Case Rounds : Case 6

by Andrea Marx, M.D.


Mrs. B is a 66 year old Caucasian woman who was treated with Celebrex for joint pain. Ten days after starting therapy she developed a diffuse, pruritic, erythematous rash and was admitted to the hospital. Dermatology consult and skin biopsy were obtained. Pathology was consistent with a drug eruption. The rash improved with intravenous steriods. On hospital day #3 she complained of dyspnea. A chest x-ray showed a new large left pleural effusion.

Past Medical History

  • “Arthritis” since the age of 13; treated only with intermittent NSAIDS and steroids.
  • Right-sided empyema one year ago treated with prolonged antibiotics and chest tube drainage.
  • History of coronary artery disease (CAD), non-insulin dependent diabetes mellitus (NIDDM), chronic obstructive pulmonary disease (COPD), depression, diverticulitis

Cardizem, Pepcid, Premarin, Remeron, Darvocet

Social History
She worked as a typist but quit because of arthritis when she was in her 20’s. She smoked 1-2 packs of cigarettes a day for 40 years.

Review of Systems

  • Diffuse joint pain and stiffness, worse in the morning, lasting all day, denies joint swelling or warmth. She is able to do all of her activities of daily living.
  • Denies constitutional symptoms
  • Mild sicca symptoms, no history of sinusitis or otitis
  • Denies prior history of rash, photosensitivity, alopecia, oral ulcers, Raynauds, paresthesias, myalgias, weakness

Physical Examination

  • The patient was frail, somewhat anxious and confused.
  • BP 130/60, pulse 70, afebrile.
  • HEENT – no alopecia, conjunctivae were clear, no nasal or oral ulcers. Lungs – decreased breath sounds at left base, no crackles or wheezes; surgical scar over right posterior chest. Cardiac and abdominal exams were unremarkable. Neurological exam was nonfocal. The skin showed diffuse erythematous macules over her trunk and extremities.
  • Musculoskeletal exam was notable for the following:
    cervical spine – mildly diminished range of motion
    shoulders, elbows – full range of motion without synovitis, tenderness, or deformity
    MCPs – synovial thickening with minimal tenderness, slight ulnar deviation, subluxations of the IPJs
    PIPs – no synovitis, deformities, or tenderness
    DIPs – Heberden nodes
    hips, knees, ankles – full range of motion without synovitis, deformities or tenderness
    feet – hallux valgus, no synovitis

Laboratory Studies

Hematocrit 37.5%; WBC 6,800; platelets 674,00; ESR 35; electrolytes normal; BUN 25; creatinine 0.9; glucose 193; calcium 9.1; albumin 2.7; total protein 5.6; liver function tests normal; uric acid 5.5 urinalysis negative for blood or protein. ABG on room air: pH 7.42 pCO2 35 p02 61, 93% saturation

Clinical Course and Radiology Studies

  • Chest x-ray one year prior to admission showed clear lung fields following drainage of the empyema.
  • Chest x-ray taken on hospital day #3 shows a large left pleural effusion.

Figure 1

  • On hospital day #3 thoracentesis produced 540cc of turbid fluid: WBC 2025, 6% neutrophils, 42% lymphocytes, 52%; reactive mesothelial cells; LDH 9638; glucose 133; total protein 4.6
  • On hospital day #4, the left pleural effusion rapidly re-accumulated, requiring a repeat thoracentesis WBC 1346,; LDH 7579; glucose 139; total protein 4.7; pH 7.1
  • Pleural fluid showed no malignancy on cytology; a negative AFB and fungal smear; a negative Grams stain and routine culture.
  • The patients dyspnea improved after the thoracentesis. She remained clinically stable with minimal joint pain throughout her hospitalization.
  • On hospital day #5, a chest CT scan showed a 2.0 x 1.5 cm lung mass at the right posterior base with right hydropneumothorax and a left pleural effusion. Multiple lung nodules were present in both lung fields.

Figure 2

  • A CT-guided transthoracic needle biopsy was performed on both the right lower and upper lung masses. Biopsy results were non-diagnostic showing only necrotic debris and inflammatory cells.
  • On hospital day #12, thoracoscopic biopsy of the left lower lung mass was performed.
  • A Rheumatology consult was obtained.

