Pulmonary Nodules in an Infliximab-Treated Rheumatoid Arthritis Patien

A Clinical Pathology Conference Held by Hospital for Special Surgery and Weill Medical College of Cornell University


Hospital for Special Surgery,
(HSS)
  • Case Presentation - Anne R. Bass, MD, Assistant Attending Physician (Rheumatology), HSS; Assistant Professor of Clinical Medicine, WMCCU
  • Radiological Findings - Robert Schneider, MD, Attending Radiologist, HSS, Associate Professor of Radiology, WMCCU
  • Differential Diagnosis - Anne R. Bass, MD
  • Diagnostic Procedure - Abraham Sanders, MD Associate Professor of Clinical Medicine (Pulmonary Diseases), WMCCU
  • Pathological Findings - Douglas Flieder, MD: Associate Professor of Pathology, WMCCU
  • Further Hospital Course - Anne R. Bass, MD
  • Immunological Discussion - Carl F. Nathan, MD, Professor of Immunology, WMCCU
  • Organizers of Rheumatology Clinical Pathology Conferences - Anne R. Bass, MD, and Doruk Erkan, MD, Assistant Attending Physician (Rheumatology), HSS; Instructor of Medicine, WMCCU

Case Presentation

A 78-year-old African-American woman was diagnosed with rheumatoid arthritis (RA) in 1996 after she presented with a symmetrical polyarthritis of the hands. Over the next four years, she was treated with multiple disease-modifying antirheumatic drugs (DMARDs) including methotrexate, hydroxychloroquine, gold, and leflunomide, all of which were stopped due to side effects or lack of response. She was started on low-dose prednisone in 1998, and was also maintained on low-dose azathioprine, which had been initiated in June.

In October 2000, the patient developed a cervical myelopathy, manifested by ataxia and hyperreflexia. Magnetic resonance imaging (MRI) of the cervical spine showed compression of the ventral cord by an enhancing epidural soft tissue mass behind the odontoid, which was thought to be pannus, as well as multilevel spondylosis with cord compression at C5-6. In December 2000, she underwent cervical spine decompression at the C5-6 level but was left with residual ataxia.

In early 2000, the patient had begun to lose weight, and this worsened after her spine surgery; she lost 20lbs between August 1999 and April 2001. Computerized tomography (CT) scan of the chest, abdomen and pelvis without contrast was normal in April 2001. Magnetic resonance imaging of the abdomen was unremarkable except for thickening of the gastric antrum. Endoscopy was normal. Bone marrow biopsy showed no evidence of malignancy. Testing for anti-gliadin antibodies and human immunodeficiency virus (HIV) were negative.

In May 2001, the patient was started on infliximab for the likelihood that RA activity was contributing to her weight loss, and also because of the myelopathy due to the presence of pannus behind the odontoid process. She received the first three infusions but was lost to follow-up.

She presented again in September 2001 with a further weight loss of 10lbs and was admitted for further evaluation. The patient's prior medical history was significant for hypertension, osteoporosis, and a pancreatic cystic mass which, when aspirated in 1998, had revealed no malignant cells. There also was an allergy to contrast dye. Medications at the time of admission were Premarin 0.625 mg qd, prednisone 5 mg qd, furosemide 20 mg qd, and atenolol 50 mg qd.

On physical examination, the patient was cachectic, weighing 66 lbs. Blood pressure was 110/80 mmHg, and she was afebrile. Significant findings included: chronic swan neck and boutonniere's deformities of the hands but no active synovitis; hyperreflexia in the lower extremities with mild left-sided dysmetria; and negative Babinski signs. Abdominal examination revealed mild left upper-quadrant abdominal tenderness without masses. Cardiopulmonary examination was within normal limits, and hemoccult stool test was negative.

The initial laboratory investigation demonstrated a leukocyte count of 3.7x109L (normal 3.4-11.2 x109L) with a normal differential; hemoglobin 9.5 g/dl (normal 12-16 g/dl); and platelet count of 201x109L (normal 150-450x109L). Liver, renal, and thyroid function tests, as well as urinalyses, were normal. Serum albumin was 2.9 g/dl and amylase was 153 mg/dl (normal: 30-110 mg/dl). Rheumatoid factor was persistently negative.

