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Case report

The use of in debilitating cavitating lung Thorax: first published as 10.1136/thx.2009.128710 on 3 June 2010. Downloaded from disease associated with rheumatoid , bronchocentric granulomatosis and aspergillosis K Neff,1 J Stack,2 S Harney,2 M Henry1

1Department of Respiratory ABSTRACT central in location. Serum antinuclear cytoplasmic Medicine, Cork University A case of debilitating cavitating lung disease associated (ANCA) was negative. Bronchoscopy did Hospital, Cork, Ireland 2 not reveal any endobronchial lesion; however, Department of , with rheumatoid arthritis and bronchocentric Cork University Hospital, Cork, granulomatosis, which failed to respond to conventional bronchial washings were positive for A fumigatus. Ireland medical or surgical treatment, is described. The patient Serum (IgE) levels were mark- was treated over 10 years with steroids, antimicrobial edly elevated at 1263 kU/l, RAST (radioallergosor- Correspondence to agents, disease-modifying antirheumatoid drugs and bent test) IgE was 4 (0e6) and the patient was Karl Neff, 30 Eccles St Dublin 7, surgery. Lung function continued to decline and the noted to have an of 1.743109/l. Ireland; ’ fl [email protected] patient presented for admission with recurrent During this period the patient sRA ared pneumonia. Abatacept was initiated to modify the intermittently, requiring treatment with disease- Received 29 October 2009 underlying immunopathology. Following 12 months of modifying antirheumatic agents (DMARDs). Accepted 30 January 2010 treatment with abatacept the patient has demonstrable was switched to metho- improvement in lung function and lung anatomy, and has trexate in 2004 but discontinued shortly after- not presented to hospital with pneumonia. She has wards due to patient intolerance. Lefluonomide tolerated the treatment without . The use of was then introduced but had to be discontinued abatacept has stabilised the lung disease in this case in in view of the recurrent infective episodes. The the medium term and prevented readmission to hospital. patient’s RA was then managed with reducing These results suggest a larger role for abatacept in those courses of steroids which were tapered to with such disease in the future and may warrant further a maintenance dose of 10 mg daily. investigation. Again, intensive treatment with broad-spectrum antibiotics and antifungal therapy proved unsuc- cessful, resulting in recurrent hospital admissions Bronchocentric granulomatosis has been described over the following 18 month period. Subsequently, http://thorax.bmj.com/ in association with rheumatoid arthritis (RA) and in October 2006, the patient underwent left upper allergic bronchopulmonary aspergillosis (ABPA). lobectomy. Examination of the resected specimen Here we describe the effective use of abatacept in found bronchocentric granulomatosis with A fumi- the case of a woman diagnosed with bronchocen- gatus identified within the cavity. TB staining and tric granulomatosis in association with RA, and cultures were negative. subsequently in the setting of colonisation by Repeated courses of antimicrobial agents, Aspergillus fumigatus. She had been suffering with including itraconazole and voriconazole, were

recurrent pulmonary sepsis, and the use of abata- prescribed postresection but were discontinued on September 30, 2021 by guest. Protected copyright. cept has been effective in stabilising her disease. following a 6 month treatment period with no clin- A 43-year-old woman presented to hospital in ical response. The antifungal agents were prescribed 1998 with a suppurative cavitating right upper lobe with high dose steroids (maximum dose¼40 mg), pneumonia. The patient had a background history of which were continued for 6 weeks postresection and RAthat had been diagnosed in 1992 when the patient then tapered again to a maintenance dose of 10 mg. was 37 years old and was at that time well controlled The patient continued to present with recurrent with hydroxychloroquine. She had no background respiratory tract infections and progressive cavi- history of or other respiratory disease at that tating lung disease. Repeated bronchoscopies at this time. The pneumonia proved resistant to conven- time did not isolate any TB or fungal pathogens. tional treatment and required right upper lobectomy. During the postoperative period the patient’s Histological analysis of the resected specimen nutritional status and weight remained stable. The reported bronchocentric granulomatosis and foci of patient’s RA did flare again, and low dose lefluo- organising pneumonia with multinucleate giant cells namide (10 mg daily) was cautiously reintroduced and pallisading histiocytes lining the cavity of the in February 2008 with minimal response. The resected lobe. Eosinophilia was not conspicuous at patient’s RA remained active, with a swollen that time, and direct staining and culture for tuber- count of 10 and a C-reactive protein (CRP) of culosis (TB) and fungi were negative. 252 mmol/l noted immediately prior to starting She represented in 2004 with recurrent lower abatacept. This CRP was taken in the absence of respiratory tract infections. Serial CT imaging of concurrent respiratory sepsis. the thorax showed enlarging bilateral apical cavities A trial of abatacept was commenced at with mediastinal , tree-in-bud 20 months postlobectomy in an effort to control opacification and localised in the her underlying disease given the lack of response to right upper lobe. This bronchiectasis was not conventional treatment. A dosage of 750 mg was

