Printer Friendly

Cavitary pulmonary nodules in rheumatoid arthritis; case reports and review of the literature.


Rheumatoid arthritis (RA), primarily affecting joints, is a systemic chronic inflammatory disorder. Respiratory complications with the involvement of pleura, airway, pulmonary vascular system, and parenchymal lung might be seen in RA (1). Drug toxicity and opportunistic infection also might cause pulmonary system symptoms in patients with RA. Pulmonary rheumatoid nodules have been reported in up to 32% of individuals with RA and require a more detailed evaluation to exclude neoplasms, tuberculosis (TB), and fungal infection (2). They usually tend to be asymptomatic and 1-3 cm in size. In rare cases, they can progress to cavitary lesions, potentially causing difficulty in differential diagnosis and more severe pulmonary symptoms. We report two patients with RA with large cavitary pulmonary nodules and provide a review of the literature based on published cases.

Case Presentations

Case 1

A 55-year-old woman with RA, diagnosed 20 years ago, was initially treated with methotrexate (MTX) 15 mg/week, hydroxychloroquine (HCO) 200 mg/day, and prednisolone (P) 5 mg/days. After 5 years of treatment, MTX and HCO were withdrawn due to vomiting and retinal toxicity and then leflunomide (LEF) 20 mg/day was started as a monotherapy. There was no other significant disease in her and her family's history.

She was admitted to our outpatient clinic complaining of fatigue, weight loss, cough, and chest pain for 2 months. In her physical examination, the tender and the swollen joint counts were 2 and 1, respectively. The 28-joint disease activity score (DAS28) was calculated to be 4.8. Serum biochemical test was normal, except for the increase in acute-phase reactants [erythrocyte sedimentation rate (ESR): 71 mm/h; C-reactive protein: 4 mg/dL; normal range <0.5]. Rheumatoid factor (RF) was found positive (143 IU/mL; normal value: <20), whereas anti-CCP, ANA, and ANCA were negative. Radiography of extremities showed erosions of the hands. Computed tomography (CT) of the chest revealed bilateral multiple nodular lesions with extensive cavitary areas in especially lower zones (Figure 1). The three negative sputum tests for acid-fast bacillus were obtained and culture examination of bronchoalveolar lavage for TB was also negative. Histopathological evaluation of pulmonary tissue obtained with transbronchial needle biopsy revealed central necrosis surrounded by granulomatous inflammation and perivascular lymphoplasmacytic infiltration with the destruction of medium-sized vessels (Figure 2a, b). Anti-TB therapy with isoniazid (5 mg/kg), rifampin (10 mg/kg), ethambutol (15 mg/kg), and pyrazinamide (20 mg/kg) was given as an empirical treatment after LEF was stopped. Anti-TB therapy was interrupted in the second month of treatment because the progression of pulmonary lesions was detected with control; the chest CT and polyarthritis worsened. It was considered as a disease activity, and prednisolone 500 mg pulse for 3 days was started followed by 1 mg/kg/day prednisolone along with rituximab treatment 1 gm intravenously on days 1 and 15. Low-disease activity of RA and considerable regression in pulmonary cavitary lesions were detected at the end of the third month of treatment.

