Dr. Crowson has received consultant fees, speaking fees, and/or honoraria (less than $10,000) from the American Society for Clinical Pathology.
Noodling and Mycobacterium marinum infection mimicking seronegative rheumatoid arthritis complicated by anti–tumor necrosis factor α therapy
Article first published online: 28 DEC 2010
Copyright © 2011 by the American College of Rheumatology
Arthritis Care & Research
Volume 63, Issue 1, pages 160–164, January 2011
How to Cite
Thanou-Stavraki, A., Sawalha, A. H., Crowson, A. N. and Harley, J. B. (2011), Noodling and Mycobacterium marinum infection mimicking seronegative rheumatoid arthritis complicated by anti–tumor necrosis factor α therapy. Arthritis Care Res, 63: 160–164. doi: 10.1002/acr.20303
- Issue published online: 28 DEC 2010
- Article first published online: 28 DEC 2010
- Accepted manuscript online: 30 AUG 2010 10:22AM EST
- Manuscript Accepted: 20 JUL 2010
- Manuscript Received: 5 MAY 2010
Patients with rheumatoid arthritis (RA) and other autoimmune diseases receiving immunosuppressive treatment are known to be at increased risk for infectious complications; this is increasingly observed with the widespread use of biologic agents (1). Reactivation of latent tuberculosis has been particularly associated with anti–tumor necrosis factor α (anti-TNFα) treatments (1). However, the risk for advancing an infection with nontuberculous mycobacteria is not known. Infectious arthritides with slow- growing organisms, including mycobacteria, rarely masquerade as RA, which is a greater concern in this era of early aggressive RA therapy with combined regimens of disease-modifying immunosuppressive antirheumatic drugs and biologic agents.
A 56-year-old man was referred to the rheumatology outpatient clinic for new-onset symmetric polyarthritis of the small joints of the hands and feet. He had been “hurting all over for years,” but his small-joint symptoms started ∼2 months earlier. Initially, left thumb swelling, which was unresponsive to amoxicillin/clavulanate, extended to the contralateral thumb, and both were unresponsive to treatment with a steroid dose pack. Pain and swelling spread to the wrists bilaterally and were treated with prednisone (60 mg/day) with taper. Although the swelling improved, the pain persisted and inflammation further involved the metacarpophalangeal joints. The patient reported a 2-month, 15-pound weight loss at presentation to the rheumatology clinic. He had had morning stiffness that gradually improved during the day. He denied fever, rash, or other symptoms.
The patient's past medical history was notable for osteoporosis and dyslipidemia. His medications included alendronate, tramadol, and pravastatin. He had no known drug allergies. He was a married factory mechanic who had lived all his life in Oklahoma and had stopped smoking more than 25 years earlier. He did not take illicit drugs, but did drink alcoholic beverages socially. Among other sports, he had fished for catfish since he was 19 years old. He had not traveled outside the US.
Upon presentation, the patient had substantial synovitis of both wrists, bilateral fourth and fifth metacarpophalangeal joints, and the left fourth proximal interphalangeal joint, with some tenderness to palpation over the remaining metacarpophalangeal joints and the metatarsophalangeal joints bilaterally. The patient's blood pressure was 118/69 mm Hg, and his heart rate was 65 beats per minute and regular. There were no murmurs, rubs, or gallops. His respirations were unlabored, and his lungs were clear bilaterally to auscultation. There was no organomegaly or lymphadenopathy, and he had no skin rash. His complete blood cell count, serum electrolytes, liver enzymes, and serum creatinine level were all normal. His acute hepatitis profile, thyroid-stimulating hormone, and iron panel were within normal limits. Additional laboratory evaluation was remarkable for no detectable rheumatoid factor, anti–cyclic citrullinated peptide (anti-CCP) antibodies, antinuclear antibodies, cryoglobulins, or antineutrophil cytoplasmic antibodies. His erythrocyte sedimentation rate was 15 mm/hour. No erosions were found in radiographs of the hands and feet.
The patient was diagnosed as having early seronegative RA and was started on weekly oral methotrexate that was titrated up to 20 mg per week. Since no improvement was noted after a month on methotrexate monotherapy, etanercept was added, once a negative pretreatment purified protein derivative test was obtained. Two months later there was no notable improvement; therefore, hydroxychloroquine was started and increased to 200 mg twice daily.
The patient was enrolled in a phase III randomized controlled clinical trial of abatacept versus placebo for active RA patients receiving disease-modifying antirheumatic drugs or biologic agents. A year after initial presentation and while receiving hydroxychloroquine, methotrexate, etanercept, and an experimental infusion of abatacept versus placebo, the patient had only a minor response in terms of morning stiffness and diffuse joint tenderness. Due to persistent disease activity, daily prednisone (15 mg) was added. A month later, etanercept was replaced by adalimumab, while hydroxychloroquine, methotrexate, and prednisone were continued.