Differential Diagnosis

Differential Diagnosis of Exudative Pleural Effusion
1.[ ]Infection (parapneumonic, tuberculosis, fungi)
2.[ ]Malignancy (bronchogenic, metastatic)
3.[ ]Pulmonary Embolism
4.[ ]Gastrointestinal disease
5.[ ]Rheumatic Conditions (rheumatoid arthritis, systemic lupus erythematosus)

Differential Diagnosis of Pulmonary Nodules
1.[ ]Infection (tuberculosis, fungi, pyogenic abscess)
2.[ ]Malignancy (bronchogenic, lymphoproliferative, metastatic)
3.[ ]Benign tumors
4.[ ]Arteriovenous malformations
5.[ ]Rheumatic conditions (rheumatoid arthritis, Wegeners granulomatosis, Churg-Strauss, sarcoidosis, amyloidosis)


Pathology Results

The gross pathologic examination revealed multiple small yellowish nodular lesions. Most of the lung showed interstitial fibrosis and chronic inflammation. There were several areas of necrosis of varying size. There were no areas of palisading cells. Special stains for mycotic and acid fast organisms were negative.

Figure 3 – Low power view of a well demarcated area of necrosis

Figure 4 – High power view showing numerous giant cells within disorganized nuclear debris and a mononuclear cell infiltrate

Figure 5 – High power view of very large giant cells

Figure 6 – Cross section of a small artery with inflammatory cells invading one portion of the vessel wall

Figure 7 – High power view of a longitudinal section of an artery showing inflammatory destruction of the vessel wall

Figure 8 – Destruction of the internal elastic lamina demonstrated on elastin stains

The final pathologic reading described changes most consistent with Wegener’s granulomatosis, but the possibility of a rheumatoid nodule could not be excluded.


Additional Diagnostic Studies

  • Rheumatoid factor was highly positive at a titer of 1:1280.
  • Anti-neutrophilic antibodies were negative.
  • CT scan of the sinuses was normal.
  • Hand x-rays showed erosions most consistent with rheumatoid arthritis.

Figure 9

Case Discussion

Mrs. B is a 66 year old smoker with a long history of “arthritis” and an empyema one year ago, who presented with a new exudative pleural effusion and multiple lung nodules. Although the pathology of the lung nodule showed features suggesting Wegeners granulomatosis (necrotizing vasculitis, giant cells, disorganized cellular infiltrate), she lacked clinical evidence to support this diagnosis. The most likely cause of her illness was seropositive, erosive rheumatoid arthritis complicated by pulmonary rheumatoid nodules, bronchopleural fistulae, and recurrent pleural effusions.



There were several unusual features of this case: the patient was a woman without nodular disease, the pleural effusions were bilateral with a normal glucose and many mesothelial cells, and the pathology was not classic for a pulmonary rheumatoid nodule. However, she lacked clinical evidence of other diagnoses, and in fact, had a very high titer rheumatoid factor as well as classic findings of erosive RA on hand x-rays. This case illustrates the importance of viewing RA as a systemic disease, not simply a problem of joints.


Learn More About Rheumatoid Nodules


The rheumatoid nodule is composed of three histologic zones:

  • Outer zone of vessels, lymphocytes and plasma cells;
  • Middle zone of monocytes migrating from outer zone blood vessels to the inner zone, with the phenotype changing to activated macrophages as they travel. These cells are arranged in a typical palisading layer;
  • Inner zone of central necrosis composed of fibrinoid material, collagen, reticulin fibers, cellular organelles, serum proteins.

Figure 10

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The earliest lesion is a focal vasculitis of the capillaries and venules, most likely resulting from immune complex deposition (large vessel vasculitis is rare). Factors involved in the pathogenesis include:

  • Genetic predisposition associated with HLA and TNF polymorphisms;
  • Trauma to small blood vessels at points of pressure causing local pooling of immune complexes;
  • Activation of macrophage by immune complexes;
  • Production of pro-inflammatory cytokines;
  • Tissue necrosis by collagenases, proteinases, and cytokines.

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Clinical Features

Rheumatoid nodules are present most commonly in men with a high titer rheumatoid factor who have active articular disease. Nodules are reported in 20-25% of cases of rheumatoid arthritis, and correlate with worse articular and extra-articular manifestations and poor function.

