Content uploaded by Phyllis R. Freeman
Author content
All content in this area was uploaded by Phyllis R. Freeman on Mar 04, 2017
Content may be subject to copyright.
Central
Bringing Excellence in Open Access
JSM Arthritis
Cite this article: Horowitz RI, Freeman PR (2016) Are Mycobacterium Drugs Effective for Treatment Resistant Lyme Disease, Tick-Borne Co-Infections, and
Autoimmune Disease?. JSM Arthritis 1(2): 1008.
*Corresponding author
Richard I. Horowitz, Hudson Valley Healing Arts Center,
4232 Albany Post Road, Hyde Park, New York 12538,
USA, Tel: 845-229-8977; Fax: 845-229-8930; Email:
Submitted: 15 June 2016
Accepted: 14 July 2016
Published: 16 July 2016
Copyright
© 2016 Horowitz et al.
OPEN ACCESS
Keywords
•Lyme disease
•Bartonella
•Tularemia
•Behçet’s Disease/Syndrome
•Rheumatoid arthritis
•Dapsone
•Pyrazinamide
•Persister bacteria
Case Report
Are Mycobacterium Drugs
Effective for Treatment
Resistant Lyme Disease, Tick-
Borne Co-Infections, and
Autoimmune Disease?
Richard I. Horowitz* and Phyllis R. Freeman
Hudson Valley Healing Arts Center, USA
Abstract
Introduction: PTLDS/chronic Lyme disease may cause disabling symptoms with
associated overlapping autoimmune manifestations, with few clinically effective
published treatment options. We recently reported on the successful use of a
mycobacterium drug, Dapsone, for those with PTLDS. We now report on the novel
use of another mycobacterium drug, pyrazinamide, (PZA), in relieving resistant
symptomatology secondary to Lyme disease and associated co-infections, while
decreasing autoimmune manifestations with Behçet’s syndrome.
Method: Disabling multi-systemic/arthritic symptoms persisted in a Lyme patient
with co-infections (Bartonella, tularemia) and overlapping rheumatoid arthritis/
Behçet’s disease, despite several rotations of classic antibiotic and DMARD regimens.
Dapsone, a published treatment protocol used for Behçet’s syndrome, recently has
been demonstrated to be effective in the treatment of PTLDS/chronic Lyme disease
and co-infections. It was superior to prior treatment regimens in relieving some
resistant chronic tick-borne/autoimmune manifestations; however, it did not effectively
treat the skin lesions and ulcers secondary to Behçet’s disease, nor signicantly affect
the granuloma formation, joint swelling, and pain associated with Lyme, Bartonella,
and RA. PZA, in combination with Plaquenil, minocycline and rifampin, relieved her
resistant symptomatology secondary to Lyme and co-infections, her Behçet’s ulcers, as
well as granulomatous skin changes. In addition, a quadruple intracellular combination
of a tetracycline (doxycycline), combined with rifampin, Dapsone, and a quinolone
(moxioxacin) was effective in treating reactivation of her tularemia.
Conclusion: Further scientic studies are needed on the role of intracellular
bacteria and mycobacterium drugs like Dapsone and pyrazinamide in the treatment
of both chronic persistent bacterial infections and resistant autoimmune phenomena.
ABBREVIATIONS
PTLDS: Post-Treatment Lyme Disease Syndrome;
RA: Rheumatoid Arthritis; AI: Autoimmune Illness; PZA:
Pyrazinamide, DMARDs: Disease-Modifying Anti Rheumatic
Drugs; VEGF: Vascular Endothelial Growth Factor, MSIDS:
Multiple Systemic Infectious Disease Syndrome
INTRODUCTION
Autoimmune diseases like rheumatoid arthritis and lupus
are rising in incidence in the United States and environmental
factors are being implicated [1-3]. Tick-borne diseases, such
as Lyme disease are also increasing in number as per recent
Centers for Disease Control (CDC) studies [4,5], and have been
associated with autoimmune manifestations [6]. Up to 20-25% of
patients may suffer the consequences of Post- Treatment Lyme
Disease Syndrome (PTLDS) [7] after a tick bite, with or without
associated autoimmune disease, leading to multiple symptoms,
including disabling fatigue, arthritis, and neuropathy.
as one of several emerging pandemic disease outbreaks that
threaten global public health and world economies [8]. The CDC
Central
Bringing Excellence in Open Access
Horowitz et al. (2016)
Email:
JSM Arthritis 1(2): 1008 (2016) 2/12
the US from 2005-2010, which led to revised estimates of over
300,000 new cases per year [5]. In August 2015, CDC researchers
revised their estimates upwards once again, showing a 320%
increase in Lyme cases in the past 20 years [9]. Birds are known
to carry ticks and spread the infection across the US and Europe,
accounting for part of the increased numbers [10].
Ticks now contain multiple bacterial, viral, and parasitic
infections that can be simultaneously transmitted with Borrelia
burgdorferi, the agent of Lyme disease. Co-infection is the rule,
with ticks able to transmit multiple infections [11]. In one recent
tick, including multiple species of intracellular bacteria including:
Borrelia, relapsing fever spirochetes, Anaplasma, Ehrlichia,
spotted fever rickettsia, Bartonella spp. (henselae); ten species
of Babesia, two Theileria spp. Wolbachia spp. Coxiella burnetii
(Q-fever) and Midichloria mitochondrii, an associated symbiont
[11]. Many of these infections are increasing in parts of the United
States and worldwide [12], including tularemia, considered a
rare infection years ago. It is a febrile, granulomatous, infectious
zoonosis caused by Francisella tularensis, an aerobic, gram-
negative, pleomorphic bacillus, which is found in ticks. F.
tularensis is one of the most infectious bacterial species known
[13]. Patients infected with Lyme disease and associated tick-
borne co-infections like Babesia, Bartonella and tularemia are
much sicker and often resistant to standard therapies, and may
present with atypical clinical presentations [14].
Patients with chronic symptoms after standard treatment
for Lyme disease/PTLDS have been hypothesized to have
multi factorial causes for their illness [15], including persistent
autoimmune phenomenon and/or tissue damage responsible
for ongoing morbidity. We recently published on the effective
use of Dapsone for Chronic Lyme disease/PTLDS [16], a
the treatment of Behcet’s syndrome. Behçet’s disease is a multi
vasculitis, of unknown etiology [17]. Common symptoms include
and arthritis. In the case report presented here, we describe
a patient with a history of treatment resistant Lyme disease,
and associated intracellular co-infections including probable
Babesiosis, Bartonella henselae, and Francisella tularensis,
associated autoimmune disease, including seronegative
rheumatoid arthritis and Behçet’s syndrome, who responded to
a novel combination of multiple intracellular antibiotics used for
other persister bacteria. The goal of this paper is to demonstrate
the effect of pyrazinamide (PZA), another mycobacterium drug,
in combination therapy as an effective treatment for Lyme
disease, autoimmune phenomenon and associated intracellular
co-infections.
CASE PRESENTATION
The patient is a 49-year-old white female with a past medical
arthritis. She was diagnosed 19 years ago by a rheumatologist after
complaining of chronic pain all over her body, described as being
severe, bilateral and symmetric in nature. She had previously
seen three rheumatologists, and been on multiple DMARD
She failed all of the above regimens, including her present
regimen of Imuran (azathioprine) 50 mg, 2 PO QD with Plaquenil
(hydroxychloroquine) 200 mg, one PO BID, complaining of
chronic severe pain and joint swelling. She was also on Ultram
(tramadol) 50 mg, 1 to 2 PO TID, prn for her joint pain, with
Cymbalta (duloxetine) 60 mg per day for her neuropathy and
intermittent use of prednisone, she still complained of severe pain
in multiple joints, with neuropathic symptoms in her extremities.
