Infections (General - PRA)

There is debate about whether palindromic rheumatoid arthritis (PRA) is an early, seronegative form of rheumatoid arthritis (RA) or a distinct variant of rheumatic disease. Research that has focused on infections associated with PRA and its treatment with antibiotic therapy, for the most part, applies to both disease manifestations. However, due to the limited available research with a focus on the infectious causes of PRA and to make it simpler to locate these studies, they have been grouped together below.

Mycoplasma fermentens

The following study is significant for its results, in which 5/7ths of palindromic rheumatoid arthritis (PRA) patients were found to be positive for mycoplasma fermentens.

Palindromic rheumatism. Clinical and immunological studies. Ann Rheum Dis. 1971 Jul; 30(4): 375-380.

In a study of 35 patients (13 male and 22 female) with palindromic rheumatoid arthritis (PRA), 25 were found to be antigen-positive by leucocyte migration inhibition test for Mycoplasma fermentens. This result was consistent with testing results of patients with rheumatoid arthritis (RA) and the authors discuss the likelihood that PRA is either a variant of RA, or that it may precede RA onset. Remarkably, the study authors mirror Dr. Brown’s researches by concluding that PRA may be the result of cell-mediated (delayed type) hypersensitivity to the antigenic substances produced by mycoplasma fermentens.

Lyme disease

Palindromic rheumatoid arthritis (PRA) differs from RA in the sense that sufferers will experience transient eruptions of swift-onset, severe, non-destructive inflammatory arthritis that migrates around the body from joint to joint. The infectious cause of Lyme disease, Borrelia burgdorferi (Bb), has been dubbed, “the second great imitator,” the first being a similar spirochetal organism that causes syphilis (Treponema pallidum), and has also been described as presenting with severe, migrating arthralgia and myalgia that may be episodic in waxing and waning manner, closely resembling PRA.

Joint manifestations of Lyme borreliosis in Czechoslovakian patients. Z Rheumatol. 1990 Jul-Aug;49(4):192-6.

In a study of 50 Czechoslovakian patients, 33 with known tick bites and 29 describing skin reactions (the classic rash is called an erythema chronicum migrans, ECM or bulls-eye rash), three types of episodic arthralgia or migratory musculoskeletal pain were described in addition to neurologic symptoms in 40 of these patients and one with complete heart block.

Lyme disease: musculoskeletal manifestations. Rheum Dis Clin North Am. 1989 Nov;15(4):649-56.

The authors of this commentary at University of Minnesota School of Medicine, in Minneapolis, Minnesota, describe the observed musculoskeletal syndrome experienced by some patients with Lyme disease and several distinct patterns with which it presents when untreated. In early Lyme, widespread, diffuse muscle achiness and stiffness is experienced. If left untreated, this early stage is followed by recurrent, episodic bouts of arthritis. In late stage Lyme disease, a chronic form of oligoarticular arthritis can be experienced, often large joints like the knees. These authors describe Lyme as closely resembling reactive arthropies and that it can also mimic connective tissue diseases, like juvenile rheumatoid arthritis, rheumatoid arthritis, myositis, and scleroderma.

Tropheryma whipplei

Studies on Whipple’s Disease, primarily affecting middle-aged, Caucasian males, have been included in this section, as this infection, originating in the gut, typically presents with migrating, episodic attacks of arthritis, very similar to palindromic rheumatism (PRA), but can be misdiagnosed and have severe consequences if it is inappropriately treated.

Whipple’s arthritis. Joint Bone Spine. 2016 Dec;83(6):631-635.

Whipple’s disease is a chronic systemic infection that is due to the bacterial agent Tropheryma whipplei and it classically presents with diarrhea, weight loss and episodic bouts of arthritis, which if left undiagnosed can progress to chronic septic, destructive polyarthritis. PCR testing of joint fluid, feces or saliva may prove positive for the infection, but study authors state that rheumatologists should suspect Whipple’s disease (especially in middle-aged, Caucasian men) if a patient presents with unexplained, seronegative, intermittent oligoarthritis and other symptoms indicative of this gut infection, which can be cured by antibiotic therapy, but may be fatal if misdiagnosed and inappropriately treated.

Arthralgia and blood culture-negative endocarditis in middle Age Men suggest tropheryma whipplei infection: report of two cases and review of the literature. BMC Infect Dis. 2015 Aug 18;15:339. doi: 10.1186/s12879-015-1078-6.

Study authors conclude the importance of assessing patients for the infection, Tropheryma whipplei, the causative pathogen of Whipple’s disease, in patients with a history of transient arthralgia and culture-negative pericarditis, prior to treatment with immune-suppressants, to ensure appropriate treatment with combination antibiotic protocols. In the cases described, trimetoprim-sulfamethoxazol (Bactrim), was administered long-term.

[Whipple’s disease and Tropheryma whipplei infections in internal medicine. When to think about it? How to treat?]. Rev Med Interne. 2014 Dec;35(12):801-7.

Although new diagnostic tools that include genomic sequencing testing can identify the causative pathogen of Whipple’s disease that leads to weight loss, diarrhea, and intermittent bouts of arthritis, the diagnosis can be easily missed. Treatment with disease-modifying anti-rheumatic drugs (DMARDs) and other immune-suppressive medications will result in treatment failure with clinical worsening of symptoms. Clues to diagnosis may come in the shape of patients who note improvements when treated with antibiotics for an unrelated acute infection. Whipple’s disease is typically treated with doxycycline (200mg/day) and hydroxychloroquine (600 mg/day) for a length of 12 months, followed by a lifetime treatment by doxycycline (200 mg/day) to avoid reinfection. Less severe, localized infections may be treated with doxycycline (200mg/day) and hydroxychloroquine (600 mg/day) for 12 to 18 months, but close follow-up for life is recommended.

Palindromic rheumatism: Consider Whipple’s disease. Int J Rheum Dis. 2013 Aug;16(4):475-6.

Tropheryma whipplei, the causative micro-organism of Whipple’s disease, classified as a form of Actinobacteria, may present with migrating, episodic attacks of arthritis, similar to palindromic rheumatism (PRA). The authors of this review state that up to 50% of Whipple’s disease patients are “misdiagnosed” as having PRA and “wrongly treated,” sometimes with fatal consequences, with disease-modifying anti-rheumatic drugs, corticosteroids and anti-TNF agents and specific testing methods to identify this pathogen are outlined to ensure appropriate treatment with antimicrobial agents.

Whipple’s disease with axial and peripheral joint destruction. South Med J. 1990 Jun;83(6):684-7.

Inappropriate immune-suppressant treatment of a man with a 16-year history of palindromic rheumatism (PRA) with biopsy-proven infection with Tropheryma whipplei, the causative organism of Whipple’s disease.  PRA then progressed to joint destructive disease with HLA genetic-typing revealing the B7 antigen, typical of ankylosing spondylitis. The authors “… challenge the generally held notion that Whipple’s arthropathy is a nondestructive joint disease.”


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