On the first day of the hospitalization, the patient developed a low-grade fever. Blood and urine cultures were negative. Echocardiogram revealed no vegetations. Colonoscopy was normal. A percutaneous endoscopic gastrotomy tube was placed to optimize the patient's nutritional status.

Radiological Findings

A postero-anterior view of the chest showed small patchy nodular densities in both lungs (upper more than lower, right more than left), which were new compared to prior chest radiographs. No hilar adenopathy or pleural effusions were noted.


Figure 1: Postero-anterior View of the Chest
Patchy nodular densities in both lungs (upper more than lower, right more than left).

The CT scan of the chest showed prominent interstitial markings throughout the chest, with more confluent abnormalities in the right lung apex. There were multiple pulmonary nodules of various sizes throughout the lungs (most prominent in the upper lungs) and fibrolinear scarring in the lung apex and bases, which were also new since April 2001. No cavitation, calcification or consolidation was noted. Precarinal adenopathy was present.

Figure 2: Computerized Tomography of the Chest


Multiple pulmonary nodules throughout the lungs

The differential diagnosis of multiple pulmonary nodules in RA includes metastatic disease, infectious processes, inflammatory diseases, or rheumatoid nodules. Metastatic diseases do not develop within weeks and are an unlikely diagnosis in this patient since the pulmonary nodules occurred very quickly. A specific diagnosis could not be made based on radiographic findings.

Differential Diagnosis

This case has a broad differential diagnosis process, falling into three categories that must be considered: malignancy, autoimmune diseases, and infection.

With regard to malignancy, multiple pulmonary nodules occur primarily as a manifestation of metastatic disease, which can come either from an adenocarcinoma of the lung or from a distant primary. Although it is not always recognized during life, 30 to 40% of cancer patients have pulmonary metastases at autopsy. Parenchymal metastases, as opposed to endobronchial metastases, are often asymptomatic. This patient had had a negative non-contrast CT of the chest, abdomen, and pelvis five months prior to her admission -- arguing against malignancy.

At the same time, she had a history of pancreatic cyst. Although the cyst was benign on prior aspiration and was not seen on recent scans, the patient did have increased amylase levels on admission, as well as left upper quadrant abdominal tenderness suggesting the cyst might be relevant to her illness. Could this cyst have transformed into a malignant lesion and metastasized? Benign mucinous cystic neoplasms of the pancreas can proliferate, and 10% become malignant over time. They occur predominantly in women, and the malignant potential is high enough that the resection is recommended[1]. This was a diagnostic possibility in this patient.

Lung involvement can be seen in hematologic as well as solid tumors. In the case of lymphoma, however, lymphangitic spread is far more common than multiple nodules in the lung. Lymphoproliferative disorders can cause pulmonary nodules, particularly lymphomatoid granulomatosis (LG). Half of patients with LG also have skin involvement in the form of nodules or rashes, and many have central nervous system disease. Pathology shows a granulomatous angiitis but, unlike that seen in Wegener's granulomatosis, the inflammatory infiltrate in LG consists of immature, atypical B cells. Ten to 25% of these patients develop lymphoma. The best arguments against LG in this patient are the radiographic findings. In LG, pulmonary nodules tend to be quite large and occur in the lower and peripheral lung fields, not at the apices. You can see cavitation in the lung in LG, but adenopathy, such as seen in this patient, is rare[2].

Autoimmune diseases, including Wegener's granulomatosis (WG), can also produce pulmonary nodules. Half of WG patients have pulmonary disease at the time of presentation, and 87% of patients over the course of their disease. Pulmonary nodules in these patients can be multiple, bilateral, and they can cavitate. Arguments against this diagnosis in the presented case are the absence of renal or respiratory disease and the patient's relatively indolent course. There is no link between Wegener's granulomatosis and RA, so one would have to posit a second autoimmune disease.

Sarcoidosis can also involve the lungs. There is usually prominent hilar and mediastinal adenopathy, which was not the case in our patient, and chest radiographs usually show interstitial infiltrates. Small pulmonary nodules can be seen in sarcoid, but they usually follow a bronchovascular distribution.