Other symptoms included persistent fatigue, occasional chills,
The patient had been seen by dermatology years ago, for
surfaces of her hands. A skin biopsy returned as positive for
Winkelman’s granulomas [18,19], of unknown etiology. Churg-
Strauss granulomatous vasculitis [20] was considered in the
differential diagnosis, but she had no history of allergic rhinitis,
asthma, or eosinophilia, ruling out the diagnosis. She also had
large recurrent ulcers throughout her mouth, palate and tongue,
in the genital area (anus, labia), as well as papulo-pustular lesions
which would come and go on her extremities, consistent with
Behçet’s syndrome [21]. She was using Imuran, colchicine, magic
mouth wash (diphendyramine 12.5mg/5 ml; hydrocortisone 60
mg; Nystatin suspension 30 ml), and prednisone intermittently,
Family history was positive for hypertension and heart
disease, but no history of familial autoimmune illness. Social
history was positive for having given up smoking several years
ago (one pack per day for several years), with minimal caffeine
and alcohol use. She lived in a known epicenter for tick-borne
illness, but did not remember any tick bites or rashes consistent
with an erythema migrans rash. She had a pet rabbit, but there
was no known wild animal exposure. Review of systems was
infrequent, heavy periods, unexplained hair loss and weight
loss (several pounds), a recent cough that was nonproductive,
intermittent chest pain, and joint pain throughout her body. She
now complained of stiff, hot, red swollen joints, with associated
bilateral edema of the lower extremities.
Physical examination revealed a well-developed, well-
nourished white female in no apparent distress. She had a low-
grade temperature of 99.7 degrees Fahrenheit, with a normal BP,
pulse and respiratory rate. Initially, there were no orthostatic
changes going from a sitting to standing position, although
mild symptoms of dysautonomia developed over time, with a
drop in her BP from 106/69 sitting to 89/71 standing, with an
associated mild tachycardia. HEENT revealed multiple deep,
large ulcerations on her inner lips, upper palate, and tongue,
with a normal thyroid, carotids were 2+ bilateral and symmetric
with no bruits, and there was minimally enlarged axillary lymph
node. Cardiovascular, pulmonary and abdominal examination
Central
Bringing Excellence in Open Access
Horowitz et al. (2016)
Email:
JSM Arthritis 1(2): 1008 (2016) 3/12
was WNL; Lower extremities revealed 1+ edema, pulses were
2+ bilateral and symmetric, and her neurological exam was
intact except for a slightly ataxic gait. Skin examination revealed
rheumatoid changes of her hands and feet, with hot, swollen joints,
well as her elbows and forearms, painful to the touch.
Laboratory values revealed a negative Borrelia burgdorferi
C6 ELISA, but positive CDC IgM Western blot [22], a low positive
Borrelia hermsii IgG IFA (1:64 +, normal less than 1:64), possible
prior exposure to tularemia, with a low level titer at 1:20 +, prior
exposure to Mycoplasma pneumonia (IgG antibody, positive
at 1.21, normal less than 0.90), a slightly elevated IgM level
at 276 mg/dL (normal levels are below 271 mg/dL; she was
subsequently ruled out for Waldenström’s macroglobulinemia);
positive autoimmune antibodies, including a positive ssDNA
IgG AB (80 u/mL, normal less than 69 u/mL), positive double-
stranded DNA at 10 IU/ ml (normal levels less than 4), positive
anti ganglioside antibodies (Anti-GM1, positive at 1:800; normal
less than 1:800) consistent with an immune mediated neuropathy,
normal less than 1 mg/dL), hs-CRP (49.4 mg/L, normal less
than 1.0 mg/L), sedimentation rate (ESR) at 68 mm/h (normal
less than 26 mm/h), with a mildly elevated platelet count at
431,000 (normal limits between 144 and 400,000/uL). She had
borderline anemia (hemoglobin 12.6, normal greater than 13.2
g/dL; hematocrit 37.8, normal greater than 38.5) with normal
of chronic disease. S. cerevisiae (ASCA) IgA and IgG levels were
normal. A comprehensive metabolic panel was within normal
limits, as was her urine micro albumin. ANA, rheumatoid factors,
cyclic citrullinated peptides (CCP), Sjögren’s AB’s (SS-A, SS-B),
CPK and complement studies were within normal limits (except
for an isolated increase in CH50), as were blood levels of mercury,
lead, and arsenic. Serum antigliadin antibodies and tissue
transglutaminase levels (TTG) were also negative, ruling out
celiac disease or gluten sensitivity as a cause of her skin lesions
iodine (35, normal between 50 to 109 mcg/L) and low zinc (57,
normal levels between 68-161); other vitamin levels were normal
(i.e., B12, folic acid and methylmalonic acid levels), but she was
MTHFR positive with an elevated homocysteine level at 12, and
history of sick euthyroid syndrome with normal T4 and TSH, with
an isolated low T-3. She was in perimenopause with irregular
menses, with an elevated LH, but normal FSH, progesterone
as a cause of her night sweats). Tick-borne testing including
Babesia microti and WA-1/duncani, Ehrlichia, Anaplasma,
Rocky Mountain spotted fever, Q-fever and Brucella titers were
negative, as was IgE food allergy testing. Adrenal testing, as well
as viral titers and PCR’s were ordered for her chronic fatigue,
and a Vitamin D level and DEXA scan was ordered to check her
bone density, since she had intermittently been on prednisone
for many years. HHV-6 titers were initially 1:320 (normal less
than 1:10) with a negative PCR, and EBV VCA AB IgG was 4.99
(normal less than 0.91) with a negative PCR, consistent with
prior exposure to both infections. Coxsackie A10 antibodies were
low positive at 1:8 (normal less than 1:8), with prior exposure
to HSV-2 (IgG greater than 8, normal less than 0.9 AI). DHEA/
cortisol testing revealed adequate cortisol levels. The Vitamin
D level returned WNL, but the DEXA scan returned positive for
severe osteoporosis.
A chest X-ray and CT angiography of the chest was done with
contrast to evaluate her chest pain and cough. Mildly enlarged
bilateral axillary lymph nodes were seen with a normal heart,
pericardium, and lung parenchyma. X-rays bilaterally of her
hands revealed degenerative changes in the bilateral radiocarpal
bilateral carpal bones and distal radius, consistent with osseous
hip revealed severe osteoarthritis and early osteonecrosis of the
left femoral head, related to frequent steroid use over the past
several years.
The patient was initially started on Minocin (minocycline)
100 mg PO BID, Plaquenil (hydroxychloroquine) 200 mg, one PO
BID (both a Lyme disease and DMARD regimen), Nystatin 500,000
units, two PO BID, with a sugar-free diet and high dose probiotics.
Occult Babesia was suspected since the patient complained of
frequent drenching night sweats and chills with associated “air
hunger” (which are classic symptoms of babesiosis). Malarone
(atovaquone 250 mg/proguanil hydrochloride 100 mg) [23]
an anti-malarial drug, was therefore added to her protocol, and
was temporarily helpful in decreasing her sweats and chills.
She had already been ruled out for other causes of drenching
sweats, such as menopause, hyperthyroidism, brucellosis,
non-Hodgkin’s lymphoma or tuberculosis. She was on Imuran,
an immunosuppressive drug, known to be a risk factor for
cancer and/or reactivation of latent intracellular infections like
tuberculosis [24].
Multiple rotations of intracellular drugs were needed in
the next few months, as the patient continued to complain of
extreme fatigue, night sweats and chills, severe migratory joint
pain and neuropathy of her extremities (consistent with active
Lyme disease), which interfered with sleep. These drug regimens
initially included double and triple intracellular antibiotic
regimens, such as a tetracycline with Zithromax (azithromycin)
250 mg PO BID and Malarone, 2 PO BID, or tetracyclines
(doxycycline 100 mg PO BID or minocycline 100 mg PO BID)
with rifampin 300 mg PO BID, Bactrim DS (sulfamethoxazole/
trimethoprim) one PO BID and Malarone, with herbal treatments
Cryptolepis sanguinolenta 20 drops PO BID, and capsules of
Artemisia annua [26,27] 250 mg PO TID. There was only a partial
response in symptoms, with a slight decrease in joint pain and
swelling, but no change in her severe fatigue or poor sleep. She
also continued to develop new oral ulcers on this regimen with
painful granulomatous lesions of her extremities, with elevations
(ESR 63), and high levels of hs-CRP (35.3). She was rotated to a
different regimen including Omnicef (cefdinir), with Plaquenil
and Zithromax, but it had little effect on her symptoms. Low-
dose naltrexone (4.5 mg HS) [28], in combination with Lyrica
(pregabalin, 200 mg HS), Voltaren (diclofenac) 75 mg, one PO
Central
Bringing Excellence in Open Access
Horowitz et al. (2016)
Email:
JSM Arthritis 1(2): 1008 (2016) 4/12
BID with meals), with Cytotec (misoprostol), 200 µg one PO
use), while her rheumatologist increased her Imuran to 50 mg
visit of December 2014, the patient was placed on a quinolone,
prior drug regimens. After 2 months on this regimen, her malarial
(ESR decreased from 50 to 38; CRP decreased from 39 to 1.6),
but there was no major shift in her systemic symptoms, and
or painful granulomas of the extremities. Levaquin was therefore
discontinued, and Dapsone, 100 mg PO QD, with leucovorin 5
mg per day, with extra folic acid was added to her minocycline,
rifampin, and Malarone. Dapsone is known to be effective in
treating Behçet’s syndrome [29]. When the patient returned 2
months later, her sweats had decreased to twice a month from
once a day; there was no further air hunger; there were less
frequent and severe neuropathic symptoms; and she had a slight
decrease in her joint pain. Her clinical response was the best it
had been in the past year (and was the best since starting DMARD
regimens back in 1999). She still complained however of painful
ulcers on the side of her tongue (Figure 1), as well as swollen
joints and painful granulomas (Figure 2), and blistering lesions
which appeared all over her body (Figure 3).
