11 EULAR on-line course on Rheumatic Diseases

Infection and arthritis.

Reactive arthritis - Lyme -
Whipple - HIV - Viral
arthritis - Septic arthritis

Ashish J Mathew, Debashish Danda, Hill Gaston

A previous version was coauthored by Maxime Breban, Riita Koivuniemi, Marjatta
Leirisalo-Repo, Ben A. Dijkmans, Kari K. Eklund and Janneke Tekstra.

IN-DEPTH DISCUSSION II

Diagnosis and treatment of Lyme arthritis

 Infection and arthritis. Reactive arthritis - Lyme - Whipple - HIV - Viral arthritis - Septic arthritis– Module 11

Diagnosis of borrelia infection

As joint symptoms are common in the population, and ticks (and ticks infected with borrelia) are widely
distributed, the patient history focussing on the previous tick bites, and possible erythema migrans are
important in the clinical diagnosis. A travelling history is important, as in Europe, Lyme borreliosis is primarily
caused by the three species (Borrelia burgdorferi sensu stricto, B. afzelii and garinii), while B. burgdorferi sensu
stricto is the only human pathogenic species in the US (1). The clinical spectrum is different in patients infected
with different borrelia species.

Erythema migrans develops in about 70% of the patients at the site of the tick bite. A red papule developing
immediately at the site of the bite is not an indication of borrelia infection. The infection has an incubation
time of a few days to one month, after which the skin lesion develops, starting as a red macula or papule that
slowly expands. However, as indicated above, the skin manifestation is lacking in one third of the patients.
Erythema migrans is so typical that its presence can be taken as an indication of borreliosis. In those who do
not develop erythema migrans, antibody detection methods can be used. Detection of the causative agent by
culture isolation and PCR is confined to special situations.

Serology The serological examination consists of a serological screening assay (a sensitive ELISA assay),
supplemented in the event of positive or equivocal result, by a confirmatory assay (immunoblot). As the
borrelia species differ between US and European infections, the US serological, immunoblot or PCR tests
cannot be used in European patients. Recently various recombinant antigens for better accuracy in ELISA tests
have been developed (2). For optimal diagnostics, a close collaboration and discussion between the clinician
and the local laboratory is recommended. The frequency of positive serology depends on the detection
methods used by the local laboratory, and on the timing of the infection. Borrelia antibodies of IgM class start
to rise 2-4 weeks after infection, peak within 6-8 weeks after which the production is switched to IgG class. In
early localized disease, the sensitivity of positive antibody response is 20-50%, and most of the antibodies are
of IgM class. If borreliosis is strongly suspected, serological follow-up is recommended. In early disseminated
disease, the sensitivity rises to 70-90%. The majority of patients with short disease duration have IgM class
antibodies, while in those with long disease duration, the IgG class of antibodies predominant.

Patients with late disease (e.g. arthritis or acrodermatitis) are nearly always seropositive with IgG class
antibodies (see 2). Thus, a positive IgM antibody and negative IgG antibody result speaks against late disease.
IgM and IgG class antibodies can persist in some patients for many years, even after therapy. Serology cannot
be used as an indication of the effect of antibiotic therapy. Furthermore, after clinically successful therapy,
there is no need to treat raised antibody levels.

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 Infection and arthritis. Reactive arthritis - Lyme - Whipple - HIV - Viral arthritis - Septic arthritis– Module 11

For confirmation of the preceding infection by immunoblot, use of recombinant antigens is recommended (2).
There are differences between different tests with respect to the antibody binding patterns. Here, as with
antibody tests, the tests used in the US and Europe differ and the European tests should be used for European
patients. Patients with early disease have immune response restricted to only a few proteins, but patients with
late disease (e.g. arthritis) have IgG antibodies to a broad spectrum of antigens.

Antigen detection Culture of borrelia is a time consuming method and has a low sensitivity, especially in body
fluids. For synovial fluid, PCR is positive in 50-70% of the patients, while culture is very seldom positive (2).

Treatment of Lyme arthritis

In the US, arthritis is the most frequent manifestation of disseminated and chronic borreliosis, about 60% of
the patients developing joint manifestations months to years after the tick bite (3). However, a survey among
German physicians showed that about 25% of patients with Lyme borreliosis had arthritis (4). There are no
internationally accepted guidelines on how to treat Lyme arthritis. Some experts use parenteral antibiotics
(ceftriaxone 1 g twice a day for 14-21 days) as the first-line therapy. However, Schnarr et al. recommend as
first choice doxycycline 200 mg/day for 30 days. An alternative choice is amoxicillin 500-750 mg three
times/day for a child or a pregnant patient. In the case of failure of previous treatment, ceftriaxone 1 g twice a
day i.v. for 14-21 days is recommended. Alternative choices are cefotaxime 2 g 3 times a day i.v. or penicillin G
5 million units 4 times a day, for 14-21 days (3).

The arthritis often resolves within 3 months of the onset of treatment. In resistant cases, antibiotics have
been used for up to 3 months. Besides antibiotics, patients need analgesics and anti-inflammatory drugs. The
administration of systemic or intra-articular corticosteroids is controversial, because the treatment may impair
the eradication of the spirochete (5). Physiotherapy is often of benefit, especially in the case of knee synovitis.
The prognosis of arthritis is usually good, about 10% of untreated patients with arthritis recover per year. The
majority of the patients respond to the antibiotic treatment (6). If the arthritis persists after adequate
antibiotic therapy, synovectomy can be considered. Use of disease-modifying antirheumatic drugs is an option
in the resistant case with active joint inflammation.