Finally, RA itself can produce lung disease. In addition to nodular lung disease, one can see pleural disease, interstital fibrosis, bronchiolitis, arteritis with pulmonary hypertension, and small airway disease. Rheumatoid nodules generally occur in the lower lung zones, rather than being scattered throughout the lungs. The diffuse nature of this patient's pulmonary nodules, and their upper lobe localization, argue against the possibility that they are rheumatoid nodules.

Many infectious diseases can cause pulmonary nodules, including bacterial (embolic or non-embolic), fungal, and mycobacterial infections. Embolic disease is unlikely in this patient given her normal echocardiogram, but other types of infection must be seriously considered given her immunosuppression.

Bacterial infections to consider include nocardia, a gram-positive aerobic bacteria of the actinomyces family. Patients with nocardia tend to have impaired cell-mediated immunity, and pulmonary disease is seen in 75% of cases. Patients can be asymptomatic or have bronchopneumonia, but occasionally patients present with solitary or multiple nodules or abscesses. Generally, there is no hilar lymphadenopathy and no calcification of the nodules[3].

Histoplasmosis is the most common endemic mycosis in the United States, but it is primarily seen in the south and north central states. The organism exists in the soil, is inhaled, multiplies in pulmonary macrophages, and migrates to neighboring lymph nodes, the reason why these patients generally have prominent lymphadenopathy. Patients can be asymptomatic, have a flu-like illness, or they can have chronic cavitary lung disease[4]. The most severe disease is seen primarily in immunocompromised patients, particularly those with HIV. Lung nodules are generally a late radiographic finding, however. Initially patients develop an interstitial pneumonitis. Later, there can be organization of tissue into round nodules and cavitation. This is not consistent with this patient's history. This patient had a normal CT of her lungs several months before, and other than weight loss, she was essentially asymptomatic until she presented with pulmonary nodules. In addition, pulmonary nodules in histoplasmosis generally involve the lower lung zones.

Blastomycosis can be seen not only in immunocompromised patients, but also in immunocompetent patients. The geographical distribution of blastomycosis is similar to that of histoplasmosis; central, south central, and southeastern United States. Patients can have a variety of clinical presentations ranging from no symptoms, to a flu-like illness to the gradual onset of fever, cough, or weight loss. Patients generally do not have hilar adenopathy. Forty to eighty percent of patients have skin involvement in the form of subcutaneous nodules. These develop not from direct inoculation but from bacteremic spread from the pulmonary focus. On chest radiographs these patients can have chronic pneumonia, fibronodular infiltrates, or single or multiple nodules; however nodules are generally located in the lower lung fields[4].

Coccidioidomycosis (desert fever) is generally seen in the deserts of southwestern United States. Patients can have a flu-like illness, pneumonitis, or the slowly progressive disease seen in this patient. This infection is of interest to rheumatologists because it can be associated with erythema nodosum and arthritis. Pulmonary infiltrates can evolve into spherical lesions, which do not calcify and can mimic cancer[4]. Apical cavitary disease can be seen and mimic tuberculosis (TB). This patient's radiographic findings are consistent with coccidioidomycosis, but the absence of recent travel to an endemic area is against the diagnosis.

Tuberculosis can certainly present with multiple pulmonary nodules. Reactivation of Mycobacterium tuberculosis (M. tuberculosis) usually involves the upper lobes, in contrast to primary TB, which is usually a lower lobe disease. Calcification is common. Recent reports suggest an increased incidence of TB in recipients of infliximab. An article published in October 2001, one month after this patient's admission, reported 70 cases of TB after treatment with infliximab for a median of 12 weeks[5]. Forty-eight out of 70 patients developed TB after 3 or fewer infusions, and 40/70 had extrapulmonary disease (17 disseminated, 11 lymph node disease, 4 peritoneal, 2 pleural, 1 each meningeal, enteric, paravertebral, bone, genital, and bladder). The authors estimated that 147,000 patients had received infliximab in the U.S. at the time of the study, and they calculated the rate of TB in RA patients receiving infliximab to be 24.4 cases/100,000, compared to a 6.2/100,000 background rate.