Although the patient’s clinical response was improved from
prior regimens, where her functional status improved from 30%
to 50% of normal (with Borrelia hermsii titers turning negative),
there was a sudden fourfold increase in her tularemia titers,
going from 1:20 to 1:320, with Bartonella titers turning positive
(Bartonella henselae, 1:64 +) with a simultaneous increase in
vascular endothelial growth factor (VEGF) [30], a biochemical
marker for active vasculitis (known to be associated with
Bartonella). VEGF levels were previously undetectable, and were
now 96 (normal less than 86 pg/ml). Her prior ESR which had
temporarily decreased to 37, was now 69 mm/h, antiganglioside
antibodies increased from 1:800 to 1:3200, and HHV-6 titers
rose temporarily to 1:1280 (a fourfold rise). It appeared that
the Dapsone, although helping to decrease her symptoms, was
unmasking underlying dormant infections. We added Avelox
rifampin 300 mg PO BID, Plaquenil 200 mg PO BID, and Dapsone
100 mg PO QD (a four drug intracellular combination), and she
was sent to an infectious disease (ID) physician for a second
opinion regarding IV therapy (streptomycin, gentamicin), since
she had already been on a triple intracellular combination of a
against tularemia. She was immune compromised, and might
require more aggressive therapy. The ID physician left the
regimen in place, and felt that IV treatment was unnecessary,
since tularemia titers subsequently decreased from 1:320 to
1:80 one month later, further decreasing to 1:40 and then 1:20
positive (baseline) titers over the next few months.
By December 2015, the patient had made continuous
progress with some systemic symptoms, and was off the Avelox,
but still had symptomatic joint pain interfering with sleep. She
still had ongoing severe dermatological manifestations of blood-
Figure 1 Large Behçet’s ulceration on the tongue.
Figure 2 Granulomas and swelling of the joints (before Minocycline, Rifampin
and Pyrazinamide).
Figure 3 Papulo-pustular lesions.
Central
Bringing Excellence in Open Access
Horowitz et al. (2016)
Email:
JSM Arthritis 1(2): 1008 (2016) 5/12
appearing everywhere except her chest and back. She was placed
on a dairy free, gluten free diet, since the patient reported increased
dermatological symptoms when she was off her diet during her
honeymoon (despite negative celiac testing [31] and IgE allergy
This was partially effective in helping decrease pain, swelling
and fatigue, but was inadequate to relieve her worst symptoms.
Due to her recalcitrant course, and prior positive response to
Dapsone (an intracellular mycobacterium drug used for leprosy
and Behçet’s) [32], we discussed starting her on pyrazinamide,
(PZA) [33], another intracellular mycobacterium drug, with
Plaquenil, minocycline and rifampin, since no regimen had been
effective in clearing the ulcers and painful granuloma formation.
The rheumatologist wanted to place her on Rituxan (rituximab)
for her resistant RA and granulomatosis with poly angiitis, but
since she previously reactivated intracellular infections while
of PZA, 2 PO QD (based on her body weight), combined with
rifampin and minocycline as her last option. We monitored her
liver function every two weeks and provided liver support with
alpha lipoic acid 600 mg PO BID and milk thistle 250 mg PO BID.
To our surprise, during the 2nd month on the regimen, she had
of normal functioning, where she started at 20% to 30% during
her initial consultation, with improvement in her most resistant
(see Figure 4), the granulomas were breaking up on her skin (see
Figure 5), and according to the patient, it was the best medication
protocol she had tried in the past 20 years.
The patient’s liver functions remained WNL during two
months on the protocol, and since she was continuously
improving, we left her on the PZA for one additional month. Her
sweats, chills, fatigue, shortness of breath, swollen glands, joint
pain, stiffness, and poor balance improved, and she was taken off
The patient underwent a left hip replacement for
osteonecrosis of the femoral head, and was placed on Plaquenil
200 mg PO BID, Minocin 100 mg PO BID, Rifampin 300 mg PO
BID, Bactrim DS one PO BID and Nystatin 500,000 U PO BID,
with high dose probiotics post-op. She was anemic and zinc
levels were low at 61 ug/dl post-op (normal greater than 68
ug/dl), so she was prescribed a multi mineral supplement with
iron and zinc. Within seven to ten days off the pyrazinamide
she did have a return of papulo-pustular lesions in between her
toes, plantar surfaces of her feet, legs, buttocks and face, with a
minor return of tongue ulcerations (but still greatly improved).
visit, and her systemic symptoms were otherwise stable and
improved. Her ESR had decreased to 45 mm/h, and we were
able to lower her Imuran dose. The mycobacterial combination
drug protocols were the most effective for her resistant Lyme
for the dermatological manifestations of Behçet’s and arthritic/
granulomatous changes.
DISCUSSION
The rising incidence of multiple tick-borne infections, such
as Lyme, other Borrelia species, Babesia, Bartonella [34], and
tularemia [35,36], requires a high index of suspicion in any patient
with an unexplained chronic fatiguing, musculoskeletal illness.
Unfortunately, the insensitivity of the present two-tiered testing
for Lyme and other Borrelia species (like B. miyamotoi), using an
ELISA followed by a Western blot, as well as the inability of the
newer C6 Lyme ELISA [37,38] to pick up all positive cases, can
lead to inaccurate diagnoses [39]. This patient had a negative C6
ELISA and a CDC positive Western blot indicating prior infection.
There are multiple species of Borrelia in the United States, and
the lack of a gold standard for their diagnosis makes producing
to the B. burgdorferi sensu lato complex have a worldwide
distribution, yet they are rarely considered or tested for [40].
The same testing issues exists for Babesia and co-infections
sensitivity to pick up all pathogenic species, leading to inaccurate
diagnoses [41,42]. Several of these bacteria like Bartonella are
stealth intracellular/intravascular pathogens, avoiding immune
surveillance. That was initially the case for this patient, although
later in her clinical course, she reactivated several intracellular
infections while on immunosuppressive therapy.
Multiple bacterial and parasitic tick-borne infections in the
increase comorbidity. Human babesiosis, for example, has
multiple species [43] which may be transmitted at the same time
Figure 4 Clearing of tongue ulcers.
Figure 5 Decreased joint pain/granulomas.
Central
Bringing Excellence in Open Access
Horowitz et al. (2016)
Email:
JSM Arthritis 1(2): 1008 (2016) 6/12
as a tick bite causing Lyme disease [44], increasing the duration
and severity of symptoms, [45, 46] but do not always cause classic
malarial type presentations, such as frank hemolytic anemia,
and/or thrombocytopenia and elevations in liver functions. It
should be suspected in splenectomized and otherwise immune
compromised individuals with severe febrile illnesses, but can
also be found in those with unexplained drenching night sweats,
day sweats and chills with respiratory complications [47,48].
Babesia is able to establish a chronic infection in the animal
population [49], and has been found to persist in humans after
standard antibiotic therapies [50-52].
Tularemia can also present with one of several different
clinical presentations and persist in the human host. Although
the patient did not have classic clinical manifestations of
tularemia, i.e., the ulceroglandular, oculoglandular, typhoidal or
pneumonic forms [53], it is highly likely that the combination of
immune suppressive drugs and multiple overlapping infections
like Bartonella altered her clinical presentation.
