July 25, 2025
11 min learn
Lyme illness is a fancy situation with an extended historical past of misdiagnosis, and Lyme arthritis, a late manifestation of the illness, isn’t any completely different.
And though these infections have primarily been discovered — at the very least in america — throughout the Northeast, Mid-Atlantic and higher Midwestern areas, they’ve lately been spreading outward, to the purpose the place the Northeastern and Midwestern focuses could ultimately merge. Because of this, illness incidence has elevated from roughly 300,000 instances per yr to 475,000 instances per yr prior to now decade, in keeping with consultants.
“The deer tick, which transmits the Lyme illness agent, continues to unfold,” Allen Steere, MD, director of translational analysis in rheumatology at Massachusetts Normal Hospital, and professor of medication Harvard Medical College, informed Healio.
That is of concern as a result of many clinicians with no historical past or familiarity with Lyme illness are actually managing this rising affected person inhabitants.
Sheila L. Arvikar
“It is vital for rheumatologists and different suppliers to grasp the place endemic publicity could happen,” Sheila L. Arvikar, MD, of the Middle for Immunology and Inflammatory Ailments at Massachusetts Normal Hospital, stated in an interview. “Infections are nonetheless principally occurring within the Northeast, the mid-Atlantic area and the Higher Midwest, however there’s an rising geographic unfold of infections from greater incidence areas to neighboring ones.”
Nonetheless, increasing distribution shouldn’t be the one problem.
“As with many types of arthritis, the severity and period of Lyme arthritis is extremely variable,” Steere stated.
In response to John Miller, MD, assistant professor of medication within the division of rheumatology at Johns Hopkins College, Steere “wrote the guide” on Lyme arthritis. Years of analysis from his lab have proven how the physique reacts to Borrelia an infection, resulting in Lyme illness itself. Then, if not acknowledged early within the illness, or if the early phases of the an infection are asymptomatic, Lyme arthritis could develop. In a small proportion of sufferers with Lyme arthritis, a post-infectious complication with autoimmune options could happen.
John Miller
“That is what generates probably the most curiosity for rheumatologists,” Miller stated. “Dr. Steere has described an immune-mediated phenomenon. It’s a nice instance of the intersection between an infection and autoimmunity.”
This intersection shouldn’t be all the time straightforward to establish. The phenomenon begins with a chunk of a tick carrying a spirochetal bacterium known as Borrelia burgdorferi, which can lead to Lyme illness itself. After a few years of trial and error, this situation now may be identified comparatively simply.
Nonetheless, if not handled within the early phases, the an infection could progress to Lyme arthritis.
“These sufferers normally have the best antibody titers seen in Lyme illness, as decided by ELISA, with growth of the antibody response to many spirochetal proteins, as proven by Western blot,” Steere stated.
Early antibiotic remedy can get rid of Lyme illness and, consequently, the danger for Lyme arthritis. In some instances, a second spherical of antibiotics is required to remedy the preliminary an infection.
Nonetheless, it’s a completely different story for sufferers who fail to reply to antibiotics or, worse, by no means acquired a prognosis of Lyme illness within the first place.
“As a result of early Lyme illness is normally acknowledged and handled with antibiotics, which prevents late manifestations of the sickness, Lyme arthritis is normally seen now in people in whom early illness is asymptomatic, with arthritis because the presenting manifestation of the illness,” Steere stated.
The opposite vital complication is that each Lyme illness and Lyme arthritis can take a big period of time to develop.
In response to Janis J. Weis, PhD, of the division of pathology on the College of Utah, it takes as much as 4 days for the Borrelia burgdorferi spirochetal bacterium to alter to allow them to induce an infection.
The Borrelia burgdorferi stay within the mid-gut of the tick through the winter months. With a blood meal within the late spring or summer time, the micro organism proliferate and transfer to the tick’s salivary glands.
“The Borrelia burgdorferi that proliferate within the tick and migrate by the salivary glands change their metabolic state and outer floor antigenic constructions,” stated Weis. “These adjustments result in alteration in expressed proteins that allow them to invade the host, a course of takes as much as 4 days.”
In response to Steere, it equally typically takes months for arthritis to develop after the transmission of the spirochete to the human host. This occurs inside an immune response to an rising array of spirochetal proteins, he stated. As well as, a number of extra months are normally required earlier than sure sufferers develop the extreme, dysregulated immune response which will result in antibiotic-refractory Lyme arthritis.
Understanding the pure historical past, prognosis and therapy of this particular sort of arthritis may also help practitioners reduce comorbidities and keep forward of the quickly altering epidemiology.