At the time of this patient's hospitalization, TB or malignancy was felt to be the most likely diagnosis. The upper lobe predominance of the patient's pulmonary nodules argued against histoplasmosis and blastomycosis. Her geographic location was against these infections and coccidomycosis. The precarinal lymphadenopathy was more suggestive of TB than nocardia.

Diagnostic Procedure

This is a situation in which an immunocompromised patient with weight loss and fever was found to have new, small pulmonary nodules. Pulmonary evaluation was requested. Our differential diagnosis was similar to that of the referring physicians: infection, malignancy, or inflammation. A diagnostic procedure was recommended, as the patient was unable to produce sputum for analysis.

Open lung biopsy is most likely to be diagnostic; specific diagnosis is expected in 60% of those with underlying malignancy and infiltrates. Complications, including mortality, vary from 11 to 20% in different series with different patient groups. We reserve this procedure for those in whom less invasive procedures are not diagnostic.

Transthorocic needle aspiration performed under fluoroscopic, CT, or occasionally ultrasonographic guidance can be used to evaluate pulmonary nodules or infiltrates. In those with carcinoma, sensitivity varies from 70-95% with up to 30% false-negative results. Infections can be diagnosed in 70%, and inflammatory disease or other benign processes can also be identified. A diagnostic yield of 70% has been reported in immunocompromised patients. Complications such as bleeding or pneumothorax can occur in nearly one-third of patients.

Flexible bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsy can be performed with an expectation of diagnosis in 50-96% of patients, depending on their underlying disease and pulmonary problem In acquired immunodeficiency syndrome (AIDS) patients with Pneumocystis carinii pneumonia (PCP), the diagnosis can be expected in more than 95% of patients. In non-AIDS patients with PCP, the diagnosis is expected in 50-80%. Other infectious diseases or non-malignant conditions, such as drug toxicity or inflammation, are less likely to be diagnosed by this procedure. In those with negative sputum smears for tuberculosis, bronchospcopy may provide the diagnosis in up to 50% of patients. Complications such as hypoxemia, bleeding, or pneumothorax are uncommon. This was the procedure we initially chose.

Pathological Findings

An adequate transbronchial biopsy showed alveolar parenchyma without significant histopathologic changes. No granulomas, vasculitis or tumor were seen. Special stains for fungi including Pneumocystis carinii (Grocott-Methenamine silver) and acid-fast organisms (Ziehl-Neelsen) were negative.

Figure 3: Transbronchial Lung Biopsy


Transbronchial biopsy demonstrates normal bronchial wall and underlying alveolar parenchyma. Note the open airspaces and absence of interstitial inflammation.

Further Hospital Course

Pathology and cytology were both normal. Acid-fast smears and routine cultures on the bronchoscopy specimen were negative. DNA probes on the bronchoscopy specimen, however, were positive for M. tuberculosis and, ultimately cultures were also positive for M. tuberculosis.

Immunological Discussion

The immunology of tumor-necrosis factor as it relates to the intersection of RA and TB involves three important points: a) like many cytokines, TNF has complex effects, which include induction of pro-inflammatory actions followed by anti-inflammatory actions; b) exacerbation of latent tuberculosis by neutralization of TNF is predictable based on what we know; and c) if that logic is convincing, then it falls on us to try to predict what other consequences might be less common but might also be expected in the setting of immunosuppression.

The adverse effects of TNF (see Table 1) that eventually led to the development of etanercept and infliximab historically began with the systemic effects. These were discovered at the Sloan-Kettering Institute by Elizabeth Carswell and Lloyd Old, and then at Rockefeller University and Cornell University Medical College by Anthony Cerami, Bruce Beutler, Steven Lowry, Kevin Tracey and their colleagues[6],[7],[8]. These effects include the hemorrhagic necrosis of tumors, cachexia, and mediation of septic shock, and systemic inflammatory response syndrome (SIRS). However, the inhibition of TNF in RA is really directed more to the local effects and, of those, the best known is the central role in driving a cytokine cascade that perpetuates inflammation and proteolysis as shown by Feldman and colleagues and others[9].



