Atypical or nontuberculous mycobacteria are normal commensals of water, soil, dust, and cattle milk. Human infections are relatively uncommon, but an increasing number of cases have been reported in the context of human immunodeficiency virus (HIV) or therapeutic immunosuppression (1). Mycobacterium avium complex and Mycobacterium kansasii account for most episodes of nontuberculous systemic diseases. Besides many reports of patients with HIV, there are only rare published examples of patients with chronic inflammatory arthritides under immunosuppression therapy. Most of these reports describe Mycobacterium marinum infections (2–4). In the last 7 years, there have been only a few reports of M kansasii infections in patients with chronic inflammatory rheumatic diseases (5–11). Nakamura et al (8) collected references on 11 patients from the literature since 1963. Bernard et al (9) described a French retrospective study of 26 patients from their own clinic and the literature who had M kansasii septic arthritis and no underlying disease. This indicates that, overall, this infectious complication is very rare. However, the incidence might increase as we tend to use more aggressive immunosuppressants (especially tumor necrosis factor α inhibitors) with a more relevant impact on the immune system. Moreover, with better diagnostic possibilities and better awareness of the necessity of an aggressive treatment, immunosuppression therapy will start much earlier.
We report a patient with long-lasting seronegative rheumatoid arthritis and a more recent local tenosynovitis. We identified a local M kansasii infection as the cause for the tenosynovitis on the basis of a positive bacterial culture result.
Although M kansasii is second only to M avium complex as the causative agent of nontuberculous lung disease, which often involves the upper lobe, it is rarely identified as a cause of extrapulmonary infection, especially arthritis or tenosynovitis. The infection primarily infects the lungs with rare precipitation in joints, tendons, or bone (9, 12). When affecting the joints, monarthritis is usually erosive (11, 13). Infections with M kansasii are environmentally acquired. It has been isolated from tap water in the warm southern US states (Texas), where it can survive for up to 12 months (14, 15).
A 48-year-old female farmer (including dairy farming) was diagnosed with seronegative nonerosive rheumatoid arthritis on the basis of symmetric polyarthritis of the metacarpophalangeal (MCP) joints and wrists when she was 35 years old. She was first treated with corticosteroids alone, then later a combination of disease-modifying antirheumatic drug therapy with chloroquine and methotrexate was necessary to optimally control the disease. This was continued for 10 years without symptoms; corticosteroids were tapered and stopped. The patient had no other underlying illnesses.
In 2003, she developed a primarily soft (later scar-forming) tenosynovitis of her second flexor tendon in her right hand, which later spread to the third finger and then affected the wrist on her palmar side. The swelling increased in size over a period of weeks. She did not report night sweats or fever. The tumor was surgically removed, and the histology showed unspecific inflammation. With the possibility of chronic rheumatic tenosynovitis, chloroquine was stopped and leflunomide was added to the continued methotrexate therapy. However, after 2–3 months the swelling recurred, which hindered the patient's daily activities. For that reason, she again underwent tenosynovectomy in 2004; however, the swelling recurred some months after surgery. Short-term corticosteroid therapy did not reduce the scar tissue. Therefore, a third surgery was necessary in 2005, methotrexate was increased to 20 mg/week, leflunomide was replaced by sulfasalazine, and corticosteroid treatment was initiated postsurgery. Again, this did not affect the recurrence of swelling that occurred some weeks after the third surgery. Microbiologic tests of the resected tissue were not performed prior to that time.
At that time the patient was referred to our clinic (Figure 1). Her laboratory results including autoimmune parameters, blood count, C-reactive protein level, and routine serology were not indicative of any diagnosis. Radiographs of the hands were normal, excluding erosive arthritis and any affection of the bones in her right wrist or MCP joints (Figure 2). The images, however, visualized the significant noncalcareous swelling of her palm and her wrist. Based on the patient's history, her profession as a dairy farmer, and the inefficacy of the antiinflammatory therapy, we suspected an infectious cause including atypical mycobacterial tenosynovitis as a possible reason for the recurrent swelling.
Because culture of affected tissue is the most sensitive way of diagnosing an infection with atypical mycobacteria, we again sent the patient to surgery. The histologic picture showing a nonspecific “young” granuloma with central necrosis surrounded by cell layers but no giant cells is presented in Figure 3. This young granuloma was seen only in a few histologic sections; the other specimens only showed nonspecific inflammation. A Gram stain from the excised material was negative; similarly, an auramine and Tan-Thiam-Hok stain did not indicate acid-fast bacilli. A 16S ribosomal RNA polymerase chain reaction (16S rRNA PCR) using universal, degenerate primer did not produce a PCR product. However, culture of the material using the BACTEC MGIT system (Becton Dickinson, Mountain View, CA) resulted in growth of acid-fast bacilli after 3 weeks. Subcultivating revealed a photochromogenic species. For further differentiation, a 16S rRNA PCR was performed, which revealed a weak band that was subsequently used for sequencing. This allowed for the identification (457/458 bp = 99% identity with type strain) of M kansasii. Due to the photochromogenic growth, the isolate could be differentiated from the phylogenetically closely related Mycobacterium gastri.
