Lyme arthritis: A small piece of the larger autoimmunity puzzle
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Spotting and managing early Lyme disease can be easy: Just look for the bullseye. But when the rash goes away and the infection remains untreated for a prolonged period, Lyme arthritis can develop. That is when the real challenges begin.
To be fair, even Lyme arthritis can be easily recognizable, according to Robert Kalish, MD, rheumatologist and director of rheumatology education at Tufts Medical Center. “Lyme arthritis is generally going to be a swollen knee in around 90% of patients,” he told Healio Rheumatology.
“Clinically, the knee or knees have a large effusion even after joint aspiration,” Cassandra Calabrese, DO, of the department of rheumatologic and immunologic disease at the Cleveland Clinic, added.
Calabrese noted that the remainder of cases can manifest as persistent or intermittent pain and swelling in other larger joints, such as the shoulders, ankles or elbows. “It can go on for years, generally being more persistent than intermittent,” she said.
In some cases, patients are misdiagnosed with Lyme arthritis, when, in fact, they have another form of arthritis altogether. “It is also important to recognize that some patients develop systemic autoimmune forms of arthritis, including rheumatoid arthritis, spondyloarthropathies or psoriatic arthritis, following soon after treatment for Lyme disease, most commonly after early infection,” Allen C. Steere, MD, principal investigator at the Center for Immunology & Inflammatory Diseases at Massachusetts General Hospital, said in an interview. “This may be confused with Lyme arthritis, but the treatment should be appropriate DMARD therapy.”
An important recent data set from Lochhead and colleagues in Nature Reviews Rheumatology addressed this confusion between Lyme arthritis and other arthritic conditions. They wrote that Lyme arthritis is “characterized by high amounts of interferon (IFN)-gamma and inadequate amounts of the anti-inflammatory cytokine [interleukin]-10.” This poorly regulated pro-inflammatory response in the synovium can mimic other arthritic conditions, which lead the researchers to conclude that deeper understanding of post-infectious processes in the joints could shed light on other chronic autoimmune or autoinflammatory arthritides.
“We see in Lyme arthritis that an infectious trigger can induce an immune response that leads to persistent symptoms,” Klemen Strle, PhD, a research scientist at the Laboratory of Microbial Pathogenesis and Immunology and the division of infectious diseases at the Wadsworth Center in New York, said in an interview. He believes that the “concept of infection-induced autoimmunity” could be a new frontier in the field and has implications across conditions and disease states.
However, there is still much to be learned – and the clock is ticking. Warming temperatures linked to climate change are projected to expand the range of suitable tick habitat in the United States, driving endemic Lyme disease into new regions and forcing more rheumatologists to manage the resulting arthritic complications.
Beyond the Bullseye
Rheumatologists have played a pivotal role in the story of Lyme disease since it was first discovered by Steere in 1976, following an outbreak of juvenile arthritis or “arthritis of unknown cause” in Lyme, Connecticut.
From those inauspicious beginnings and a motley collection of symptoms – the telltale bullseye rash, fevers and aches, Bell’s palsy and rheumatological manifestations – Steere proceeded to lay down the foundation for the current understanding for what has become the most commonly reported vector-borne disease in the U.S., with an estimated 476,000 cases of Lyme disease each year.
Understanding the basics of Lyme disease is essential to distinguishing Lyme arthritis from other forms of arthritis, according to Steere. “Lyme arthritis is a tick-borne infection caused by a spirochetal bacterium, Borrelia burgdorferi,” he said. “The infection is found primarily in the Northeastern United States and in Mid-Atlantic states, but locations in the Upper Midwest are also affected. Sporadic cases also occur on the West Coast.”
Asking a patient with unexplained joint pain if they have traveled to or live in an area where Lyme is endemic is the first step in the clinic, Calabrese suggested. “You should also ask if they have or had a skin lesion, called erythema migrans, that occurs at the site of the tick bite,” she said, describing the classic bullseye shape. “The spiral disseminates throughout the body and may be accompanied by flu-like symptoms, myalgia or arthralgia.”
The only problem with obtaining this medical and travel history from a patient is that the early stages of Lyme infection can be completely asymptomatic. Moreover, while the dissemination can happen over the course of days or weeks, arthritis does not usually develop until months or years later, according to Steere. It is for this reason that a thorough understanding of the nature of Lyme arthritis itself is also necessary when the medical history does not provide clues.
“The dissemination occurs within the context of an expanded antibody response to the organism,” Steere said. “Affected joints, frequently one or both knees, often become very swollen and ruptured Baker’s cysts are common. However, the swelling is often out of proportion to the pain.”