Table 1: Adverse Effects of Tumor-Necrosis Factor (TNF) Systemic: Cachexia
Systemic inflammatory response syndrome
Shock
Hemorrhagic necrosis

Local: Drives a cytokine cascade that perpetuates inflammation and -proteolysis
Triggers neutrophils to degranulate and undergo a massive respiratory burst:
   - releasing serine proteases
   - inactivating protease inhibitors
   - activating metalloproteinases


Another set of effects has been studied for the last 15 years in our laboratory, among others, and that is the ability of TNF to trigger neutrophils to degranulate and undergo a massive respiratory burst[10]. When neutrophils do so, they release proteases such as elastase and cathepsin G. The respiratory burst-derived oxidants can inactivate proteinase inhibitors such as alpha-2 trypsin inhibitors and the secretory leukocyte protease inhibitor. The oxidants can also activate metalloproteinases through oxidizing the cysteine residues which coordinate the zinc ion that normally helps hold the enzymes in their inactive form.

Some photomicrographs of normal human neutrophils in culture make this vivid. What happens when you add TNF to them? The photomicrographs in Figure 4 were taken 30 minutes apart at the same magnification. The cells spread out, bring granules to the surface, discharge their contents, and have a massive respiratory burst. Thus, neutralizing TNF in RA not only works but also it makes sense. It's gratifying when efficacy and rationale come together.

Figure 4: Photomicrographs of human neutrophils in culture

A: Normal.
B: The cells spread out, bring granules to the surface, discharge their contents, and have a massive respiratory burst 30 minutes after addition of tumor necrosis factor.

Among the toxicities of TNF we are focusing on is reactivation of TB. What's extraordinary about reactivation of TB in the setting of TNF neutralization is that about 80% of the cases are not confined to the lung: 56% are extrapulmonary and 24% are disseminated. This is not the only toxicity of TNF-neutralizing interventions that have been suspected; others such as demyelinating disease, systemic and cutaneous lupus, and lymphoma are far less well-established and will require careful attention as clinical experience accumulates[11].

What's special about TB infection? First, consider the enormous magnitude of TB on the global scale. The fact that the incidence of TB in American patients treated with infiximab went up four-fold doesn't really tell you what you might expect if this kind of treatment were more widespread. M. tuberculosis, the causative agent of TB, is such a successful pathogen first of all because its infectivity is extremely high, as distinct from the disease rate. About a third of people in the world are infected, that is, carrying the organism in a viable form in the body. When M. tuberculosis enters the body, whether or not disease develops, our best understanding is that infection is usually lifelong. The incidence of death has been estimated at almost three million per year. Although this reflects only 5-10% of infected people developing disease and then failing to receive effective treatment, it is nonetheless the largest burden of death from any single bacterium. The pathology of TB is central to the life cycle of M. tuberculosis, because it provokes tissue destruction and cough, which disseminates infectious aerosols[12].

After inhalation of M. tuberculosis, the bacteria are taken up by alveolar macrophages and dendritic cells that migrate to the hilar nodes. The mycobacteria win the first round of the battle because there has not been an immunologic activation. M. tuberculosis disseminates hematogenously all over the body, including back to the lung by the hematogenous route. By then, adaptive immunity develops, and most often the bacteria disappear from notice, even though some viable organisms persist. In 90-95% of people, this whole process is asymptomatic and remains so throughout life. The macrophages, which ingest the TB everywhere it goes, seem to control it well in most organs but less well in the lung.

Anything that suppresses the immune system can lead to reactivation of M. tuberculosis infection. Usually reactivation occurs in the lung but, if the immune system is profoundly suppressed, which seems to be the case with inhibition of TNF, then the dormant M. tuberculosis at other sites can also resume replication. Other immunosuppressive factors can include HIV infection, age, silicosis probably via elevation of TGF-B, and corticosteroid therapy.

In this patient, M. tuberculosis may have reactivated prior to the infliximab in response to corticosteroid therapy. The ensuing course of infliximab may just have let the TB progress more rapidly.