What to do, if the arthritis continues?

If the objective symptoms and signs persist for more than 1 year after adequate antibiotic therapy, the patient
is considered to have treatment-resistant Lyme disease (3). However care must be taken in these cases to re-
evaluate the evidence for Lyme disease to ensure that there is some certainty about the diagnosis and hence
that the condition is definitely treatment-resistant. If persistent infection (positive PCR in the synovial
fluid/synovial membrane, or in rare cases, positive borrelia culture) is demonstrated, the recommendation is
to aim at eradication of the microbe (3). This includes switching from oral to parenteral antibiotics. There are

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 Infection and arthritis. Reactive arthritis - Lyme - Whipple - HIV - Viral arthritis - Septic arthritis– Module 11

no controlled studies and the treatment options are usually based on case reports or on small open series of
treated patients. Based on experience on 135 US patients with Lyme arthritis treated with various protocols,
Steere and Angelis (5) propose a step-wise approach to the diagnosis and treatment of the patients with
antibiotic-refractory arthritis (Figure 1).

Post-Lyme syndrome

Some patients proceed to have continuous subjective symptoms (such as fatigue, musculoskeletal aches,
neurocognitive dysfunction) without objective arthritis. Two controlled studies showed minor or no benefit
with antibiotics in such cases. However, the discussion continues with pro (7) and con (8) views for prolonged
use of antibiotics for the Post-Lyme syndrome; the situation is complicated by the fact that the symptoms in
many patients following their Lyme disease may stem from anxiety or have a psychological basis. The current
opinion is that taking into consideration the adverse effects of prolonged antibiotics, such therapy can be
hazardous to the patient and is not recommended (3, 9).

References:

1. Wang G, van Dam AP, Schwartz I, Dankert J (1999). Molecular typing of Borrelia burgdorferi sensu lato:
taxonomic, epidemiological, and clinical implications. Clinical Microbiology Reviews 12: 633-653

2. Wilske B, Fingerle V, Schulte-Spechtel U (2007). Microbiological and serological diagnosis of Lyme

borreliosis. FEMS Immunology and Medical Microbiology 49: 13-21

3. Schnarr S, Franz JK, Krause A, Zeidler H (2006). Lyme borreliosis. Best Practice & Research Clin-ical
Rheumatology 20:1099-1118

4. Priem S, Munkelt K, Franz JK, Schneider U, Werner T, Burmester GR, Krause A (2003). Epidemi-ologie und
Therapie der Lyme-Arthritis und anderer Manifestationen der Lyme-Borreliose in Deutsch-land. Zeitschrift für
Rheumatologie 62: 450-453

5. Steere AC, Angelis SM (2006): Therapy for Lyme arthritis. Strategies for the treatment of antibiotic-
refractory arthritis. Arthritis & Rheumatism 54: 3079-3086

6. Girschick HJ, Morbach H, Tappe D (2009). Treatment of Lyme borreliosis. Arthritis Research & Therapy 22:
258 (doi: 10.1186/ar2853)

7. Stickler RB (2007). Counterpoint: Long-term antibiotic therapy improves persistent symptoms asso-ciated
with Lyme disease. Clinical Infectious Diseases 45: 149-157

8. Auwaerter PG (2007). Point: Antibiotic therapy is not the answer for patients with persisting symp-toms
attributable to Lyme disease. Clinical Infectious Diseases 45: 143-148

9. Puéchal X, Sibilia J (2009). What should be done in case of persisting symptoms after adequate antibiotic
treatment for Lyme disease? Current Problems in Dermatology 37: 191-199

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 Infection and arthritis. Reactive arthritis - Lyme - Whipple - HIV - Viral arthritis - Septic arthritis– Module 11

Figure 1. Algorithm for the diagnosis and treatment of Lyme arthritis (Steere and Angelis 2006)

I
• Patient with monoarticular or oligoarticular arthritis, especially of a knee
• Exposure in an area endemic for Lyme disease
• Positive IgG antibody response to B. burgdorferi by ELISA and Western blot

Optional: Positive PCR result for B. burgdorferi DNA in joint fluid

Initial treatment

• Oral doxycyclin, 100 mg twice daily for 30 days

• Oral amoxicillin, 500 mg three times daily for 30 days
• In cases with neuroborreliosis, use i.v. regimens

Mild persistent arthritis after Moderate to severe persistent arthritis

30 days of therapy after 30 days of therapy

Repeat oral antibiotic • i.v. ceftriaxone, 2 g daily, for 30 days

regimen for another 30 days
• i.v. cefotaxime, 2 g three times daily, for 30 days
• i.v. penicillin G, 20 million U daily, for 30 days

Persistent arthritis after 60 days of antibiotics,

including 30 days of i.v. therapy

• If PCR result for B. burgdorferi DNA is still positive, treat with oral antibiotic
therapy for one more month
• If PCR result is negative, treat with NSAIDs
• If arthritis still persists, add hydroxychloroquine

If arthritis persists for 3-6 more months

Consider arthroscopic synovectomy

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