Thorax 2010;65:545e546. doi:10.1136/thx.2009.128710 545 Case report

administered at monthly intervals and, to date, the patient has Thorax: first published as 10.1136/thx.2009.128710 on 3 June 2010. Downloaded from completed 12 infusions of abatacept over 12 months. Our patient has responded well to abatacept and, since commencement of treatment, she has not required further admission to hospital. An improvement is also seen in her pulmonary function tests, with tests prior to and after 12 months of treatment recording an improvement in forced vital capacity (FVC) from 2.41 (71% predicted) to 2.87 (95% predicted) and an improvement in forced expiratory volume in 1 s (FEV1) of 1.89 (68% predicted) to 2.28 (88% predicted). Lung anatomy has also improved on CT imaging. Figures 1 and 2 illustrate this improvement. Clinically, the patient’s arthritis is quiescent and CRP measurements have fallen from 252 mmol/l on commence- ment of abatacept to <5 mmol/l at 12 months of treatment. Figure 2 CT thorax 12 months after onset of abatacept. An improvement in appearance of cavities in the right middle and lower DISCUSSION lobes can be seen. Bronchocentric granulomatosis is a histological diagnosis that is associated with numerous diseases including RA and ABPA. downregulate activation, an important process in RA Bronchocentric granulomatosis was identified in our patient on pathogenesis. Upregulation of Tcell activity via the activation of fi co-stimulatory pathways may have facilitated the immune two separate occasions; rst in the setting of RA and secondly in + the setting of both RA and Aspergillus colonisation. There were response to Aspergillus, where chemotaxis of CD4 T helper 2 (Th2) specific for A fumigatus has been shown to therefore two aetiologies: a reaction and an 6 autoimmune process, which were then potentially accelerated occur. Abatacept (which inhibits T cell co-stimulation) was therefore chosen as a preferable biological agent for treatment of by exposure to bacterial antigens. ’ Previously, treatment of bronchocentric granulomatosis-asso- both the patient s RA and lung disease. Rates of TB are certainly lower with abatacept than with anti-TNF agents and also ciated lung disease has focused on treating the underlying condi- 7 tion. In cases without an obvious cause, steroids have been used overall infection rates are lower with abatacept. with some success.1 There are no previous reports in the literature Abatacept is a soluble between CTLA-4 (cytotoxic T--associated antigen 4) and the Fc regarding the use of abatacept in bronchocentric granulomatosis, e although there have been cases of omalizumab in treating ABPA in portion of IgG1 (CTLA4 Ig). fi 23 In our case, the use of abatacept proved successful in treating the context of cystic brosis, with impressive results. ’ Our patient had severe cavitating lung disease that was both the patient s bronchocentric granulomatosis-associated cavitating lung disease and her arthritis. We propose that resistant to standard medical treatment with antimicrobial http://thorax.bmj.com/ agents, immunosuppressant agents and surgery. The underlying abatacept may also have played a role in suppressing the mechanism is probably multifactorial, but proteolytic enzyme underlying Aspergillus-associated bronchocentric granulomatosis activity is likely to be an important part of the condition given in our patient via T cell inhibition. the concomitant RA and the anatomical appearance. In this CONCLUSION case, the could be stimulated by proinflammatory Treatment with abatacept in this case has resulted in a signifi- pathways, which can be activated or catalysed by tumour cant improvement in the patient’s clinical condition from both factor a (TNFa).4 a respiratory and an arthritis point of view. This has led to Anti-TNF treatment was considered for the patient’s systemic on September 30, 2021 by guest. Protected copyright. a reduced incidence of infection, prevented hospital admission arthritis, but case reports have shown infliximab (chimeric and enhanced our patient’s quality of life. As such, we believe to TNF) to have worsened ABPA5 and this to be the first case report of abatacept being used success- thus these particular agents were not used in this case. fully in the treatment of bronchocentric granulomatosis-associ- In RA there are several co-stimulatory and co-inhibitory ated lung disease with co-commitant RA. pathways, and signals through these can either upregulate or Competing interests None. Patient consent Obtained. Provenance and peer review Not commissioned; externally peer reviewed. REFERENCES 1. Westhoff M, Welim B, Mu¨ller KM. Bronchocentric granulomatosis (in German). Pneumologie 2005;59:804e10. 2. Van der Ent CK, Hoekstra H, Rijkers GT. Successful treatment of allergic bronchopulmonary aspergillosis with recombinant anti-IgE antibody. Thorax 2007;62:276e7. 3. Kanu A, Patel K. Treatment of allergic bronchopulmonary aspergillosis (ABPA) in CF with anti-IgE antibody (omalizumab). Pediatr Pulmonol 2008;43:1249e51. 4. Moreland LW, Baumgartner SW, Schiff MH, et al. Treatment of rheumatoid arthritis with a recombinant human (p75)eFc fusion protein. N Engl J Med 1997;337:141e7. 5. Judson MA. Allergic bronchopulmonary aspergillosis after infliximab therapy for : a potential mechanism related to T-helper balance. Chest 2009;135:1358e9. 6. Knutsen AP, Chauhan B, Slavin RG. Cell-mediated immunity in allergic bronchopulmonary aspergillosis. Immunol Clin N Am 1998;18:575e99. 7. Salliot C, Dougados M, Gossec L. Risk of serious infections during , Figure 1 CT before abatacept treatment. Cavities are illustrated in the abatacept and treatments for rheumatoid arthritis: meta-analyses of right middle and lower lobes. randomised placebo-controlled trials. Ann Rheum Dis 2009;68:25e32.

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