Generalized stiffness, joint aches, and tenderness persisted, with synovitis becoming more pronounced over the left second and fourth proximal interphalangeal joints. Erosive and osteolytic changes and soft tissue swelling in the above joints were evident on radiographs, whereas the remaining proximal interphalangeal and the metacarpophalangeal joints were bilaterally without erosive changes (Figure 1A). Because of suspicion for infection, synovectomies of the left second and fourth proximal interphalangeal joints were performed (Figure 1B). Synovial biopsy findings showed acute and chronic synovitis with focal necrosis and granuloma formation (Figures 1C and D). Microscopy was negative for crystals and infectious pathogens; cultures for bacteria, fungi, and acid-fast bacilli (AFB) were negative. Pathology from the subcutaneous induration over the left elbow was consistent with a rheumatoid nodule (Figures 2A and B).
With persistent disease 2 years after diagnosis, adalimumab was replaced by infliximab, prescribed in addition to methotrexate, hydroxychloroquine, prednisone, and infusion of the study drug. Infliximab was administered following the recommended dosing regimen and leflunomide was started and titrated to 20 mg daily. Nine months later, the infliximab dose was tripled to 10 mg/kg, again without noted benefit.
Three years following the initial diagnosis of seronegative RA, and 2 months after infliximab dose maximization, the patient presented with a 2-week to 3-week history of fever and shaking chills, dry cough, rash, fatigue, anorexia, persistent joint stiffness, swelling, and pain. He denied headache, visual disturbances, dizziness, chest pain, dyspnea, abdominal pain, or dysuria. The patient's blood pressure was 121/77 mm Hg, the heart rate was 81 beats per minute and regular with no murmurs, rubs or gallops, the temperature was 98.4°F, and the respiratory rate was 18 breaths per minute with lungs clear to auscultation bilaterally. The abdomen was soft and nontender with no organomegaly. In addition to tenderness to palpation and chronic synovitis over both hands, wrists, elbows, and feet, the patient had multiple, movable, and minimally tender subcutaneous nodules and plaques over his hips, left forearm, and left leg. There was a large 7 cm × 8 cm plaque over the right hip and a multilobulated 14 cm × 5 cm subcutaneous plaque over the distal medial aspect of the left forearm (Figure 3A).
An opportunistic infection was suspected. A few days before hospitalization for further evaluation, punch biopsy samples of the left forearm lesion were sent for pathology and culture. Immunosuppressive medications, except prednisone, were held upon hospitalization. Skin biopsy findings (right hip and left forearm) showed granuloma annulare–like and erythema nodosum–like histopathology. Special stains for fungi and AFB were negative (Figures 3B and C).
Bronchoscopy with bronchoalveolar lavage was performed for evaluation of bilateral nodular interstitial infiltrates on chest radiography, which were confirmed by high-resolution computed tomography. A synovial biopsy of the left wrist was performed (Figure 3D).
Blood cultures collected on hospital admission yielded Histoplasma capsulatum, which, along with Klebsiella oxytoca, also grew on culture of the bronchoalveolar lavage. The patient was started on itraconazole and ceftazidime. After 3 weeks, mycobacterial cultures of the left forearm punch biopsy yielded Mycobacterium marinum, also subsequently isolated from the left wrist synovial culture.
The patient was diagnosed as having disseminated histoplasmosis and cutaneous and synovial M marinum infection. He gave a history of “noodling,” which is the bare-handed capture of catfish by entering the hands into the mouths of fish that are out of sight under rocks and underwater overhangs in the streams and lakes of the Southern US. Lacerations are quite frequent and act as a nidus for infection with water-borne organisms, which were suspected to be the source of M marinum in this patient.
The patient symptomatically improved while taking appropriate antibiotics and was discharged receiving itraconazole, clarithromycin, and ethambutol. Prednisone was continued upon discharge. Aspiration of his left second interphalangeal joint a month after discharge, and of his left wrist 2 weeks thereafter, both yielded positive smears for AFB, along with positive cultures for M marinum.
Four months later, because of persistent synovitis, etanercept was added to the prednisone. Steroids and etanercept were each administered for a year and then stopped. Itraconazole, clarithromycin, and ethambutol were continued for a total of at least 8 months. Due to persistent nodular lesions of the left forearm, punch biopsies were repeated twice (16 and 27 months after diagnosis), revealing only granulomatous dermatitis with negative fungal and mycobacterial cultures (Figures 4A and B).