Source: Tufts Medical Center.
Kalish stressed that while conditions like osteoarthritis or RA can gradually build up over time, Lyme arthritis will usually have a more direct or sudden onset. “It can look like several conditions including a knee injury or flare of osteoarthritis or a crystal arthritis, such as calcium pyrophosphate deposition disease or pseudogout,” he said. “That is why it is so important to aspirate the joint and check Lyme titers when Lyme arthritis is suspected.”
For rheumatologists who suspect Lyme arthritis but are still uncertain after taking a patient history and aspirating the joint, there is a recommend diagnostic approach available in the 2020 joint American College of Rheumatology/Infectious Diseases Society of America guidelines.
Two-tiered System
“Serologic testing, using a two-test approach of enzyme-linked immunosorbent assay (ELISA) and Western blot, is the major test available to support the diagnosis,” Steere said.
Research has shown that the IgG antibody response to B. burgdorferi has been positive in 100% of patients with Lyme arthritis, according to Steere. He added that prior to antibiotic therapy, about 70% of patients have a positive polymerase chain reaction (PCR) result for B. burgdorferi DNA in joint fluid, but culture of the spirochete from joint fluid has not frequently been possible.
“We hang our hat on this two-tiered testing method,” Calabrese said. “These testing methods are nuanced.”
Calabrese referred clinicians to the ACR/IDSA joint clinical practice guidelines for more detailed information about Lyme arthritis diagnosis.
But even with the guidelines in place, Steere suggested that a number of pitfalls in serologic testing are important to keep in mind. “First, positive IgM tests alone should not be used to support the diagnosis and are more likely to represent a false-positive result or previous early Lyme disease,” he said.
Sheila Arvikar, MD, director of quality assessment and improvement in rheumatology and of the division of rheumatology, allergy and immunology at Massachusetts General Hospital, agreed that the diagnostic protocol is useful but not perfect. “A major weakness of the two-tier system is lack of sensitivity in early Lyme disease,” she said, noting that approximately 30% of patients with erythema migrans may lack antibody responses, even with convalescent testing.
“However the sensitivity of two-tier testing in Lyme arthritis is high,” Arvikar continued. “Patients with Lyme arthritis universally have positive results by two-tier testing for serum IgG antibodies. IgM antibodies may or may not be present.”
Because Lyme arthritis is a late manifestation of the initial infection, patients usually have “markedly expanded” antibody responses with seven to 10 IgG bands as assessed by Western blot, according to Arvikar.
If there is another potential drawback of serologic diagnostic testing, it is that the antibody response in Lyme arthritis can persist for years, even decades, after the infection has resolved. “Antibody testing cannot be used to distinguish active from resolved infection in Lyme arthritis patients, and cannot be used as a test of resolution,” Arvikar said.
Like many experts, Arvikar hopes that direct detection methods for infection will be developed in the future. “The persistence of the antibody response also complicates the diagnosis of Lyme disease for patients in endemic areas who may have had Lyme disease in the past and may have persistent antibody responses, making it difficult to sort out whether Lyme disease is the cause of their current presentation,” she said.
Despite the prevalence of misdiagnoses and patients who go untreated for years, many patients do, in fact, undergo successful treatment for both Lyme disease and Lyme arthritis; the critical point is to adhere to the ACR/IDSA recommendations.
Antibiotics and Next Steps
“If you catch Lyme disease early, doxycycline for 10 days is recommended,” Calabrese said. “If it persists to arthritis, the first-line therapy is doxycycline for 4 weeks. Many patients do get better with that.”
But not everyone. In patients who are refractory to this approach, another course of doxycycline may be recommended, or an IV course of the drug. Ceftriaxone may also be considered for patients who are refractory to doxycycline.
When Lyme arthritis persists after antibiotic treatment, a DMARD like methotrexate may be effective.
“In antibiotic-refractory cases, sometimes I will start hydroxychloroquine for patients who are hesitant to go on methotrexate,” Kalish said. “But it usually does not really work, and I often end up using methotrexate anyway.”
Kalish also has had “some success” with TNF inhibitors.
“There are not a lot of data for steroids or biologics as yet,” Calabrese added.
It is important to keep in mind that the joint effusions are not as large in this type of antibiotic-refractory Lyme arthritis, according to Steere. “But massive synovial proliferation develops, usually in one or both knees,” he said. “The synovial lesion in these patients is similar to that seen in other forms of chronic inflammatory arthritis, including RA.”
Clinical experience has shown that peer-reviewed approaches work. The larger concern is when patients go untreated for long periods of time.