Case 2

A 61-year-old female patient was admitted to our clinic with complaints of cough and pain and swelling of the wrists and small joints of the hands, shoulders, and knees. She also showed fatigue, weight loss, and loss of appetite. Joint symptoms started 2 years ago, and she was treated with LEF 20 mg/day and HCO 200 mg/day for 10 months with the diagnosis of RA. There was no comorbidity. Physical examination showed severe polyarthritis (DAS28 score was 7.2) and necrotic skin lesions in the breast (Figure 3). Laboratory examination revealed an increase of the acute-phase reactant (ESR: 88 mm/h; C-reactive protein: 17 mg/dL; normal range <0.5). The other serum biochemical test was in normal range. RF, anti-CCP, and anti-MPO were found positive [569 IU/mL (<20), 201 IU/mL (<12), and 93 IU/mL (<18), respectively]. Periarticular osteopenia and few lytic lesions were detected in X-ray of the hands. Chest CT indicated cavitary pulmonary nodules (Figure 4). Skin biopsy revealed dermal lymphocyte and neutrophil infiltration. A percutaneous transthoracic needle biopsy was performed, and the subcutaneous nodule disclosed a necrotizing area surrounded by a palisade of histiocytes and chronic inflammatory cells and lymphoplasmacytic inflammation in all layers of vessels (Figure 5a, b). There were no laboratories or histopathological findings to support infectious diseases, including fungal diseases and TB. It was not possible to make an exact diagnosis between ANCA-associated vasculitis (AAV) and RA vasculitis (RV) because the findings of the former coincide with the latter. Since corticosteroid and immunosuppressive treatment could have been effective in both conditions, we started pulse methylprednisolone (1 gm 3 days) and cyclophosphamide (15 mg/kg/day) intravenously after excluding infective etiologies. Pneumothorax was observed in the second week of treatment. In follow-up, all symptoms resolved. Methylprednisolone dose was continued 1 mg/kg/day and diminished 10% daily dose per week.


Rheumatoid pulmonary nodules contained central necrosis surrounded by epithelioid histiocytes, lymphocytes, plasma cells, and proliferating fibroblasts. They are observed more frequently in smokers, males, and patients with advanced seropositive RA (3). The necrotic central zone may develop into cavitation as a result of the resolution of necrosis and consequent inflation due to airfow (4). In this case, more severe symptoms could be seen, and the differentiation of RV, AAV, and/or pulmonary TB in patients with RA may be difficult with regards to similar histopathological findings. The detection of caseification necrosis or mycobacteria with specific microbiological tests is diagnostic for TB. In our first case, we started anti-TB therapy empirically because TB infection was not clinically excluded. We thought that pulmonary lesions may be associated with RA due to the progression of pulmonary lesions observed under the anti-TB therapy. The differential diagnosis was also difficult for the second patient with RA, with vasculitic findings in histopathological evaluation and anti-MPO positivity. According to RA cohorts, the rate of ANCA positivity in ELISA is up to 32% (5). Other studies reported that ANCA and anti-CCP double-positive patients with RA may more frequently present with pulmonary nodules (6, 7). Histopathological findings of pulmonary nodules may not be helpful enough at differentiating RV from AAV in RA. Necrotizing granulomatosis inflammation and perivascular lymphocyte infiltration might be seen in both diagnoses. Therefore, we could not be sure that the diagnosis was RV or AAV in our second patient.

We searched case reports and case series published in the last 30 years with keywords including "rheumatoid arthritis," "cavitary pulmonary nodules," and "vasculitis" in the PubMed database (8-15). Case reports diagnosed with diseases other than RA and suspicions of infectious disease which can cause cavitary pulmonary nodules were excluded. Consequently, clinical and histopathological features of 11 patients with RA (7 female) and two female patients with RA with cavitary pulmonary nodules are seen in Table 1. The disease duration ranged 2-20 years, and seven of the patients were older than 60 years. Skin ulcers were detected in two patients. Five cases were complicated with pneumothorax. Eleven of 12 patients with RA were seropositive. ANCA was positive in one of nine patients. There was usually granulomatous inflammation with necrosis in pathological specimens. Favorable outcomes were reported with corticosteroids and/or other immunosuppressive therapy except for 2 cases who died of sepsis and interstitial pneumonia.

Leflunomide was a remarkable anti-rheumatic drug in the treatment of 10 patients. LEF inhibits the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), which plays a key role in the de novo synthesis of pyridine-containing ribonucleotides (rUMP). This agent targets the activated T cells and suppresses inflammatory reaction on synovium in RA (16). Although LEF therapy was reportedly less than other anti-rheumatic drugs such as MTX, TNF-alpha inhibitors in patients with RA with pulmonary non-cavitary nodules and fatal interstitial lung disease in this review, the high frequency of LEF therapy in patients with RA with cavitary pulmonary nodules should be emphasized (17-19). However, the underlying mechanism for the association between LEF therapy and the pulmonary cavitary lesion is not known at present.