Patients with Bartonella have a broad range of clinical
manifestations resembling other diseases, the result of over
30 different species/subspecies; at least 18 are implicated in
human infections [54]. Bartonella are Gram-negative bacteria
B. henselae (ticks), the
agent of cat scratch fever, B. quintana, the agent of trench fever
(lice), and B. bacilliformis, i.e., Carrion’s disease, transmitted by
B. koehlerae have recently
Bartonella henselae, B.
koehlerae, or was found to be high
in Lyme disease (46.6%), arthralgia/arthritis (20.6%), chronic
causal role [55]. Bartonella species are also known to cause
rheumatologic manifestations resembling RA and Lupus, with
associated myositis, osteomyelitis and systemic vasculitis.
Immunocompromised patients are at risk for severe, life
threatening illness [56]. No single treatment has been shown to
be effective for all Bartonella-associated disease.
Published research demonstrates that the effects of co-
infections in humans is diverse and complex [57], and there is
develop chronic symptoms despite standard courses of treatment
for Lyme and co-infections. One hypothesis regarding PTLDS, is
that persistent infection with Borrelia burgdorferi, apart from
autoimmune phenomenon and tissue damage, is underlying
chronic symptomatology. Evidence of the persistence of Lyme
disease comes from xenodiagnostics studies [58] and evidence
species [59,60]. Research also demonstrates that Borrelia
can form persister cells [61-64] while able to avoid immune
surveillance through changing outer surface proteins through
gene recombination [65], and avoid complement mediated
killing [66], hiding in the intracellular compartment [67,68].
Other persister bacteria exist as intracellular infections like
TB, leprosy, and Q-fever, and treatment failures may be due to
using intracellular drugs not known to be effective in treating
persister bacteria, like mycobacterial infections. Bartonella,
an intracellular infection, is known to persist with bacteremia,
potentially spanning decades in duration, even in immune
competent hosts [69]. Some of these bacteria, such as Lyme and
Bartonella, also cause autoimmune manifestations, increasing
arthritic complications in rheumatologic diseases [70,71], while
causing a vasculitis (Borrelia, Bartonella) [72,73], and associated
granuloma formation (Bartonella, tularemia) [74,75].
Many pathogenic bacteria are able to persist, driving
intracellular compartment [76]. One example is Mycoplasmas,
which like Lyme disease [77], have been shown to interact non-
immunity promoting autoimmune reactions and rheumatoid
cytokines including IL-1, 2, and 6. Bartonella species also can
cause arthritis with polyclonal B-cell activation, commonly found
[55]. Our patient had evidence of exposure to Lyme disease,
relapsing fever Borrelia (B. hermsii), Mycoplasma spp., tularemia
and Bartonella, with probable Babesiosis. These infections may
an autoimmune illness. This patient also had low zinc levels,
not until the underlying infections were treated with PZA, that
Bartonella have been associated with chronic bacteremia
and/or chronic endocarditis, and one of the classic manifestations
is bacillary angiomatosis [81,82]. The cutaneous lesions of
bacillary angiomatosis are papules or subcutaneous nodules with
ulcerations, where Bartonella species cause a systemic vasculitis
secondary to increased oxidative stress affecting blood vessels.
The main mechanism of oxidative stress-induced angiogenesis
involves hypoxia-inducible factor/vascular endothelial growth
factor (VEGF) signaling [83], which was seen in this patient,
who had evidence of increased oxidative stress (increased
homocysteine, ESR, CRP) and elevated levels of VEGF. The
granulomas, papules and ulcers present eventually responded to
antibacterial therapy.
including uveitis and retinitis, with a broad range of multi systemic
manifestations, including various rheumatological, neurological
[84], cardiovascular, and gastrointestinal manifestations
[85]. These are some of the same clinical manifestations
seen in Behçet’s syndrome, which results in a vasculitis
with ulcerations, with associated cardio-pulmonary disease
(pericarditis, pleuritis, cough), ophthalmological problems
(uveitis), G.I. problems (nausea, pain, diarrhea), arthritic and
neurological problems (chronic meningoencephalitis, balance
problems) with accompanying systemic manifestations of severe
fatigue [21]. Is it possible that Bartonella species are in part
responsible for Behçet’s disease? The patient’s clinical response
to multiple intracellular medications, especially pyrazinamide,
in combination with a tetracycline and rifampin, implies one or
more intracellular infections as the primary etiology.
Behçet’s disease was named in 1937 after the Turkish
Central
Bringing Excellence in Open Access
Horowitz et al. (2016)
Email:
JSM Arthritis 1(2): 1008 (2016) 7/12
but it was previously referred to as “Silk Road Disease”, since
an increased prevalence was seen in the areas surrounding the
old silk trading routes in the Middle East and Central Asia [86].
The higher prevalence of Behçet’s in those areas implies either
genetic (HLA B-51) and/or environmental precipitating factors.
Bartonella species, such as B. quintana are highly endemic in
those geographic areas; B. quintana induces the same lesions seen
in bacillary angiomatosis; and parasites that are endemic to the
Middle East [87] could hypothetically be associated factors with
Bartonella in the etiology of Behcet’s disease, since leishmaniasis,
caused by protozoan parasites and spread by the bite of
mucocutaneous, or visceral forms, all of which all involve ulcer
formation, which can involve the skin, mouth, and nose [88,89].
Dapsone, effective in Behçet’s disease, has both antibacterial
and anti-parasitic properties. We recently demonstrated that
Borrelia burgdorferi (a
bacteria) as well as Babesia species, which are intraerythrocytic
parasites [16]. Multiple overlapping infections may therefore
be responsible for Behçet’s disease, which is presently of
unknown etiology. Advanced microbiological techniques were
unavailable years ago to determine if an infectious cause was
other granulomatous illness like Wegener’s granulomatosis [90].
Dapsone, which inhibits bacterial synthesis of dihydrofolic acid,
via competition with PABA (like other sulfonamide antibiotics),
can be helpful in some patients with Behçet’s syndrome [17],
again implying an infectious etiology, and similarly, Bartonella
species which cause granulomas, are usually responsive to sulfa
antibiotics.
Bacterial infections are one known cause of autoimmune
disease. Lyme disease, a multi systemic illness like Bartonella, can
be associated with a vasculitis, and autoimmune manifestations
[91-101]. Rheumatoid factor correlates with antibody titers
against Borrelia species, such as Borrelia garinii (a European
geno species of Borrelia) [102] 57% of patients with RA in some
studies show reactivity to multiple Borrelial antigens [93], and
Lyme arthritis, a disease caused by a bacterium, can mimic RA
alpha, IL-1, IL-6, as well as elevations in chemokines (CXCL-9,
CXCL-10, CCL-19) [103,104] with autoantibody production,
especially with molecular mimicry against neural tissue [105],
are also a known feature of the infection. Overlapping bacterial
illness. Low dose naltrexone, which has been used in bacterial
[28], such as Crohn’s disease [106] and MS [107], may also have
It should be considered as an immune modulator in those
with AI disease. Immunosuppressive therapies like Imuran
and prednisone, although necessary and lifesaving in some
autoimmune illnesses, may cause reactivation of underlying
infections, with other potential side effects, like osteonecrosis of
the hip, seen in this patient.
Animal and human data suggest that bacterial organisms
also play some role in the initiation and propagation of
autoimmune disease like RA, as well as other forms of arthritis,
such as osteoarthritis. Bacterial cell wall components, i.e., lipo
cartilage (chondrocytes) [108], and LPS appears to trigger the
toll-like R4. FSTL-1 is also a protein/immune modulator, induced
by an infection with Borrelia burgdorferi, with an established
role in autoimmune arthritis [109], and depending on the geno
species of Borrelia [110] we are infected with, and our own HLA
manifestations.