Long-term Complications
For Kalish, a paper by Steere and colleagues published in the Annals of Internal Medicine in 1987, is the defining data set for the natural history of joint involvement in untreated Lyme disease. “At that point, it was not yet proven that Lyme disease was a bacterial infection and therefore patients were not yet routinely treated with antibiotics,” Kalish noted.
The researchers followed 55 patients who had early Lyme disease for a mean duration of 6 years. Results showed that 20% subsequently went asymptomatic, while 18% experienced intermittent joint pain without swelling starting 1 day to 8 weeks after disease onset. Importantly, 51% experienced at least one episode of “frank arthritis” – joint pain and swelling – at some point within 2 years after disease onset.
The proportion of patients who continued to have recurrent arthritic episodes decreased by 10%-20% per year, according to the findings. Arthritis that persisted more than a year without resolution was reported in 11% of the cohort, while two patients experienced erosions and one patient reported permanent joint disability.
“The study showed that, most commonly, Lyme arthritis was waxing and waning spontaneously over time,” Kalish said.
A body of data in subsequent years has borne out these results. In a 2015 paper in the Journal of the American Academy of Orthopedic Surgery, Matzkin and colleagues found that approximately 60% of untreated Lyme cases persisted to Lyme arthritis. In 2020, Schoen published a paper in Current Opinions in Rheumatology that largely mirrored Steere’s 1987 result. “For the rheumatologist, Lyme arthritis should be recognized by a pattern of attacks of asymmetric, oligoarthritis,” he wrote.
Because the arthritis is so unpredictable, and because there are often so many confounding symptoms, many patients drift in unexplained and uncertain territory as their episodes wax and wane. Consequently, many patients end up in the care of physicians who are willing to operate outside of clinical practice guidelines.
‘Lyme Literate’ Physicians
When patients suffering from debilitating, yet vague symptoms are unable to obtain a concrete diagnosis from their physician due to the lack of objective evidence, they may go looking for information on their own. For patients looking for answers, information on the internet can be persuasive.
The burgeoning online “chronic” Lyme disease community not only consists of patients who are symptomatic and Lyme disease activists, but also groups of ‘Lyme literate’ physicians who specialize in diagnosing and treating these patients, even if those treatments have minimal scientific backing.
Calabrese encourages rheumatologists to use a respectful, nonjudgmental tone when such a patient walks into the clinic seeking another opinion. “I do not say that the doctor who has been managing them was wrong or use any derogatory terms at all,” she said.
Kalish added that patience and kindness are absolutely essential in these conversations. “These patients have devoted a lot of time, energy and research to the subject of Lyme,” he said. “Suddenly being told that it may not be Lyme, or that they may have RA or something else altogether, can really pull the rug out from under them.”
Some patients may have already been thinking that they do not, in fact, have Lyme disease or Lyme arthritis. In those cases, the conversation can be relatively easy. “Other patients feel as though everything they have ever been told has been violated,” Kalish said. “You just have to acknowledge the mix of emotions they may be feeling.”
Once some degree of trust has been forged, “de-escalation” of any inappropriate botanicals and medications is the next step, according to Calabrese. “Start with a clean slate, and then begin dealing with the symptoms,” she said.
While many patients present with fibromyalgia or chronic fatigue syndrome, arthralgia or arthritis may also be present. “Make them feel better without specifically targeting a disease,” Calabrese said. “Take an overall approach to wellness and be sure to continue to listen to the patient.”
An ongoing positive message is critical, Kalish added. “I tell these patients, ‘Let’s talk about RA, because there are so many good things we can do for you to make you feel better,’” he said.
Recognizing Other Arthritides
In their study published in Arthritis & Rheumatology, Arvikar and colleagues identified 30 patients who had developed a new-onset systemic autoimmune joint disorder a median of 4 months after Lyme disease.
The researchers found that 15 patients had RA, 13 had PsA and two had peripheral spondyloarthritis. Polyarthritis was common in this group, compared with a group of 43 patients with confirmed Lyme arthritis who typically presented with monoarticular knee arthritis. “The majority of cases were following treatment of early Lyme disease, most commonly erythema migrans, but 6 cases followed treated Lyme arthritis, according to Arvikar.”
Patients with PsA or SpA often had previous psoriasis, axial involvement or enthesitis, according to the findings. Compared with Lyme arthritis patients, the majority of patients with systemic autoimmune joint disorders were positive for B. burgdorferi IgG antibodies, yet exhibited significantly lower titers and lower frequencies of Lyme disease–associated autoantibodies.