In conclusion, patients with RA with cavitary pulmonary nodules tend to present with seropositive, long disease duration, and more severe pulmonary findings compared with non-cavitary lesions. Anti-rheumatic drugs, especially LEF, may play a role in the development of this clinical presentation. On the other hand, the vasculitic course in RA might be responsible for the development of cavitary pulmonary lesions. In literature, there is insufficient data about evaluations of vasculitis in such patients. We need to collect more information from new studies designed with descriptive clinical, laboratory, and histopathological perspective to manage these challenging patients. Written informed consent was obtained from the patients.

Informed Consent: Written informed consent was obtained from patients who participated in this study.

Peer-review: Externally peer-reviewed.

Author Contributions: Concept - N.A.K., S.C.; Design - N.A.K., S.Y.O.; Supervision - E.C., C.B.; Resources - H.N.U., N.A.K.; Materials - H.N.U., N.A.K.; Data Collection and/or Processing - N.A.K., S.C.; Analysis and/or Interpretation - N.A.K., S.C.; Literature Search - N.A.K., S.C.; Writing Manuscript - N.A.K., S.C.; Critical Review - C.B., E.C.; Other - S.Y.O., E.C.

Conflict of Interest: No confict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study has received no financial support.


(1.) Brown KK. Rheumatoid lung disease. Proc Am Thorac Soc 2007; 15: 443-8. [CrossRef]

(2.) Gomez Herrero H, ArraizaSarasa M, Rubio Marco I, Garciade Eulate Martin-Moro I. Pulmonary rheumatoid nodules: presentation, methods, diagnosis and progression in referenceto 5 cases. Reumatol Clin 2012; 8: 212-5. [CrossRef]

(3.) Zif M. Rheumatoid nodule. Arthritis Rheum 1990; 33: 761-7. [CrossRef]

(4.) Cortet B, Flipo RM, Remy-Jardin M, Coquerelle P, Duquesnoy B, Remy J, et al. Use of high resolution computed tomography of the lungs in patients with rheumatoid arthritis. Ann Rheum Dis 1995; 54: 815-9. [CrossRef]

(5.) Pagnoux C, Seror R, BerezneA, Rouabhia S, Goulvestre C, Guillevin L. Remittent non-destructive polysynovitis in p-ANCA-positive vasculitis patients with anti-CCP antibodies. Joint Bone Spine 2010; 77: 604-7 [CrossRef]

(6.) Chinoy H, Mc Kenna F. Wegener's granulomatosis in patients with rheumatoid arthritis. Rheumatology (Oxford) 2002; 41: 588-9. [CrossRef]

(7.) Bosch X, Llena J, Collado A, Front J, Mirapeix E, Ingelmo M, et al. Occurrence of antineutrophil cytoplasmic and antineutrophil (peri)nuclear antibodies in rheumatoid arthritis. J Rheumatol 1995; 22: 2038-45.

(8.) Corcoran J P, Ahmad M, Mukherjee R, Redmond KC. Pleuro-pulmonary complications of rheumatoid arthritis. Respir Care 2014; 59: 55-9. [CrossRef]

(9.) Kim SH, Yoo WH. Recurrent pneumothorax associated with pulmonary nodulesafter leflunmide therapy in rheumatoid arthritis: a case reportand review of the literature. Rheumatol Int 2011; 31: 919-22. [CrossRef]

(10.) Rozin A, Yigla M, Guralnik L, Keidar Z, Vlodavsky E, Rozenbaum M, et al. Rheumatoid lung nodulosis and osteopathy associated with leflunomide therapy. Clin Rheumatol 2006; 25: 384-8. [CrossRef]

(11.) Be M, Cha HJ, Park C, Park Y, Jung H, Lee Y, et al. Multiple pulmonary cavitary nodules with pyoderma gangrenosum in patient with rheumatoid arthritis. Ann Transl Med 2016; 4: 39.