Associated viral infections and environmental triggers may
also play a role in autoimmune (AI) disease. CMV antibodies
have been found more frequently in patients with RA, varicella
virus was recently shown to trigger giant cell arteritis [113,114],
and MS patients may have reactivation of EBV infections as an
underlying trigger [115]. Our patient reactivated HHV-6 and had
evidence of prior exposure to EBV. BPA, an endocrine disruptor,
also may provoke autoimmune reactions, causing molecular
mimicry [116], and small particle pollution has recently been
shown to be a strong environmental risk factor for RA, JIA,
Lupus, and scleroderma [3]. Environmental toxins increase
and other AI illness [117]. One of the disabling manifestations
of Lyme and associated co-infections (such as Bartonella) is
severe neuropathy, which can be worsened with environmental
toxins, such as mercury, lead, arsenic, and BPA. Our patient’s
neuropathy improved with both Dapsone and pyrazinamide
glutathione. The MSIDS model of chronic disease, described by
where several overlapping factors, including chronic infections
and environmental toxins, can increase disease manifestations.
The interaction of multiple bacteria (Borrelia, Bartonella, and
tularemia), parasites (Babesia), viruses (HHV-6, Coxsackie),
and autoimmune illness [119].
The four-fold rise in tularemia titers, with simultaneous
evidence of other relapsing infections (new Bartonella titers
with an elevated VEGF, and elevations in HHV-6 titers) with a
positive clinical response to a tetracycline, rifampin, Dapsone
and a quinolone (Avelox) with tularemia titers returning
to baseline, argues for multiple latent infections. Lyme,
Bartonella and other tick-borne diseases are known to relapse
in immune suppressed individuals [120,121]. Our patient was
on Imuran, an immunosuppressive agent, and had multiple
tick-borne infections (some of which are known to also have
an immunosuppressive effect) [122,123], causing particularly
severe clinical manifestations.
Tularemia is a particularly recalcitrant and relapsing
disease if not caught early in the course of the illness. Treatment
or gentamicin for severe resistant disease (which are potentially
nephrotoxic and ototoxic). Although some research supports the
and relapse rates of up to 50% have been reported with these
Central
Bringing Excellence in Open Access
Horowitz et al. (2016)
Email:
JSM Arthritis 1(2): 1008 (2016) 8/12
agents [125,126]. The patient had a positive clinical response to
Plaquenil with a four drug intracellular antibiotic combination,
i.e., Avelox (a fourth generation quinolone), doxycycline,
rifampin, and Dapsone, despite being on immunosuppressive
medication (Imuran). Whether this novel combination of
antibiotics could be an effective treatment for tularemia requires
further investigation. Our prior experience with Dapsone [16],
Babesiosis, when combined with other intracellular antibiotics.
The combination of Dapsone with a quinolone, tetracycline and
for tularemia in this patient. Plaquenil, which was part of the
protocol, also seems to be an important component in helping
those suffering with Lyme, intracellular co-infections, and
autoimmune manifestations. It has an effect in both Lyme [127]
and lupus [128], while alkalizing the intracellular compartment,
persister bacterium [129].
Pyrazinamide may be another option in our antibiotic
arsenal for persistent tick-borne infections and autoimmune
manifestations. The patient in our case report had failed
a cephalosporin (Omnicef), tetracyclines (doxycycline,
minocycline), rifampin, Bactrim, and quinolones (Levaquin) for
her tick-borne co-infections, while inadequately responding to
multiple DMARD regimens, as well as Dapsone for her Behçet’s
and vasculitis. Despite meeting the established international
criteria for Behçet’s syndrome (oral apthtous ulcers, which were
present at least three times in 12 months, genital ulcers, and skin
lesions which were papulo-pustular in nature) [21] and taking
established therapies for Behçet’s, it was not until pyrazinamide
was prescribed that she had a positive clinical response.
Pyrazinamide’s known biological mechanism of action in
infections includes disruption of M. tuberculosis membrane
transport and energetics by pyrazinoic acid, with both
bacteriostatic and bacteriocidal effects [130]. It is a key sterilizing
to treat, chronic infections leading to high rates of morbidity
and mortality? PZA is a critical drug for treating persistent TB
infections, by killing persisters (Yin) as in the Yin–Yang model of
persisters and latent infections described in 2014 by Zhang [61].
In a growing population of bacteria, there is a small population of
non-growing or slowly growing persisters, which may revert to
a small number of growing bacteria (reverters). Combinations of
multiple intracellular and extracellular antibiotics, which address
both actively growing bacteria and non-growing, or slowly
bacterial forms, may be necessary to fully eradicate underlying
pathogens. Due to the potential side effects of PZA, including
possible liver toxicity at high doses [132], and the potential for
resistance [133], we need further clinical prospective research
chronic rheumatologic and autoimmune disease. Although our
patient had no elevation in LFT’s on PZA, we recommend further
like milk thistle and alpha lipoic acid [134,135].
Conclusion: This case report on the use of mycobacterium
drugs (Dapsone, PZA) in Lyme, associated co-infections, and
Behçet’s syndrome implies that there may be a broader utility for
these drugs in persistent intracellular infections with autoimmune
manifestations. The Dapsone and PZA protocols were the most
effective for resistant Lyme and autoimmune symptoms, with PZA
of Behçet’s and arthritic/granulomatous changes. Although this
is a single case report on the use of PZA, it models and extends
our previous study in which Dapsone was clinically effective in
a cohort of 100 individuals with Lyme and associated tick-borne
infections. Large prospective studies need to be undertaken
multiple chronic infectious diseases.
ACKNOWLEDGEMENTS
We thank our patient for allowing us to share her case and
Sonja Siderias, LPN for her expert research assistance.
REFERENCES
1. Selmi C. The worldwide gradient of autoimmune conditions.
Autoimmun Rev. 2010; 9: A247-A250.
2. Parks CG, Miller FW, Pollard KM, Selmi C, Germolec D, Joyce K, et
al. Expert panel workshop consensus statement on the role of the
environment in the development of autoimmune disease. Int J Mol Sci.
2014; 15: 14269-14297.
3. Pfau JC, Serve KM, Noonan CW. Autoimmunity and asbestos exposure.
Autoimmune Dis. 2014; 782045.
4. Centers for Disease Control Lyme disease Data and Statistics.
5. Nelson CA, Saha S, Kugeler KJ, Delorey MJ, Shankar MB, Hinckley AP,
et al. Incidence of clinician-diagnosed Lyme disease, United States,
2005–2010. Emerg Infect Dis. 2015; 21.
6. Peschken CA, Hitchon CA. Rising prevalence of systemic autoimmune
rheumatic disease: increased awareness, increased disease or
increased survival? Arthritis Res Ther. 2012; 14: A20.
7. Cameron DJ, Johnson LB, Maloney EL Evidence assessments and
guideline recommendations in Lyme disease: the clinical management
of known tick bites, erythema migrans rashes and persistent disease.
Expert Review of Anti-infect. 2014;12: 1103-1135.
8. National Science Foundation Special Report: Ecology of Emerging
Infectious Diseases.
9. Kugeler KJ, Farley GM, Forrester JD, Mead PS. Geographic distribution
and expansion of human Lyme disease, United States. Emerg Infect
Dis. 2015; 21: 1455-1457.
10. Newman EA, Eisen L, Eisen RJ, Fedorova N, Hasty JM, Hasty JM,
et al. Borrelia burgdorferi sensu lato spirochetes in wild birds in
northwestern California: Associations with ecological factors, bird
behavior and tick infestation PLoS One. 2015; 10: e0118146.
11. Moutailler S, Valiente Moro C, Vaumourin E, Michelet L, Tran FH,
Devillers E, et al. Coinfection of ticks: The rule rather than the
exception. PLoS Negl Trop Dis. 2016; 10: e0004539.
12. Centers for Disease Control Tick-borne diseases of the United States:
A reference manual for health care providers. 2015.
13. Tularemia: News & Perspectives Medscape.
14. Diuk-Wasser MA, Vannier E, Krause PJ. Coinfection by Ixodes
tick-borne pathogens: Ecological, epidemiological, and clinical
consequences. Trends Parasitol. 2016; 32: 30-42.
Central
Bringing Excellence in Open Access
Horowitz et al. (2016)
Email:
JSM Arthritis 1(2): 1008 (2016) 9/12
15. Horowitz RI. Why can’t I get better? Solving the mystery of Lyme and
chronic disease. 2013.
16. Horowitz RI, Freeman PR. The use of Dapsone as a novel “persister”
drug in the treatment of chronic Lyme disease/Post Treatment Lyme
Disease Syndrome. J Clin Exp Dermatol Res 2016; 7: 345.