An ‘extreme, dysregulated immune response’
In 2024, Steere printed a complement article on Lyme arthritis within the Journal of Infectious Ailments. Entitled “Lyme Arthritis: A 50-Yr Journey,” the article particulars Steere’s half-century lengthy historical past finding out the illness, beginning in 1975 when, 4 months into his rheumatology fellowship, he acquired a name to hitch an investigation into kids creating arthritis — thought on the time to be juvenile rheumatoid arthritis — in and across the city of Lyme, Connecticut.
The paper that resulted from that preliminary investigation — printed in 1977 in Arthritis & Rheumatology, with Steere because the lead writer — was the primary to establish and identify “Lyme arthritis” as it’s identified right this moment.
In his 2024 article, Steere wrote that in a small proportion of sufferers, Lyme arthritis doesn’t resolve with applicable oral and IV antibiotic remedy, resulting in a situation known as post-infectious, antibiotic-refractory Lyme arthritis.
“The results of this extreme, dysregulated immune response within the synovia of affected joints, which started through the an infection, results in vascular injury, autoimmune and cytotoxic processes, and marked synovial fibroblast proliferation and fibrosis,” he informed Healio. “That is the pathologic lesion of power inflammatory types of arthritis, together with rheumatoid arthritis.”
Nonetheless, there are vital elements that differentiate Lyme arthritis from RA and different arthritides.
“Obliterative microvascular lesions are seen within the synovia of about half of those Lyme arthritis sufferers, which aren’t present in different kinds of arthritis,” Steere stated. “In post-infectious Lyme arthritis, autoantigens have been recognized from three vascular related proteins and 4 extracellular matrix proteins, which had been earlier websites of spirochetal an infection. Though stay spirochetes should not nonetheless alive after applicable antibiotic remedy, remnants of the organism, significantly B. burgdorferi peptidoglycan, are sometimes present in joint fluid, and seem to play a task within the perpetuation of the proinflammatory response within the post-infectious interval.”
This description led to an entire physique of analysis on the topic, in Steere’s lab and from others. In a paper printed in Nature Evaluations Rheumatology in 2021, Lochhead and colleagues investigated the mechanisms at play in Lyme arthritis.
“The central characteristic of post-infectious Lyme arthritis is an extreme, dysregulated pro-inflammatory immune response through the an infection section that persists into the post-infectious interval,” Lochhead and colleagues wrote. “This response is characterised by excessive quantities of IFN and insufficient quantities of the anti-inflammatory cytokine IL-10.”
All of those processes are just like these reported in different arthritides like RA, they added. As such, post-infectious Lyme arthritis “gives a mannequin for different power autoimmune or autoinflammatory arthritides” during which an infectious agent, alongside genetic elements, can result in advanced immune responses, Lochhead and colleagues wrote.
Wanting deeper into the physique of analysis, Weis has spent vital effort investigating these pro-inflammatory responses.
“We have now targeted on elements of the innate immune response and located that mice who lack B and T lymphocytes nonetheless develop extreme Lyme arthritis,” she stated. “That is one thing you wouldn’t be capable to examine in human affected person populations.”
Over time, their work led the researchers to concentrate on the response of macrophages, neutrophils, endothelial cells and fibroblasts to the an infection.
“Our mouse fashions even have proven that mice missing the anti-inflammatory cytokine interleukin (IL)-10 develop far more extreme arthritis than mice possessing this cytokine following an infection with Borrelia burgdorferi,” Weis stated. “This has turn into a mannequin for extreme post-treatment arthritis as these mice show excessive ranges of the inflammatory cytokines IL-6, IFN-gamma CXCL9 and CXCL10, just like sufferers with post-infectious arthritis.
“These are hallmarks of an inflammatory response,” she added. “They’re main drivers of post-treatment Lyme arthritis.”
Importantly, the interaction between the an infection and the immune response can influence the severity of the issues. Sufferers with gentle Lyme arthritis could expertise signs for less than a number of weeks or months, even with out antibiotic therapy, in keeping with Steere.
“On the extreme finish of the spectrum, Lyme arthritis could trigger extreme, persistent arthritis, normally affecting one or each knees, lasting a number of years or extra,” he stated.
A extreme course is related to each spirochetal and host genetics, Steere added.
“Sure strains of B. burgdorferi, significantly OspC sort A, are extremely inflammatory,” he stated. “As well as, explicit genotypes throughout the human inhabitants result in larger irritation.”