With the exception of low-dose corticosteroid treatment, all immunosuppressants were stopped. After review of the literature, we decided to start an antibiotic regimen with rifampin (600 mg/day), clarithromycin (2 × 500 mg/day), and ethambutol (25 mg/kg/day for the first 2 months, then 15 mg/kg/day). After 2 months, the tenosynovitis was significantly improved with further improvement observed after 6 months (data not shown).
Under this regimen, the arthralgias recurred after a few weeks for a short time only, with no necessity to reinitiate a more stringent antiinflammatory treatment.
Atypical mycobacterial infection is normally localized to the lungs and occurs in immunocompromised hosts such as patients with HIV or patients with long-term immunosuppression, after chemotherapy or with aggressive tumors. Deeper infections such as tenosynovitis, septic (then usually erosive) arthritis, and osteomyelitis spread by means of the lymphatics.
Among the nontuberculous mycobacteria, M kansasii is the most common cause of monarthritis, usually exhibiting erosive changes (11, 13). The duration from first symptoms to final diagnosis is long (1–60 months in the literature , 36 months in our case). In the literature, as in our case, tests for acid-fast bacteria in synovial fluid or tissue are often negative; from this perspective, the culture of the bacteria is the most sensitive diagnostic method, even exceeding a 16S rRNA PCR.
Overall, only 50 cases of M kansasii arthritis or tenosynovitis have been described during the past 40 years; these were reviewed by Bernard et al in 1999 (9). Since that time, only a few cases could be added in the literature. Among these 50 cases, approximately half had an underlying disorder (HIV, inflammatory rheumatic diseases), but for some, previous joint puncture or trauma was suspected as the route and cause of entry (16). Trauma might be the cause in our patient because she works as a farmer and frequently has open wounds. Regularly, these patients do not report night sweats or fever (9). In the chest radiograph, we did not see signs of pulmonary infection; this seems to be the rule for patients with localized M kansasii infection (9).
In patients with M kansasii arthritis or tenosynovitis, routine laboratory investigations are not helpful and a purified protein derivative test is usually negative or weakly positive. Diagnosis requires the culture of synovial fluid or biopsy sample of the synovium or affected tissue. Even though PCR and DNA hybridization tests are recommended to instantly identify the infectious microorganism (17), negative results do not exclude an infection of atypical mycobacteria. The value of culturing articular tissue to diagnose an atypical mycobacterial infection is again emphasized by our case.
It is unclear whether in our case the infection resulted from inhalation of contaminated water or infection from the milk of the patient's cattle, or directly from a wound that may have allowed entry of the bacteria through contaminated water in her right palm. There was neither a family history of mycobacterial infection nor mycobacterial pulmonary lesions on the patient's chest radiograph (a computed tomography scan of the chest was not performed).
Optimal therapy for M kansasii arthritis has not been established in a controlled trial. It is accepted that immunocompetent patients respond better to combined synovectomy and antibiotic therapy than do immunodeficient patients (18, 19). Generally, treatment with 3 or 4 antibiotic drugs in combination for 18–24 months has been recommended at least for a pulmonary infection. Unfortunately, in vitro susceptibility tests do not always correlate with clinical response; however, a combination of isoniazid, rifampin, and ethambutol or of clarithromycin, rifampin, and ethambutol are the most frequently used combinations (10). We treated our patient with the latter combination, which led to a significant reduction of the tenosynovitis with improved mobility of the fingers and reduced pain. We will continue this regimen for another 12 months to completely eradicate the M kansasii infection.
In conclusion, our case again highlights the importance of considering alternative explanations for atypical inflammatory signs such as monarthritis or localized tenosynovitis in patients with chronic inflammatory rheumatic diseases and concomitant immunosuppression. This is especially important and should be considered if patients report risk factors such as contact with milk cows or fish farming, which may predispose patients to an infection with an atypical mycobacterium. The importance of a culture of the biopsy tissue for the diagnosis of atypical mycobacteriosis as the most sensitive diagnostic tool has been confirmed in our case and cannot be emphasized enough. In contrast, 16S rRNA PCR of infected tissue was not sensitive enough to detect the infectious agent in this case. With the appropriate diagnosis, eradication of the infection is possible.
Dr. Lorenz had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study design. Lorenz.
Acquisition of data. Lorenz, Dalpke, Deboben, Ho, Greiner, Jung, Fiehn.
Analysis and interpretation of data. Lorenz, Dalpke, Deboben, Ho, Greiner.