“It is not yet clear whether this outcome is coincidental or Lyme disease has a triggering role in the development of other diseases,” she said. “However, it is important for clinicians to be aware of this possibility as a post-infectious syndrome so patients can be diagnosed and treated appropriately.”
“Prolonged undiagnosed or untreated Lyme arthritis definitely does a number on the knee, and sets up a bad mechanical situation that is more likely to contribute to earlier osteoarthritis further down the line,” Kalish said.
“But whether Lyme disease, or even Lyme arthritis, triggers the immune system to go bad and cause rheumatoid arthritis or psoriatic arthritis is still up in the air,” he said. “I think it may trigger it as I have seen a few cases where it just seems too close – but it is just hard to prove that.”
Intersection of Lyme and Autoimmunity
Additional findings from the Lochhead study showed that the dysregulated IFN-gamma and IL-10 immune response may be caused by both spirochetal and host genetic factors.
“The spirochetal strain called OspC type A, which is common in New England, can lead to particularly high levels of inflammation,” Steere said. “Patients infected with this strain who have a polymorphism in a TLR-1 gene are at risk for excessively high IFN-gamma levels,” he said.
Vascular damage may occur as a result of this excessive proinflammatory response in Lyme synovia, as may autoimmune and cytotoxic processes, fibroblast proliferation and fibrosis.
The knowledge that Lyme disease is triggered by the Borrelia bacteria and disseminates into the skin and joints provides the research community insight into autoimmune processes in Lyme and other types of arthritis, according to Strle. “In certain predisposed individuals, there is an excessive immune response,” he said. “High levels of cytokines and chemokines produced by CD4-positive T cells recruit immune cells into the joints, and these cells are thought to be a key component in the perpetuation of Lyme arthritis.”
“Many patients get treated with antibiotics,” Strle said. “In most cases, when the infection goes away, the arthritis goes away.” The confounding factor is that in some patients, the arthritis persists even after there is little or no evidence of infection following antibiotic therapy.
Another layer to this puzzle is that some of the molecules that present antigen to T cells are a risk factor for post-infectious refractory Lyme arthritis, according to Strle. While genetic factors may not be ready for prime time, at least in terms of the ability to act on them on a routine basis in the clinic, Strle noted that a polymorphism in Toll-like receptor-1 may be a “characteristic signature” in the joints of patients who are predisposed to Lyme arthritis. “Higher frequency of this polymorphism leads to more inflammation,” he said.
All of this information may one day be common knowledge to rheumatologists, but for now, simply understanding that an increasing number of regions will be endemic to Lyme is essential. “Rheumatologists in more locations will need to learn about Lyme disease and its rheumatic manifestations,” Steere said.
These rheumatologists have their work cut out for them, according to Calabrese. “What is still not entirely clear is why Lyme disease persists to Lyme arthritis in some people and not others,” she said.
But for Steere, there is one bit of positive news that is worth consideration. “Lyme arthritis is usually very gratifying to treat because most patients can be cured by oral antibiotic therapy,” he said. “In contrast, rheumatologists are not used to curing most of the diseases that we treat.”
- References:
- Arvikar et al. Arth Rheum. 2017;doi:10.1002/art.39866.
- Lantos PM, et al. Arth Rheum. 2020;doi:10.1002/art.41562.
- Lochhead RB, et al. Nature Rev Rheum. 2021;doi:10.1038/s41584-021-00648-5.
- Matzkin E, et al. J Am Acad Orthop Surg. 2015;doi: 10.5435/JAAOS-D-14-00388.
- Schoen RE. Curr Opin Rheumatol. 2020;doi:10.1097/BOR.0000000000000698.
- Steere A, et al. J Clin Invest. 2020;doi:10.1172/JCI138062.
- Steere AC, et al. Ann Intern Med. 1987;doi: 10.7326/0003-4819-107-5-725.
- For more information:
- Sheila Arvikar, MD, can be reached at Rheumatology, Yawkey 4B, 55 Fruit St., Boston MA, 02114; email: sarvikar@mgh.harvard.edu.
- Cassandra Calabrese, DO, can be reached at 9500 Euclid Ave., Cleveland, OH, 44195; email: calabrc@ccf.org.
- Robert Kalish, MD, can be reached at 800 Washington St., Boston, MA, 02111; email: jlechan@tuftsmedicalcenter.org.
- Allen C. Steere, MD, can be reached at 55 Fruit St. #148, Boston, MA 02114; email: asteere@mgh.harvard.edu.
- Klemen Strle, PhD, can be reached at New York State Department of Health; Dock J - P1 Level; Empire State Plaza; Albany, New York 12237; email: klemen.strle@health.ny.gov.
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