising strategy for inflammatory arthritis. But sometimes, these are not viable options for a variety of reasons, including the specific joint causing the problem. 

If the disability from the one inflamed joint is significant enough and there isn't another reason the clinician can identify that explains why, then therapy escalation may truly be the most appropriate option, Birnbaum said. 

"The wrist is a common spot that people need to use and that seems to flare up often," he said. "You might use that as a reason to go to a biologic therapy if they've been on methotrexate and you've done everything else you can think of — you've splinted it, you've injected it, and you don't find another cause [of the inflammation]."

This is the point where Ayesha is also likely to step up systemic therapy. Until trial evidence provides more guidance, the question of whether the potential harms of stepping up systemic therapy, with accompanying infection risk, for example, is worth the tradeoff of taming a single but significant joint will be individual for each patient.

"If you don't find anything else, you need to be very clear with the patient," Ursini said. "You need to clearly express that we don't know what is best for him, and we need to choose together, but systemic treatment requires months to achieve the maximum benefit, so it's not something that you try like trial and error." 

Ursini reported travel or speaking fees from AbbVie, Novartis, Pfizer, Alfasigma, and UCB. Birnbaum reported being a speaker for AbbVie. Ayesha had no disclosures. 

Tara Haelle is a science/health journalist based in Dallas.