Rare infection in patient with rheumatoid arthritis treated with adalimumab

Abstract

Mycobacterium haemophilum is a rare pathogen, predominately present in the immunocompromised population. It is especially studied in HIV and haematological malignancy patients. Given its unique living conditions, it is often difficult to establish its diagnosis, but it is often suspected by its classic association with ulcerating skin findings. Our case is unique in that our patient is immunocompromised by his rheumatoid arthritis treatment, and presented without any skin lesions, but was found to have this rare pathogen causing a constellation of unusual symptoms.

Background

This report describes a rare presentation of a relatively rare infection, and discusses the importance of clinical decision-making. It is important to have cases like this one published to remind physicians to keep a wide differential when making diagnoses in patients, especially those on immunosuppressants. A background literature review was also done and is discussed regarding the rarity of the disease.

Case presentation

A 35-year-old man of East-Asian ancestry with prior medical history of seropositive rheumatoid arthritis (RA) and hypertension presented with chief complaints of blurry vision, followed 24 hours later by sudden onset of right-sided facial, arm and leg numbness with right-sided facial droop and altered mental status. He presented urgently to the emergency room, and at time of arrival, right-sided weakness had resolved, but he had double vision with associated headache, body aches and fevers.

Regarding prior medical history, patient’s RA was diagnosed 4 years prior to presentation. Initially, he was treated with methotrexate, hydroxychloroquine and sulfasalazine for 2 years with poor response. He was transitioned to adalimumab and was in clinical remission after 2 years of treatment. His hypertension was controlled on hydrochlorothiazide. He was born and raised in the USA and had no recent travel history or incarcerations. The patient denied high-risk sexual behaviours, history of tobacco use, alcohol use or illicit substance use.

Initial physical examination revealed a fever of 103°F. He had chronic abnormal visual acuity with right eye 20/25 and left eye 20/50, with a new bilateral partial rectus palsy. The rest of his cranial nerve examination was unremarkable. There was no synovitis and his musculoskeletal exam was benign. He had difficulty with tandem gait. He had no active ulcers, lesions or rashes on his skin.

Investigations

Imaging on admission included CT, MRI and MRA brain. MRI brain was significant for diffuse, bilateral optic nerve sheath enhancement (figure 1). The bilateral sixth nerve palsy was attributed to perineuritis, as evidenced by the optic nerve sheath enhancement. A lumbar puncture (LP) performed on presentation was significant for elevated opening pressure (34 cmH₂O), pleocytosis (485/µL, >90% lymphocytes), elevated protein (140 mg/dL) and normal glucose (56 mg/dL) levels. He was initially started on broad spectrum antibiotics for atypical meningitis with vancomycin, ceftriaxone and acyclovir for herpes simplex virus and varicella zoster virus coverage. However, as pyogenic meningitis was considered unlikely in light of the cerebrospinal fluid results, antibiotics were discontinued after 5 days and acyclovir was discontinued when HSV and VZV PCR results returned negative. At 7 days postadmission, a repeat LP was done for continued fevers to evaluate for cerebrospinal fluid changes. The results demonstrated improvement in opening pressure, but increased pleocytosis, elevated protein and decreased glucose levels.

Figure 1.

Orbit/ocular nerve MRI: bilateral optic nerve sheath enhancement.

CT chest was performed because of the continued fever, and revealed a necrotic appearing mediastinal node and right hilar lymphadenopathy with right apical opacity (figure 2). The patient was started on tuberculosis (TB) treatment with rifampin, isoniazid, pyrazinamide and non-tuberculosis mycobacteria (NTM) with addition of azithromycin and levofloxacin, and placed on airborne precautions. An endobronchial ultrasound and mediastinoscopy for enlarged lymph nodes was performed and a pretracheal lymph node was biopsied. On histology, the lymph nodes revealed necrotising granulomatous inflammation with rare acid-fast bacilli (AFB) consistent with Mycobacteria (figures 3 and 4). Two days later, TB PCR returned negative from the bronchial washing. Airborne precautions were removed due to low risk for pulmonary TB. However, empiric TB and NTM treatment was continued due to inability to completely rule out TB due to absence of culture growth and the patient’s immunocompromised state. The patient was discharged on treatment for TB and NTM, a prednisone taper for prevention of immune reconstitution inflammatory syndrome and RA treatment, and adalimumab was discontinued. He was also discharged with close follow-up with infectious disease, rheumatology and ophthalmology.

Figure 2.

Chest CT: necrotic mediastinal and right hilar lymphadenopathy.

Figure 3.

H&E section of the lymph node with necrotising granulomas 10x magnification.

Figure 4.

Acid-fast bacilli seen on a Fite stain 100x magnification (oil immersion).