These embody a Toll-like receptor 1 polymorphism (1805GG), a variant within the late cornified epithelial cell 3 (LCE3) locus, and sure HLA-DR alleles, such because the HLA-DRB1*0401 or HLA-DRB1:1501 alleles, in keeping with Steere.
For Miller, the groundwork laid by these researchers concerning the intersection of an infection and immunity would be the new frontier.
“We see now that that is an immune-mediated course of,” he stated. “That’s what we will likely be specializing in within the subsequent 10 to fifteen years.”
As well as, though each diagnosing clinician could not must know the particulars of what’s occurring within the synovium of their sufferers with Lyme arthritis, understanding the background actually may be useful when assessing each basic and extra ambiguous instances.
“On the optimistic aspect, Lyme arthritis is mostly simpler to diagnose than early Lyme illness itself,” Arvikar stated.
‘Not normally that delicate’
By way of scientific prognosis, the irritation of Lyme arthritis is normally simply recognizable, in keeping with Miller.
“We are inclined to see these large, swollen joints, and normally within the knee,” he stated. “It isn’t normally that delicate.”
Nonetheless, this swelling can fluctuate.
“Pediatric populations are inclined to have effusions which can be there for a couple of days or even weeks, however by the point they get to the physician’s workplace, it has gone down,” Miller stated.
In response to Arvikar, 90% of instances are marked by swelling in a single or each knees.
“It isn’t symmetrical polyarthritis, like RA, which normally entails many swollen joints, typically in each palms or each toes,” she stated.
Assessing a affected person’s ache degree may also be helpful.
“In Lyme arthritis, the swelling tends to be out of proportion to the ache,” Arvikar stated.
The character of each Lyme illness and Lyme arthritis can current diagnostic hurdles, she added.
“The gold normal check for Lyme arthritis is a serologic check for IgG antibodies within the blood,” Arvikar stated. “Sufferers with Lyme arthritis have had Lyme illness for months, so there’s plenty of IgG antibody towards Borrelia burgdorferi within the blood, and it’s simpler to make the prognosis.”
The problem is available in looking for early Lyme illness earlier than arthritis even occurs.
“Serologic testing could also be unfavourable early within the illness,” Arvikar stated, including that antibodies are only one concern with the prognosis of Lyme illness.
“There’s additionally an index of suspicion downside,” she stated.
“Lots of people who get Lyme arthritis are younger and wholesome; they’re lively, spending time outdoors mountaineering or doing different outside actions,” she added. “They could suppose they’ve an harm, so that they see an orthopedist first.”
A further complication is that accidents can probably induce the arthritis.
“In some sufferers with Lyme illness, trauma or insult to the physique serves as an inciting occasion for the onset of arthritis,” Arvikar stated.
Though orthopedists have gotten more proficient at differentiating Lyme arthritis from accidents or different kinds of arthritis, this may occasionally nonetheless be a problem for different suppliers who’re much less aware of the illness, in keeping with Arvikar. Nonetheless, this isn’t the one impediment.
“Lyme illness is a seasonal an infection, so the early an infection typically occurs through the summer time season,” Arvikar stated. “The issue is that the arthritis typically develops many months later, which may result in a false impression that it’s not the best time of yr for a Lyme disease-associated situation. It could throw suppliers off observe on this prognosis.”
The literature from Steere means that Lyme arthritis could develop between 6 months to 2 years after the preliminary an infection.
“It isn’t a long time, but when 1 or 2 years cross earlier than the arthritis develops, it could actually make prognosis a problem,” Arvikar stated.
The dearth of an apparent tick chunk or hallmark bullseye rash may lead suppliers away from the prognosis, she added. Nonetheless, in present instances most sufferers with Lyme arthritis lack a historical past of a tick chunk or bullseye rash.
“After all, if the affected person had seen the tick or the rash, they might have doubtless gotten therapy that might have prevented Lyme arthritis,” she stated. “However many, or most, folks by no means discover the chunk or rash.”
Local weather change, and the related unfold of illness vectors into extra areas of the nation, have solely exacerbated this downside.
Westward growth
In response to Steere, the deer tick is now extremely endemic in western Pennsylvania and is spreading westward into Ohio, Indiana and Michigan.
“A longstanding focus within the northern Midwestern states of Wisconsin and Minnesota can also be spreading,” he stated. “As well as, places in Canada are actually affected.”
The West Coast has moreover seen a rise within the illness, primarily in northern California, however the epidemiology of the illness is completely different there, in keeping with Steere.