What is it about TNF that helps the host to resist tuberculosis? We can get some answers from mice, where the literature goes back to the 1980s[13]. In wild-type mice infected with M. tuberculosis, it's typical to see well-structured granulomas with epithelial macrophages in the center and a mantle of monocytes and CD4 and CD8 lymphocytes surrounding. But in the setting of TNF or TNF receptor deficiency, the granulomas are ill-formed. The same number of cells is present, if not more, but they don't form a tightly organized structure. While wild-type mice survive the infection over the study period, TNF knock-out mice die within a few weeks of infection. Early in the infection, TNF knock-out mice had a deficiency in the ability to make chemokines. Later on, they make more chemokines than wild-type mice, probably reflecting that the bacterial burden is so much greater[14],[15]. Initially the chemokine response of TNF-deficient mice is not brisk enough, and that may be why these granulomas are not well formed. Thus, tuberculous pneumonitis is much more severe in TNF-deficient than in wild-type mice. It's a parodoxical picture; TNF is proinflammatory, yet here, the lack of TNF is proinflammatory.

To summarize immunologic defects in the absence of TNF: a) initials steps generating a new immune response are impaired as dendritic cells don't mature and migrate normally[16]; b) granuloma formation in response to mycobacteria is impaired[14],[15]; c) an intrinsic bactericidal defect of macrophages is manifest in vitro, which we cannot explain yet[17]; d) impaired apoptosis of neutrophils and its attendant prolonged retention of neutrophils can exacerbate the inflammatory response[18]; e) prolonged production of IL-12 and interferon-G which lead to failure to resolve inflammation[19]. Thus impaired survival of mice after infection with M. tuberculosis when they don't have TNF is the result of at least two things: a) inadequate killing of M. tuberculosis and b) exaggerated pneumonitis and excessive inflammation[20].

Thus, patients on anti-TNF therapy should be considered to immunodeficient. One of the implications of this is that it has led to routine pre-treatment PPD, chest X-ray, and history relevant to possible latent infections, as should be done before corticosteroid therapy. In the anti-TNF treated patient, one should anticipate possible recrudescence of other latent infections besides M. tuberculosis, such as Leishmania donovani, Trypanosoma cruzi or Listeria monocytogenes. Finally, in an era when we are contemplating live virus vaccines such as against smallpox, patients on anti-TNF therapy should be considered potentially susceptible to severe complications.

Conclusions

We are taught that when we hear hoof beats, we should think "horse" before we think "zebra." But that which is "horse" may evolve over time as our understanding of a disease and the drugs used to treat it evolve, as evidenced by this case.

This patient was not screened for TB prior to initiation of infliximab; indeed, such screening was not standard in May 2001 when therapy initiated - although it became so before the end of the year. The U.S. Food and Drug Administration's Arthritis Drugs Advisory Committee heard updated postmarketing adverse event data in August 2001 from the manufacturers of infliximab and etanercept - reports that reflected updated information since FDA's approval of these drugs in 1999 and 1998 respectively and that led to new recommendations. These guidelines were summarized by HSS Physician-in-Chief Stephen A. Paget, MD, in Postmarketing Adverse Event Data for TNF-alpha Antagonists, which was published on this site in October 2001. Although at that time the FDA began requiring a PPD on all patients prior to initiating infliximab, Dr. Paget has recommended the same precautions with other TNF-blockers based on similarity of mechanisms and (albeit fewer) case reports.

Thus, had infliximab been prescribed for the patient in this case in the fall rather than the spring of 2001, in all likelihood a PPD would have been performed. In the presence of a positive PPD, the patient would have been put on INH for three months prior to initiating infliximab.

At the time of TB diagnosis, she was placed on INH and her rheumatoid arthritis is being treated with low-dose prednisone. The pulmonary nodules were slightly smaller on follow up CT scan in January 2002. Dr. Sanders comments that they may not disappear. The patient's clinical status has improved slightly, with a resolution of fevers and a weight increase to about 80 lbs., which has stabilized. Overall, the patient is stable but may never return to her pre-c spine surgery baseline.


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