17. Alpsoy E. Behçet’s disease: A comprehensive review with a focus
on epidemiology, etiology and clinical features, and management
of mucocutaneous lesions. J Dermatol. 2016; 43: 620–632. doi:
10.1111/1346-8138.13381
18. Wilmoth GJ, Perniciaro C. Cutaneous extravascular necrotizing
with systemic disease. J Am Acad Dermatol. 1996; 34: 753-759.
19. Thomsen I, Dulek DE, Creech CB, Graham TB, Williams JV. Chronic
granulomatous disease masquerading as Behçet disease: a case report
and review of the literature. Pediatr Infect Dis J. 2012; 31: 529-531.
20. Finan MC, Winkelmann RK. The cutaneous extravascular necrotizing
granuloma (Churg-Strauss granuloma) and systemic disease: a review
of 27 cases. Medicine (Baltimore). 1983; 62: 142-158.
21. International Team for the Revision of the International Criteria for
Behçet’s Disease (ITR-ICBD). The International Criteria for Behçet’s
Disease (ICBD): a collaborative study of 27 countries on the sensitivity
2014; 28: 338-347.
22. Craft JE, Fischer DK, Shimamoto GT, Steere AC. Antigens of Borrelia
burgdorferi recognized during Lyme disease: appearance of a new
immunoglobulin M response and expansion of the immunoglobulin G
response late in the illness. J Clin Invest. 1986; 78: 934-939.
23. Shanks GD, Gordon DM, Klotz FW, Aleman GM, Oloo AJ, Sadie D,
prophylaxis for Plasmodium falciparum malaria. Clin Infect Dis. 1998;
27:494-9.
24. Keyser FD. Choice of biologic therapy for patients with rheumatoid
arthritis: the infection perspective. Curr Rheumatol Rev. 2011; 7:
77–87.
25. Sapi E, Balasubramanian K, Poruri A, Maghsoudlou JS, Socarras KM,
Timmaraju KR, et al. Evidence of in vivo
in borrelial lymphocytomas. Eur J Microbiol Immunol. 2016; 6: 9-24.
26. cryptolepis sanguinolenta in the
treatment of malaria. Edit commentary. Ghana Med Jn. 2010; 44: 1-2.
27. Jung M, Lee, K, Park, M. Recent advances in artemisinin and its
derivatives as antimalarial and antitumor agents. Curr Med Chem
2004; 11: 1265-1284.
28. Younger J, Parkitny L, McLain D. The use of low-dose naltrexone
Rheumatol. 2014; 33: 451-459.
29. Sharquie KE, Najim RA, Abu-Raghif AR. Dapsone in Behcet’s disease: a
double-blind, placebo-controlled, cross-over study. J Dermatol. 2002;
29: 267-279.
30. Beerlage C, Varanat M, Linder K, Maggi RG, Colley J, Kempf VA, et
al. Bartonella vinsonii Bartonella henselae as
potential causes of proliferative vascular disease in animals. Med
Microbiol Immunol. 2012; 201: 319-326.
31. Vojdani A, Perlmutter, D. Differentiation between celiac disease, non
celiac gluten sensitivity, and their overlapping with Crohn’s disease: A
case series. Case Rep Immunol. 2012; 2013: 1-9.
32. WHO model prescribing information: Drugs used in leprosy. 1998.
33. Zhang Y, Yew WW, Barer MR. Targeting persisters for tuberculosis
control. Antimicrob. Agents Chemother. 2012; 56: 2223-2230.
34. Holden K, Boothby JT, Kasten RW, Chomel BB. Co-detection
of Bartonella henselae, Borrelia burgdorferi, and Anaplasma
phagocytophilum in ticks from California, USA. Vector-
Borne and Zoonotic Diseases. 2006; 6: 99-102.
35. Education Key to Stop Tick-Borne Illnesses (White Clothes Help Too).
2016
36.
Jesse Paul. 2015.
37. Ang CW, Notermans DW, Hommes M, Simoons-Smit AM, Herremans
T. Large differences between test strategies for the detection of anti-
immunoblots. Eur J Clin Microbiol Infect Dis. 2011; 30: 1027-1032.
38. Branda JA, Linskey K, Kim YA, Steere AC, Ferraro MJ. Two-tiered
antibody testing for Lyme disease with use of 2 enzyme immunoassays,
a whole-cell sonicate enzyme immunoassay followed by a VlsE C6
peptide enzyme immunoassay. Clin Infect Dis. 2011; 53: 541-547.
39. Lee SH, Vigliotti JS, Vigliotti VS, Jones W, Shearer DM. Detection of
Borrelia in archived sera from patients with clinically suspect Lyme
disease. Int J Mol Sci. 2014; 15: 4284-4298.
40. Perronne C. Lyme and associated tick-borne diseases: Global
challenges of Lyme disease. Front Cell Infect Microbiol. 2014; 4: 74.
41. Teal AL, Habura A, Ennis J, Keithly JS, Madison-Antenucci S. A new
real-time PCR assay for improved detection of the parasite Babesia
microti. J Clin Microbiol. 2011; 50; 903-908.
42. Bergmans AM, Peeters MF, Schellekens JF, Vos MC, Sabbbe LJ,
Ossewaarde JM, et al. Pitfalls and fallacies of cat scratch disease
serology: evaluation of Bartonella henselae-based indirect
1997; 35: 1931-1937.
43. Centers for Disease Control Laboratory diagnosis of babesiosis:
Babesia species.
44. Ostfeld,RS, McHenry DJ, Tibbetts M, Brunner, JL, Killilea ME, LoGiudice
K, et al. Co-infection of blacklegged ticks with Babesia microti and
Borrelia burgdorferi Is higher than expected and acquired from small
mammal hosts. PLoSOne. 2014; 9: e99348.
45. Krause PJ1, Telford SR 3rd, Spielman A, Sikand V, Ryan R, Christianson
D, et al. Concurrent Lyme disease and babesiosis. Evidence for
increased severity and duration of illness. JAMA. 1996; 275: 1657-
1660.
46. Mylonakis E. When to suspect and how to monitor babesiosis. Am Fam
Physician. 2001; 63: 1969-1975.
47. Gordon S, Cordon RA, Mazdzer EJ, Valigorsky JM, Blagg NA, Barnes SJ.
Adult respiratory distress syndrome in babesiosis. Chest. 1984; 86:
633-634.
48. Horowitz ML, Coletta F, Fein AM. Delayed onset adult respiratory
distress syndrome in Babesiosis. Chest. 1994; 106: 1299-1301.
49. Hersh MH, Tibbetts M, Strauss M, Ostfeld RS, Keesing F. Reservoir
competence of wildlife host species for Babesia microti. Emerg Infect
Dis. 2012; 18.
50. Krause PJ, Spielman A,Telford SR 3rd, Sikand VK, McKay K, Christianson
D, et al. Persistent parasitemia after acute Babesiosis. N Engl J Med.
1998; 339: 160-165.
51. Horowitz R. Chronic persistent Babesiosis after C+Q/ M+Z. Abstract
12th Int Conference on Lyme Borreliosis. 1999.
52. Wormser GP, Prasa A, Neuhaus E, Joshi S, Nowakowski J, Nelson J, et
al. Emergence of resistance to azithromycin-atovaquone in immuno
Central
Bringing Excellence in Open Access
Horowitz et al. (2016)
Email:
JSM Arthritis 1(2): 1008 (2016) 10/12
compromised patients with Babesia microti infections. Clin Inf Dis.
2010; 50: 381-386.
53. Evans ME, Gregory DW, Schaffner W, McGee ZA. Tularemia: a 30-year
experience with 88 cases. Medicine (Baltimore). 1985; 64: 251-269.
54. Birtles RJ. Bartonellae as elegant hemotropic parasites. Ann NY Acad
Sci. 2005; 1063: 270-279.
55. Maggi RG, Mozayeni BR, Pultorak EL, Hegarty BC, Bradley JM, Correa
M, et al. Bartonella spp. bacteremia and rheumatic symptoms in
patients from Lyme disease–endemic region. Emerg Infect Dis. 2012;
18: 1918-1919.
56. Mosepele M, Mazo D, Cohn J. Bartonella infection in
immunocompromised hosts: Immunology of vascular infection and
vasoproliferation. Clinical and Developmental Immunology. 2011;
2012: 1-5.
57.
network of co-infection in humans reveals that parasites interact most
via shared resources. Proc R Soc B. 2014; 281: 20132286.