Eighteen months after diagnosis the patient required no medications for arthritis. His skin lesions slowly resolved, and there was a slow progressive improvement in his synovitis. Subsequently, significant arthralgias persisted, but no synovitis was detected. Postinflammatory degenerative joint disease led to bilateral knee replacements and management with nonsteroidal antiinflammatory drugs.
Treatment of and disease outcomes for RA have been revolutionized with the biologic anti-TNFα agents. Although discovery of the anti-CCP antibodies has provided a diagnostic tool with improved sensitivity and specificity for RA (2), patients with seronegative RA remain more problematic. Additionally, since anti-CCP antibodies may be negative in early disease, the classic constellation of findings may not be present. Seronegative RA is a diagnosis of exclusion and always carries with it the possibility of a more specific underlying cause. In view of the trend for early aggressive treatment of RA with combined immunosuppression, diagnostic uncertainties are problematic when infection is in the differential or the patient is seronegative.
Subacute and chronic infectious arthritides, caused by both Mycobacterium tuberculosis (3) and nontuberculous mycobacteria, like Mycobacterium avium (4) and M marinum (5), may rarely masquerade as RA. Since most nontuberculous mycobacterial species are less virulent than M tuberculosis, symptomatic infections with these organisms are more commonly associated with local or generalized defects in host defenses. Cases of anti-TNFα–induced immunosuppression for RA (6–8) and other autoimmune diseases (9–12) complicated by M marinum infection (with or without arthritis) have been previously described, but our patient presented with a polyarthritis probably caused by M marinum before initiation of anti-TNFα therapy.
M marinum is usually acquired by local inoculation into an area of open or diseased skin after contact with fish or contaminated water, with proximal lymphangiitic spread to other structures. Infection usually manifests as cutaneous disease and occasionally involves deeper tissues, resulting in tenosynovitis, arthritis, and osteomyelitis (6). Upon initial presentation, our patient had synovitis with no evidence of overlying skin disease. Cutaneous involvement became apparent long after severe arthritis had developed, with a lesion developing proximally to the left wrist, although not contiguously to the affected joint. Nonetheless, M marinum was isolated from both the left forearm skin and the affected synovium. Moreover, the chronic synovitis was not controlled with anti-TNFα therapy, but completely resolved with antimicrobial treatment directed specifically against this organism. The history of minor trauma with exposure to fresh water and fish before the RA diagnosis, but not thereafter, further suggests this organism as the sole etiologic agent of our patient's arthritis. Although the AFB-negative synovial tissue culture a year before presenting with fulminant infection may seem to contradict this hypothesis, culture sensitivity for mycobacteria is far from absolute. In case series of cutaneous M marinum infections, cultures were positive in 3–76.5% of cases (13, 14). The sensitivity of AFB tissue stains was similarly low, ranging from 9–31% in the cases reported (13, 15). We suspect that advancing anti-TNFα therapy allowed the organism to be detected.
In the immunocompromised host, polymicrobial infections with atypical organisms are not unusual. Histoplasmosis, usually as pulmonary disease, has been repeatedly described in the context of TNFα inhibition prescribed for RA (16). Disseminated histoplasmosis is less frequent (17); it was first reported concurrently with a mycobacterial infection in our case.
Rheumatoid nodules, consisting of septal panniculitis without vasculitis with presence of histiocytes and fibrin, are a common finding in seropositive RA, but are reportedly present in only 6% of seronegative RA patients (18). In retrospect, the finding of rheumatoid nodule pathology was misleading. This usually specific finding provided support for advancing immunosuppression of a patient considered to have a more typical course of unresponsive seronegative RA.
Although usually well tolerated, TNFα antagonists considerably increase the risk of opportunistic infections, including reactivation of latent tuberculosis, especially when used in higher doses (1). Risk of serious infections is further increased by combinations of TNFα inhibitors with other biologics, including abatacept (1). Interestingly, in this case the patient was later found to have been assigned to the clinical trial placebo arm.
Absence of response to anti-TNFα treatment is not uncommon and suggests possible alternate etiologies. Certainly, the diagnosis was finally made in this case when the high doses of infliximab made the clinical expression of the M marinum infection detectable.
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Thanou-Stavraki 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 conception and design. Harley.
Acquisition of data. Thanou-Stavraki, Crowson, Harley.
Analysis and interpretation of data. Thanou-Stavraki, Sawalha, Harley.
We thank Dr. Thomas P. Lehman for providing the intraoperative picture of the patient's left hand (Figure 1B).
- 17Disseminated Histoplasma capsulatum infection presenting with panniculitis and focal myositis in rheumatoid arthritis treated with etanercept. Scand J Rheumatol 2009; 14: 1–6., , , , , .