They are often located over pressure areas, such as the elbows and feet, but are also found where direct trauma plays no role, such as the lung, larynx, eyes, heart, meninges, bladder.

The differential diagnosis of the rheumatoid nodule includes:

  • Granuloma annulare;
  • Necrobiotic lipoidica diabeticum;
  • Tophi, xanthomatosis;
  • Multicentric reticulohistiocytosis;
  • Basal cell carcinoma.

Complications of rheumatoid nodules include:

  • Pain;
  • Limited joint mobility;
  • Neuropathy;
  • Ulceration;
  • Fistula formation;
  • Infection.

Surgical removal is an option for any of the above complications, but nodules tend to reoccur in as little as a few months when they are present over an area of repeated trauma. Intranodular steroid injections may reduce the size of the nodule.

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Learn More About Pulmonary Complications of Rheumatoid Arthritis


Pulmonary involvement is the most frequent extra-articular manifestation of RA. The range of pulmonary problems includes:

  • Interstitial lung disease (ILD) – radiographic findings of ILD occur in 2-5% of patients, while diffusion capacity abnormalities occur in 40%. High resolution CT scan and histology have shown even higher rates of ILD, but clinically significant disease probably occurs in 5-10% of rheumatoid patients.
  • Airways disease – upper airway obstruction may result from cricoaretynoid arthritis, nodules on the larynx, or vasculitis of the vasa nervorum of the recurrent laryngeal nerve.
  • Bronchiolitis – bronchiolitis obliterans with organizing pneumonia (BOOP), and less commonly obliterative bronchiolitis, have been reported.
  • Bronchiectasis – ten percent of patients may show radiographic signs of bronchiectasis; it may occur in the absence of ILD
  • Arteritis – arteritis of the pulmonary artery and lung is rare; signs of systemic vasculitis are usually present.
  • Infection – respiratory infections account for 15 to 20% of deaths in rheumatoid patients.
  • Drug toxicity – acute interstitial pneumonitis may occur in 1-5% of patients treated with methotrexate. Penicillamine and gold may also cause pulmonary complications.
  • Pulmonary nodules and pleural effusions – discussed separately below

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Pulmonary Nodules

Pulmonary nodules are considered the only specific lung manifestation of RA, but as this case illustrates, the histology nevertheless may be confused with other granulomatous processes. The pathogenesis and histology of the pulmonary nodule is similar to the subcutaneous nodule. They are a rare complication, with an incidence on chest x-ray of less than 1%. The incidence is much higher using high resolution CT scan (22-28%).

As is true of other extra-articular manifestations of RA, pulmonary nodules arise more often in men with a high titer rheumatoid factor who have active articular disease. There have been reports of pulmonary rheumatoid nodules in women and seronegative patients. Smoking may be a risk factor for the development of nodules.

They are usually asymptomatic, discovered incidentally on chest x-ray. Occasionally they are associated with cough, hemoptysis, and chest pain. The nodule size ranges from a few millimeters to several centimeters (up to 7 cm). Multiple nodules are more common than a solitary nodule. The peripheral upper and mid lung zones are more common than the lower zones, except in Caplans syndrome (pneumoconiosis with rheumatoid nodules).

They may increase in size or resolve spontaneously, or appear in new sites as older ones resolve. Pulmonary nodules may behave independently or follow the course of subcutaneous nodules and arthritis. Case reports have described pulmonary nodules preceding or appearing concurrently with newly diagnosed RA.

Intervention is required only when malignancy or infection is suspected, or when one of several complications occurs:

  • Bronchopleural fistula (BPF) – occurs when the nodule erodes through to the pleural space; this complication also may be related to underlying airway or fibrotic disease;
  • Pneumothorax – results from bronchopleural fistula; pyo- or hydropneumothorax may occur;
  • Pleural effusions – occur concomitantly with nodules in one third of cases;
  • Cavitation – occurs in half of nodules, usually in single apical lesions; cavitation predisposes to colonization with organisms such as aspergillosis; the differential diagnosis includes malignancy, infection, and Wegeners granulomatosis.

Treatment options include surgical pleural decortication for BPF and resection of a nodule to rule out malignancy or infection. There are no controlled studies of medical therapy for pulmonary nodules, but case reports suggest that they may respond to steroids and/or methotrexate.