“Lyme illness instances are extra sporadic in that a part of the nation,” he stated. “For probably the most half, the species of B. burgdorferi that trigger Lyme illness in Europe are completely different than in North America, and the European strains are much less arthritogenic than these in America.”
In the meantime, the adjustments in geographic unfold have triggered a rise in Lyme illness incidence, in keeping with Miller.
“Ten years in the past, the estimated incidence of Lyme illness within the U.S. was about 300,000 instances per yr,” he stated. “More moderen estimates put that quantity at 475,000 instances per yr.”
The info on Lyme arthritis incidence have, to date, not caught up with the identified knowledge on Lyme illness incidence. Nonetheless, extrapolations may be made.
In a paper printed in Morbidity and Mortality Weekly Report in 2008, Bacon and colleagues estimated the proportion of varied Lyme illness manifestations reported to the CDC. They instructed that between 20% and 25% of instances could embody Lyme arthritis.
“Public well being campaigns have improved the discovering of Lyme illness, however it’s unclear whether or not the proportions of Lyme arthritis have modified since that report got here out,” Miller stated. “If Lyme illness incidence is rising, it ought to observe that Lyme arthritis prevalence can also be rising.”
As consultants type out the numbers, what is for certain is that many extra clinicians are more likely to have a affected person with Lyme arthritis stroll by their door. Understanding the therapy panorama is vital.
‘Most sufferers reply’
In response to Steere, therapy for Lyme arthritis begins with a 1- or 2-month course of oral doxycycline, 100 mg twice day by day.
“Most sufferers reply to this therapy, although full decision of joint swelling could lag by a number of weeks after the conclusion of remedy,” he stated.
Sadly, a small proportion of sufferers have minimal or no response to oral antibiotic remedy. These sufferers could also be handled efficiently with IV antibiotics, “normally ceftriaxone,” at 2 g day by day for 28 days, Steere stated.
“Once more, the decision of joint swelling could lag by a number of weeks after the conclusion of IV remedy,” he added.
The Infectious Ailments Society of America suggestions state {that a} second course of oral antibiotics, for as much as 1 month, “could also be an inexpensive different” for sufferers whose synovial proliferation is “modest” vs. joint swelling. Nonetheless, the authors famous that is primarily based on a “partial response,” with extra proof required to fill the data hole.
That stated, Milled said this could not deter physicians from administering a second course of antibiotics.
“The largest mistake is that clinicians typically don’t take into account a second course of antibiotics in Lyme arthritis,” Miller stated.
There’s, nevertheless, yet one more qualification right here. In a few of sufferers, the arthritis adjustments after antibiotic remedy, in keeping with Steere.
“The joint is now not as swollen, however large synovial hypertrophy develops,” he stated.
Steere inspired clinicians to doc these adjustments utilizing ultrasound or MRI.
“On condition that the affected person has beforehand acquired oral and IV antibiotics, such sufferers can typically be handled efficiently with DMARDS, corresponding to methotrexate or a TNF inhibitor,” he stated. “Most sufferers reply inside months to this remedy, and the medicine can normally be stopped in about 9 to 12 months.”
Regardless of therapy, injury could stay. In response to Steere, the an infection typically results in marked atrophy of the quadriceps and typically flexion contractures, which require bodily remedy and actions, corresponding to bike using, to regain full perform to the knee.
“We attempt to reassure sufferers with Lyme arthritis that their arthritis will typically resolve totally with applicable therapy,” Arvikar stated. “We will handle this manifestation of Lyme illness extraordinarily nicely with out the necessity for long-term medicine, as is required for different kinds of arthritis.”
References:
Bacon RM, et al. MMWR. 2008; 57(SS10);1-9.
Lochhead RB, et al. Nat Rev Rheumatol. 2021;doi:10.1038/s41584-021-00648-5.
Steere AC. J Infect Dis. 2024;doi:10.1093/infdis/jiae126.
Steere AC, et al. Arthritis Rheumatol. 1977;doi:10.1002/artwork.1780200102.
For extra data:
Shiela L. Arvikar, MD, may be reached at SARVIKAR@mgh.harvard.edu.
John Miller, MD, may be reached at jmill237@jhmi.edu.
Allen Steere, MD, may be reached at ASTEERE@mgh.harvard.edu.
Janis J. Weis, PhD, may be reached at janis.weis@path.utah.edu.
Sources/Disclosures
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Disclosures:
Steere studies receiving consulting charges from Pfizer concerning improvement of a Lyme illness vaccine, however it’s not but accessible for the prevention of Lyme illness. Arvikar, Miller and Weis report no related monetary disclosures.