Treatment, outcome and follow-up

Two weeks postdischarge, cultures and sensitivities returned as Mycobacterium haemophilum. His antibiotics were de-escalated to rifampin, levofloxacin and azithromycin. He was evaluated by ophthalmology 1 month postdischarge due to worsening blurry vision, and was found to have bilateral granulomatous uveitis. Vitreous biopsy was done, with pathology negative for granulomas and malignancy, and all cultures were negative. Treatment for his infection was changed from levofloxacin to moxifloxacin for increased ocular penetration and prednisone was continued, with improvement in symptoms. Prednisone was tapered as the ocular symptoms improved; however, his rheumatoid symptoms worsened. His right elbow had worsening swelling and tenderness, right fourth and fifth proximal interphalangeal (PIP) joints and left third PIP joints had worsening, palpable synovitis and tenderness—reducing his flexion and extension of joints and limiting his functionality. At this time, ~8 months postdiagnosis, his screening chest CT scans demonstrated worsening lymphadenopathy. Repeat lymph node biopsy revealed persistence of AFB+ organisms. His rifampin, levofloxacin and azithromycin dosages were increased, and 4 months later, chest CT scans showed improvement. Patient saw rheumatology ~12 months postdiagnosis, and was restarted on methotrexate and hydroxychloroquine, and titrated off of prednisone. Approximately 18 months postdiagnosis, he was started on leflunomide for his continued synovitis, and low-dose prednisone was restarted. RA symptoms began to improve with leflunomide and prednisone treatment. He currently also continues on rifampin, moxifloxacin and azithromycin for treatment of mycobacteria.

Discussion

The treatment of RA is dependent on multiple factors including disease presentation, severity, patient’s prior response and comorbidities.¹ The goal of treatment is control of synovitis, inflammation and achieving clinical remission.¹ Therapy is initiated with disease modifying antirheumatic drugs (DMARD) for mild to moderate disease, with or without glucocorticoids and nonsteroidal anti-inflammatory drugs.¹ Our patient was started on the DMARD methotrexate. If a patient fails initial DMARD therapy, combination of multiple DMARDs or initiation of biologics is the next step.¹ Sulfasalazine and hydroxychloroquine were added to methotrexate in our patient. Our patient was resistant to DMARD therapy and was subsequently initiated on anti-tumor necrosis factor (TNF) therapy with adalimumab. Prior to initiation of any therapy, patients are tested for hepatitis B, hepatitis C and TB due to the immunosuppressive effects of these medications and concern for reactivation of these infections.¹ If there is concern for active infection, therapy is halted until resolution of infection.¹ DMARDs are recommended to be used in patients with serious infection requiring treatment due to the less significant immunosuppressive effects when compared with biological agents.¹ Our patient was using biologics for 2 years prior to the development of this atypical infection. Most observational studies and reviews indicate biologics were associated with a higher risk of serious infections, compared both to non-use of biologics and to the use of traditional DMARDs. One review suggests the risk of serious infections was highest in the first 6 months of biological treatment, plateauing off by 24–36 months.²

NTM compromises over 140 species, many of which cause rare disease in humans.³ Since the acquired immunodeficiency syndrome (AIDS) epidemic in the 1930s, many pathogens emerged and are increasingly recognised.⁴ M. haemophilum has been commonly associated with skin and soft tissue infection since its discovery in 1978 by Dr David Sompolinksy after being found in a patient with Hodgkin’s lymphoma with ulcerated skin lesions as the presenting symptom.⁵

M. haemophilum disease most commonly presents in the immunocompromised population, especially in patients with HIV infections and haematological malignancies.^{4 6 7} The organism is ubiquitous in the environment. Its mode of transmission is unclear given its low prevalence, but case reports of clusters of infection and cutaneous lesions suspect direct contact.⁶ There are a limited number of case reports of M . haemophilum infections, and an even smaller number of patients reported to develop the infection in the setting of chronic inflammatory conditions. The most common symptom is painful, ulcerating, erythematous skin nodules.^{4 7} Less commonly, it presents as pulmonary or neurological infection.^{7 8} The organism grows best at 30–32° F, congruent with its tendency to thrive on skin flora and cause the common skin findings.⁹

This patient had an unusual presentation of M. haemophilum—meningitis, perineuritis and granulomatous uveitis—devoid of any skin involvement. There was no skin involvement at presentation and throughout the entire course, despite the severity of the infection. This case highlights the importance of clinical decision-making, particularly in immunocompromised patients, and anchoring bias. The majority of case reports depict the bacteria as a skin pathogen, and when it is not involved, the tendency to suspect this pathogen as an aetiology is low. This, along with the difficulty to grow the pathogen given its cooler temperature requirements and ferric ions, chocolate agar and supplemented media for growth,⁹ make it difficult to isolate and treat. Treatment includes clarithromycin, ciprofloxacin and one of the rifamycins; however, it is dependent on pathogen susceptibilities.⁴

Learning points.

• This is an atypical case of a rare pathogen, but an increasingly recognised pathogen, that should be considered in the differential diagnosis of immunocompromised patients.

• Mycobacterium haemophilum is most commonly associated with ulcerating skin lesions; however, the absence of these lesions does not eliminate it from the differential as it can cause meningitis, ocular and pulmonary symptoms as well.

• This case serves as important reminder to always keep a wide differential in immunocompromised patients on biological therapies.