58. Hodzic E, Imai D, Feng S, Barthold SW. Resurgence of persisting non-
cultivable Borrelia burgdorferi following antibiotic treatment in mice.
PLoS ONE. 2014; 9: e86907.
59. Ehrlich GD, Hu FZ, Shen K, Stoodley P, Post JC. Bacterial plurality as
a general mechanism driving persistence in chronic infections. Clin
Orthop Relat Res. 2005; 437: 20-24.
60. Sapi E, Bastian SL, Mpoy CM, Scott S, Rattelle A, Pabbati N, et al.
Borrelia burgdorferi in vitro.
PLoS ONE. 2012; 7: e48277.
61. Zhang Y. Persisters, persistent infections and the Yin–Yang model.
Emerging Microbes & Infections. 2014; 3: e3.
62.
stationary phase Borrelia burgdorferi from the NCI compound
collection. Emerging Microbes & Infections. 2015; 4: e31.
63. Feng J, Auwaerter, PG, Zhang Y Drug combinations against Borrelia
burgdorferi persisters in vitro: Eradication achieved by using
daptomycin, cefoperazone and doxycycline. PLoS ONE. 2015; 10:
e0117207.
64. Lewis K. Persister cells. Ann Rev Micro. 2010; 64: 357-372.
65. Berndtson K. Review of evidence for immune evasion and persistent
infection in Lyme disease. Intern J Gen Med. 2013; 6: 291-306.
66. Pausa M, Pellis V, Cinco M, Giulianini PG, Presani G, Perticarari S, et
al. Serum-resistant strains of Borrelia burgdorferi evade complement-
mediated killing by expressing a CD59-like complement inhibitory
molecule. J Immunol. 2003; 2170: 3214-3222.
67. Ma Y, Sturrock A, Weis JJ. Intracellular localization of Borrelia
burgdorferi with in human endothelial cells. Infect Immun. 1991; 59:
671-678.
68. Girschick HJ, Huppertz HI, Russmann H, Krenn V, Karch H. Intracellular
persistence of Borrelia burgdorferi in human synovial cells. Rheumatol
Int. 1996; 16: 125-132.
69. Balakrishnan N, Ericson M, Maggi R, Breitschwerdt EB. Vasculitis,
cerebral infarction and persistent Bartonella henselae infection in a
child. Parasites & Vectors. 2016; 9: 254
70. Ramesh G, Didier PJ, England JD, Santana-Gould L, Doyle-Meyers
neuroborreliosis. American Pathol. 2015; 185: 1344-1360.
71. Maggi RG, Mozayeni BR, Pultorak EL, Hegarty BC, Bradley JM, Correa
M, et al. Bartonella spp. Bacteremia and rheumatic symptoms in
patients from Lyme disease–endemic region. Emerg Infect Dis. 2012;
18: 783-791.
72. Artal C. Clinical management of infectious cerebral vasculitides.
Expert Rev Neurother. 2016; 16: 205-221.
73. Stockmeyer B, Schoerner C, Frangou P, Moriabadi T, Heuss D, Harrer
T. Chronic vasculitis and polyneuropathy due to infection with
Bartonella henselae. Infection. 2007; 35: 107-109.
74. Breitschwerdt EB, Linder KL, Day MJ, Maggi RG, Chomel BB, Kempf
VAJ. Koch’s postulates and the pathogenesis of comparative infectious
disease causation associated with Bartonella species. Comp Pathol.
2013; 148: 115-125.
75. Asano S. Granulomatous lymphadenitis. J Clin Exp Hematopathol.
2012; 52: 1-16.
76. Stricker RB, DeLong AK, Green CL, Savely VR, Chamallas SN, Johnson
treatment of neurologic Lyme disease. Int J Gen Med. 2011; 4: 639-
646.
77.
B cells to membrane blebs of Borrelia burgdorferi. Infect Immun.
1993; 61: 1460-1467.
78. Stadtländer CT, Watson HL, Simecka JW, Cassell GH. Cytopathogenicity
of Mycoplasma fermentans (including strain incognitus). Clin Infect
Dis. 1993; 17: S289-301.
79. Mühlradt PF, Quentmeier H, Schmitt E. Involvement of interleukin-1
(IL-1), IL-6, IL-2 and IL-4 in generation of cytolytic T cells from
thymocytes stimulated by a Mycoplasma fermentans-derived product.
Infect Immun. 1991; 59: 3962-3968.
80. Prasad AS, Beck FW, Bao B, Fitzgerald JT, Snell DC, Steinberg JD, et al.
Zinc supplementation decreases incidence of infections in the elderly:
effect of zinc on generation of cytokines and oxidative stress. Am J Clin
Nutr. 2007; 85: 837-844.
81. Angelakis E, Billeter SA, Breitschwerdt EB, Chomel BB, Raoult D.
Potential for tick-borne bartonelloses. Emerg Infect Dis. 2010; 16:
385-391.
82. Koehler JE, Sanchez MA, Garrido CS, Whitfeld MJ, Chen FM, Berger TG,
et al. Molecular epidemiology of bartonella infections in patients with
bacillary angiomatosis-peliosis. N Engl J Med. 1997; 337: 1876-1883.
83. Kim Y-W, Byzova TV. Oxidative stress in angiogenesis and vascular
disease. Blood. 2014; 123: 625-631.
84. Breitschwerdt EB, Maggi RG, Lantos PM, Woods CW, Hegarty BC,
Bradley JM. Bartonella vinsonii Bartonella
henselae bacteremia in a father and daughter with neurological
disease. Parasit Vectors. 2010; 3: 29.
85. Eremeeva ME, Gerns HL, Lydy SL, Goo JS, Ryan ET, Mathew SS, et al.
Bacteremia, fever, and splenomegaly caused by a newly recognized
Bartonella species. N Engl J Med. 2007; 356: 2381-2387.
86. National Institutes of Health News. Genetic mystery of Behcet’s
disease unfolds along the ancient Silk Road. 2013.
87. Rand Monograph: Parasitic diseases.
88. Leishmaniasis Fact sheet N°375. World Health Organization. 2016.
89. Barrett MP, Croft SL Management of trypanosomiasis and
leishmaniasis. Br Med Bull. 2012; 104: 175-196.
90. Tracy CL, Papadopoulos PJ, Bye MR, Connolly H, Goldberg E, O’Brian
RJ, et al. Granulomatosis with polyangiitis Treatment & Management.
Med scape Reference. 2015.
91. Cimmino MA, Trevisan G. Lyme arthritis presenting as adult onset
Still’s disease. B Clin Exp Rheumatol. 1989; 7: 305-308.
Central
Bringing Excellence in Open Access
Horowitz et al. (2016)
Email:
JSM Arthritis 1(2): 1008 (2016) 11/12
92. Chandra A, Latov N, Wormser GP,. Marques AR, Alaedini A. Epitope
mapping of antibodies to VlsE protein of Borrelia burgdorferi in post-
Lyme disease syndrome. Clinl Immunol. 2011; 141: 103-110.
93. Weiss NL, Sadock VA, Sigal LH, Phillips M, Merryman PF, Abramson
SB. False positive seroreactivity to Borrelia burgdorferi in systemic
lupus erythematosus: the value of immunoblot analysis. Lupus. 1995;
4: 131-137.
94. Wilder RL, Crofford LJ. Do infectious agents cause rheumatoid
arthritis? Clin Orthop Relat Res. 1991; 36-41.
95. Roush JK, Manley PA, Dueland RT. Rheumatoid arthritis subsequent to
Borrelia burgdorferi infection in two dogs. J Am Vet Med Assoc. 1989;
195: 951-953.
96.
B cells to membrane blebs of Borrelia burgdorferi. Infect Immun.
1993; 61:1460-1467.
97.
(Jessner-Kanof): lupus erythematosus tumidus or a manifestation of
borreliosis? Brit Jnl Derm. 2007; 157: 388-431.
98. Greco TP, Conti-Kelly AM, Greco TP. Antiphospholipid antibodies in
patients with purported ‘chronic Lyme disease’. Lupus. 2011; 20:
1372-1377.
99. Back T, Grünig S, Winter Y, Bodechtel U, Guthke K, Khati D, et al.
Neuroborreliosis-associated cerebral vasculitis: long-term outcome
and health-related quality of life. J Neurol. 2013; 260: 1569-1575.