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Pleural Effusions

Pleural disease is one of the most common pulmonary manifestations of RA. The incidence of pleural effusions is 5% by chest x-ray. Pleuritis may occur in up to 20% of patients, and may precede articular disease in as many as 20%. On autopsy 40 to 70% of RA patients have pleural disease.

The pathogenesis of pleural disease in RA may be related to the synthesis of rheumatoid factor by pleural mononuclear cells, increased complement components, and local immune injury.

Men with high titer rheumatoid factor and nodular, active articular disease have a ten-fold higher rate of pleural effusions than women. Men with pleuritis are more likely to have nodular disease than are women who have pleuritis.

Pleural effusions are usually asymptomatic unless they are large or infected. The progression of effusions is usually in parallel with the course of the articular symptoms. Reports of effusions before or at the time of diagnosis of RA are infrequent.

Three quarters of rheumatoid pleural effusions are unilateral and are of small to moderate volume. The left side seems to be more commonly involved. They tend to remain relatively unchanged for months to years.

The pleural fluid is yellow, sometimes turbid, but rarely milky or bloody. Pleural fluid analysis shows the following features:

  • Glucose of <50mg/dl in 75% of cases; <10mg/dl in 40% – low glucose is thought to arise from 1) relative block of glucose transport from blood to pleural space and 2) increased utilization
  • LDH of >1000mg/dl – the efflux of glucose metabolism products are relatively blocked
  • Total protein of >3.5mg/dl
  • pH of <7.0 – CO2 transport from the pleural space is blocked
  • Positive rheumatoid factor, low complement, cholesterol crystals, predominant lymphocytes, and characteristically few mesothelial cells

Similar findings, particularly low pH and glucose, have been noted in tuberculosis, malignancy, empyemas, and paragonomiasis.

Cytologic examination may reveal unique pleural fluid findings in RA. A triad of comet cells, giant cells, in a background of granular material is seen in as many as 80% of pleural specimens, and are considered unique to RA (Figure 11). The triad results from the exfoliation of pleural components from regions of granulomatous pleuritis. The ragocyte, or RA cell, is a leukocyte with small cytoplasmic lipid inclusions containing rheumatoid factor. These cells have been detected in tuberculosis as well.

Figure 11

Thoracoscopy may be useful in evaluating rheumatoid pleurisy: the parietal pleura has a “gritty” or frozen appearance; the surface is thickened and inflamed with numerous small granules.

Pleural biopsy shows a replacement of the mesothelial layer with pseudostratified epitheliod cells. Rheumatoid granulomas may be seen, looking like an opened-out nodule with its three layer components parallel to the pleural surface (Figure 12). In general, a thoracoscopic biopsy has a higher yield since most nodules are on the visceral pleura.

Figure 12

Complications of pleural effusions include:

  • Empyema – may be infected or sterile, resulting from the massive exudation of white cells and fibrinoid debris. Fifty percent of empyemas become infected. Risk factors for infection may be bronchopulmonary communication developing through necrotic centers of subpleural RA nodules.
  • Pleural fibrosis – rarely pleural disease may lead to fibrosis and lung entrapment.
  • Respiratory failure – a case report of respiratory failure from a massive rheumatoid pleural effusion has been described.

Treatment for recurrent or large rheumatoid pleural effusions includes repeated thoracentesis, systemic or intrapleural steroids, or pleurodesis with tetracycline. Surgical decortication of pleura for recurrent effusions or pleural fibrosis may be indicated.


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Helmers R, Galvin J, Hunninghake GW. Pulmonary manifestations associated with rheumatoid arthritis. Chest 100:235-38, 1991.

Anaya JM, Diethelm L, Ortiz LA, et al. Pulmonary involvement in rheumatoid arthritis. Sem Arthritis Rheum 24:242-54, 1995.

Yousem SA, Colby TV, Carrington CB. Lung biopsy in rheumatoid arthritis. Am Rev Respir Dis 131:770-77, 1985.

Walters M, Ojeda VJ. Pleuropulmonary necrobiotic rheumatoid nodules. A review and clinicopathological study of six patients. Med J Australia 144:648-51, 1986.

Zufferey P, Ruzicka J, Gerster JC. Pleural fluid cytology as an indicator of an effusion of rheumatoid origin. J Rheumatol 20:1449-51, 1993.

Updated: July 9, 2012

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