(12.) Kobayashi T, Satoh K, Ohkawa M, Satoh A. Multiple rheumatoid nodules with rapid thin-walled cavity formation producing pneumothorax. J Thorac Imaging 2005; 20: 47-9. [CrossRef]

(13.) Yoshikawa GT, Dias GA, Fujihara S, Silva LF, Cruz Lde B, Fuzii HT, et al. Formation of multiple pulmonary nodules during treatment with leflunomide. J Bras Pneumol 2015; 41: 281-4. [CrossRef]

(14.) Gotsman I, Goral A, Nusair S. Secondary spontaneous pneumothorax in a patient with pulmonary rheumatoid nodules during treatment with methotrexate. Rheumatology (Oxford) 2001; 40: 350-1. [CrossRef]

(15.) Ayse B, Veli C. Pulmonary nodulosis associated with leflunomide therapy in rheumatoid arthritis: report of four cases and review of the literature. J Clin Exp Invest 2016; 7: 98-102. [CrossRef]

(16.) Martin K, Bentaberry F, Dumoulin C, Dehais J, Haramburu F, Be'gaud B, et al. Effectiveness and safety profile of leflunomide in rheumatoid arthritis: actualpractice compared with clinical trials. Clin Exp Rheumatol 2015; 223:80-84.

(17.) Sawada T, Inokuma S, Sato T, Otsuka T, Saeki Y, Takeuchi T, et al. Study committee forleflunomide-induced lung injury, Japan College of Rheumatology. Leflunomide-induced interstitial lung disease: prevalence and risk factors in Japanese patients with rheumatoid arthritis. Rheumatology (Oxford) 2009: 48: 1069-72. [CrossRef]

(18.) Braun MG, Van Rhee R, Becker-Capeller D. Development and/or increase of rheumatoid nodules in RA patients following leflunomide therapy. Z Rheumatol 2004; 63: 84-7. [CrossRef]

(19.) Horvath IF, Szanto A, Csiki Z, Szodoray P, Zeher M. Intrapulmonary rheumatoid nodules in a patient with long-standing rheumatoid arthritis treated with leflunomide. Pathol Oncol Res 2008; 14: 101-4. [CrossRef]

Nilufer Alpay Kanitez (1), Selda Celik (1), Sibel Yilmaz Oner (1), Halide Nur Urer (2), Cemal Bes (1), Erdogan Cetinkaya (3)

Cite this article as: Alpay Kanitez N, Celik S, Yilmaz Oner S, Urer HN, Bes C, Cetinkaya E. Cavitary pulmonary nodules in rheumatoid arthritis; case reports and review of the literature. Eur J Rheumatol 2018; 5: 65-8.

(1) Department of Rheumatology, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, Istanbul, Turkey

(2) Department of Pathology, Yedikule Chest Diseases Training and Research Hospital, Istanbul, Turkey

(3) Department of Chest Disease, Yedikule Chest Diseases Training and Research Hospital, Istanbul, Turkey

Address for Correspondence:

Nilufer Alpay Kanitez, Department of Rheumatology, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, Istanbul, Tu rkey


Submitted: 1 December 2016

Accepted: 17 February 2017

Available Online Date: 20 June 2017

DOI: 10.5152/eurjrheum.2017.16106
Table 1. Clinical features of patients with RA reported since 1996 and
our patients with cavitary pulmonary nodules

                       Disease             Anti-
Ref. no.  Age, y  Sex  Duration, y  RF     CCP          ANCA

6         51      F    10 years     Serop  ositive (*)  NA

7         46      F    2 years      Sero   positive     NA

8         77      M    18 years     +      NA           -

          66      M    22 years     +      NA           -

9         66      F    7 years      NA     NA           -

10        67      F    14 years     +      NA           NA

11        60      F    10 years     +      NA           -

12        64      M    >3 years     +      NA           NA

13        42      F    20 years     +      NA           -

          44      F    9 years      +      NA           -

          65      M    14 years     +      NA           -
Our       55      F    20 years     +      +            -
case 1

Our       61      F    2 years      +      +            +
case 2

                            Duration   Pulmonary
                            of LEF     radiological
Ref. no.  Therapy           therapy    findings