100. Keymeulen B, Somers G,Naessens A, Verbruggen LA False positive
ELISA serologic test for Lyme borreliosis in patients with connective
tissue diseases. Clinical Rheum. 1993; 12: 526-528.
101. Goebel KM, Krause A, Neurath F. Acquired transient autoimmune
reactions in Lyme arthritis: correlation between rheumatoid factor
and disease activity. Scand J Rheumatol Suppl. 1998; 75: 314-317.
102. Ingegnoli F, Castelli R, Gualtierotti R. Rheumatoid factors: clinical
applications. Dis Markers. 2013; 35: 727-734.
103. Steere AC, Glickstein L. Elucidation of Lyme arthritis. Nat Rev
Immunol. 2004; 4: 143-152.
104. Soloski MJ, Crowder LA, Lahey LJ, Wagner CA, Robinson WH, Aucott
disease activity. PLoS ONE. 2014; 9: 93243.
105. Alaedini A, Latov N. Antibodies against OspA epitopes of Borrelia
burgdorferi cross-react with neural tissue. J Neuroimmunol. 2005;
159: 192-195.
106. Smith JP, Stock H, Bingaman S, Mauger D, Rogosnitzky M, Zagon IS.
Low-dose naltrexone therapy improves active Crohn’s disease. Am J
Gastroenterol. 2007; 102: 820-828.
107. Cree BA, Kornyeyeva E, Goodin DS. Pilot trial of low-dose naltrexone
and quality of life in multiple sclerosis. Ann Neurol. 2010; 68: 145-
150.
108. Lorenz W, Buhmann C, Mobasheri A, Lueders C, Shakibaei M.
Bacterial lipopolysaccharides form procollagen-endotoxin
implications for the development of rheumatoid arthritis. Arthritis
Res Ther. 2013; 15: 111.
109.
C, et al. Follistatin-like protein 1 is a critical mediator of experimental
Lyme arthritis and the humoral response to Borrelia burgdorferi
infection. Microbial Pathogenesis. 2014; 73: 70-79.
110. Cerar T, Strle F, Stupica D, Ruzic-Sabljic E, McHugh G, Steere AC,
potential of Borrelia burgdorferi sensu stricto strains from Europe
and the United States. Emerg Infect Dis. 2016; 22.
111. Steere A, Klitz W, Drouin EE, Falk BA, Kwok WW, Nepom GT, et al.
et al. Antibiotic-refractory Lyme arthritis is associated with HLA-DR
molecules that bind a Borrelia burgdorferi peptide. J Exp Med. 2006;
203: 961-971.
112. Steere AC, Dwyer E, Winchester R. Association of chronic Lyme
arthritis with HLA-DR4 and HLA-DR2 alleles. N Engl J Med. 1990;
323: 219-223.
113. Pierer M, Rothe K, Quandt D, Schulz A, Rossol M,Scholz R, et al.
Association of anticytomegalovirus seropositivity with more severe
joint destruction and more frequent joint surgery in rheumatoid
arthritis. Arthritis Rheum. 2012; 64: 1740-1749.
114. Gilden D, White T, Khmeleva N, Heintzman A, Choe A, Boyer PJ, et al.
Prevalence and distribution of VZV in temporal arteries of patients
with giant cell arteritis. Neurology. 2015; 84: 1948-1955.
115. Mechelli R, Manzari C, Policano C, Annese A, Picardi E, Umeton R, et
al. Epstein-Barr virus genetic variants are associated with multiple
sclerosis. Neurology. 2015; 84: 1362-1368.
116. Kharrazian, D. The potential roles of bisphenol A (BPA) pathogenesis
in autoimmunity. Autoimmune Dis. 2014: 1-12.
117. Tabarkiewicz J, Pogoda K, Karczmarczyk, Pozarowski P, Giannopoulos
K. The role of IL-17 and Th17 lymphocytes in autoimmune diseases.
Archivum Immunologiae et Therapiae Experimentalis. 2015; 63:
435-449.
118. Horowitz RI. Clinical roundup: selected treatment options for Lyme
disease: multiple causative factors in chronic disease. Alt and Compl
Therapies. 2012; 18: 220-225.
119. Borgermans L, Goderis G, Vanevoorde J, Devroey D. Relevance
of chronic Lyme disease to family medicine as a complex
multidimensional chronic disease construct: A systematic review
International J Family Med. 2014; 2014: 1-10.
120. Lucey DM, Dolan J, Moss CW, Garcia M, Hollis DG, Wegner
S, et al. Relapsing illness due to Rochalimaea henselae in
immunocompromised hosts: implication for therapy and new
epidemiological associations. Clin. Infect. 1992; 14: 683-688.
121. Gugliotta JL, Goethert HK, Berardi VP, Telford SR. Meningoencephalitis
from Borrelia miyamotoi in an immunocompromised patient. N Engl
J Med. 2013; 368: 240-245.
122. Marcus LC, Steere AC, Duray PH, Anderson AE, Mahoney EB. Fatal
pancarditis in a patient with coexistent Lyme disease and babesiosis.
demonstration of spirochetes in the myocardium. Ann Intern Med.
1985; 103: 374-376.
123. Krause PJ, Telford SR 3rd, Spielman A, Sikand V, Ryan R, Christianson
D, et al. Concurrent Lyme disease and Babesiosis evidence for
increased severity and duration of illness. JAMA 1996; 275: 1657-
1660.
124. Pérez-Castrillón JL, Bachiller-Luque P, Martín-Luquero M, Mena-
Martín FJ, Herreros V. Tularemia epidemic in northwestern Spain:
clinical description and therapeutic response. Clin Infect Dis. 33:
573-576.
125. WHO. A brief guide to emerging infectious diseases and zoonoses.
2014.
126. Kaya K, Deveci K, Uysal IO, Güven AS, Demir M, Uysal EB, et
al. Tularemia in children: evaluation of clinical, laboratory and
therapeutic features of 27 tularemia cases. Turkish Pediatric. 2012;
54: 105-112.
127. Coblyn JS, Taylor P. Treatment of chronic Lyme arthritis with
Central
Bringing Excellence in Open Access
Horowitz et al. (2016)
Email:
JSM Arthritis 1(2): 1008 (2016) 12/12
Horowitz RI, Freeman PR (2016) Are Mycobacterium Drugs Effective for Treatment Resistant Lyme Disease, Tick-Borne Co-Infections, and Autoimmune Disease?.
JSM Arthritis 1(2): 1008.
Cite this article
hydroxychloroquine. Arthritis Rheum. 1981; 24: 1567-1569.
128. Kuhn A, Landmann A, Wenzel J. Advances in the treatment of
cutaneous lupus erythematosus. Lupus. 2016; 25: 830-837.
129. Maurin M, Benoliel AM, Bongrand P, Raoult D. Phagolysosomal
alkalinization and the bactericidal effect of antibiotics. J Infect
Dis.1992; 166:1097-1102.
130. Zhang Y, Wade MM, Scorpio A, Zhang H, Sun Z. Mode of action
of pyrazinamide: disruption of Mycobacterium tuberculosis
membrane transport and energetics by pyrazinoic acid. J Antimicrob
Chemother. 2003; 52: 790-795.
131. Lanoix JP, Betoudji F, Nuermberger E. Sterilizing activity of
mouse mode of tuberculosis. Antimicrob Agents Chemother. 2015;
60: 1091-1096.
132. Zhang Y, Shi W, Zhang W, Mitchison D. Mechanisms of pyrazinamide
action and resistance. Microbiol Spectr. 2014; 2.
133.
Streicher EM, et al. A global perspective on pyrazinamide resistance:
systematic review and meta-analysis. PloS ONE. 2015.
134. Mulrow C, Lawrence V, Jacobs B, Dennehy C, Sapp J, Ramirez G,
et al. 21 Milk thistle: effects on liver disease and cirrhosis and
clinical adverse effects: Summary. Evidence Report/Technology
Assessment no. Rockville, MD: Agency for Healthcare Research and
Quality; 2000.
135. Gomes MB, Negrato CA. Alpha-lipoic acid as a pleiotropic compound
with potential therapeutic use in diabetes and other chronic
diseases. Diabetol Metabol Syndr. 2014; 6: 80.