6         PRD, LEF          10 years   Multiple nodules, pleural
                                       effusion, PX
7         PRD, LEF,         2 years    A large right PX,
          HCO                          multiple bilateral
8         LEF               13 months  Cherry-like nodes
                                       partially with cavitation
          PRD, LEF, AZA     NA         Small nodules
                                       in right side
                                       with cavitation, PX
9         MPRD,             -          Multiple cavitary
          HCO, MTX                     consolidations
10        Only NSAID        -          Small nodules
                                       with cavities

11        LEF, Deflazacort  8 years    Multiple cavitary

12        MPRD, MTX         -          Bilateral multiple
                                       nodules and a
                                       large cavitation, PX
13        MPRD,             13 months  Pleural effusion and
          HCO, LEF                     bilateral cavitary nodules
          MTX, SSZ, LEF     15 months  Pleural effusions
                                       and four cavitary lesions
          MTX, HCO          -          A cavitary nodule
Our       LEF               15 years   Bilateral multiple nodular
case 1                                 lesions with extensive
                                       cavitary areas

Our       LEF, HCO          10 months  Bilateral massive cavitary
case 2                                 pulmonary nodules, PX

          Pulmonary                         Treatment
          histopathological                 and disease
Ref. no.  findings                          course

6         NA                                Died from
7         Necrosis, granuloma,              Favorable LEF
          epithelioid mononuclear           was stopped
          inflammation withgiant cells
8         Epithelioid and giant cell        Favorable LEF
          inflammation with necrosis        was stopped
          Histiocytes, multinucleated       Favorable
          giant cells surrounding           LEF was
          focus of necrosis                 stopped
9         NA                                Favorable

10        Fibrinoid necrosis, histiocytes,  Died from
          lymphocytes, plasma cells,        severe
          and multinucleated                interstitial
          giant cells                       pneumonia
11        Acute suppurative                 Favorable
          inflammation with                 with
          necrosis                          abatacept.
                                            LEF was
12        Interstitial lymphoid             Favorable
          hyperplasia with                  with CS MTX
          giant cells                       was stopped
13        NA                                NA

          NA                                NA

          Epithelioid histiocytes Central   NA Favorable
Our       necrosis, granulomatous           with CS and
case 1    inflammation, and                 rituximab.
          perivascular lymphoplasmacytic    LEF was
          infiltration                      stopped
Our       Giant cell inflammation           Favorable
case 2    with necrosis and                 with CS and
          ymphoplasmacytic                  cyclophosphamide.
          inflammation at                   LEF was
          vessels wall                      stopped

F: female; M: male; PRD: prednisolon; MPRD: metyprednisolon; CS:
cortiocteoid; LEF: leflunomide; HCO: hydroxichlorocine; MTX:
methotrexate; AZA: azathioprin; NSAID: nonsteroid anti-inflammatory
drugs; SSZ: sulphasalazine; NA: not available; PX: pneumothorax
(*) Only seropositivity was reported, RF or anti-CCP results were not
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2018 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Title Annotation:Case Report
Author:Kanitez, Nilufer Alpay; Celik, Selda; Oner, Sibel Yilmaz; Urer, Halide Nur; Bes, Cemal; Cetinkaya, E
Publication:European Journal of Rheumatology
Article Type:Report
Date:Mar 1, 2018
Previous Article:Parotid abscess secondary to brucellosis in a patient with primary Sjogren's syndrome.
Next Article:A clinical threat in patients with granulomatosis polyangiitis in remission: Subglottic stenosis.

Terms of use | Privacy policy | Copyright © 2019 Farlex, Inc. | Feedback | For webmasters