Characteristics of patients presenting with erythema nodosum and sarcoidosis

TM O’Connor1, A Jahangir1, A Brady2, J Fitzgibbon3, G Lee3, A El−Gammal1, NJ Brennan1

Departments of 1Respiratory Medicine, 2Radiology and 3Pathology, Mercy University Hospital, Cork

AbstractWe explored the relationship between erythema nodosum (EN) and sex, age, serum angiotensin converting enzyme (ACE), bronchoalveolar lavage lymphocytosis (BAL−l), interstitial granulomasand radiological stage in patients presenting with pulmonary sarcoidosis in Ireland. Sixty−nine patients diagnosed with sarcoidosis between 2003 and 2006 were studied. Forty one patients (59%)were male. Sixteen patients (23%) presented with EN. Forty one patients of 65 (63%) had transbronchial biopsies demonstrating non−caseating granulomas. Patients with sarcoidosis presentingwith EN were more likely to be female (p=0.042), younger (p=0.012) and have earlier stage pulmonary disease (p=0.02). There were no correlations between serum ACE, interstitial granulomasand disease stage. BAL−l did however predict increasing disease radiological stage (p=0.042). In this study, one quarter of patients with sarcoidosis presented with EN among their presentingfeatures. These patients were more likely to be young females with early stage radiological disease.

IntroductionSarcoidosis is a multisystem granulomatous disease characterized by the presence of noncaseating granulomas in involved organs. It has a worldwide prevalence but variable incidence amongdifferent geographical regions. The incidence of sarcoidosis is particularly high in Ireland. Although the aetiology of sarcoidosis remains unknown, it is widely believed that sarcoidosis results fromexposure of genetically susceptible hosts to specific environmental agents. The disease typically affects adults between 20 and 40 years of age with preponderance for females. The clinicalmanifestations of sarcoidosis can be widespread or may involve only one organ system. Cutaneous lesions are present in 20−35% of patients at presentation. While these lesions vary frommaculopapules, plaques, nodules, lupus pernio and scar infiltration, the most common lesion is erythema nodosum (EN)1−3. The association of EN with bilateral hilar lymphadenopathy (BHL),called Löfgren's syndrome, was first recognized as an acute, benign form of sarcoidosis by Löfgren and Lundbach4. EN is characterized by red or violet subcutaneous nodules that classicallydevelop in a pretibial location and is thought to represent a delayed hypersensitivity reaction to antigens associated with the various infectious agents, drugs, and other diseases with which it isassociated. Histologically, the rash is a panniculitis involving inflammation of septa in the subcutaneous fat tissue, usually without associated vasculitis, although small vessel inflammatorychanges occasionally occur. The diagnosis of this disorder is typically clinical, with biopsy required only in atypical cases. In international studies, patients with sarcoidosis who develop EN tend tobe women and possess the HLA−DR3 allele1,5,6.

There are no definitive diagnostic tests that are specific for the diagnosis of sarcoidosis. However, the presence of non−caseating granulomas on histological examination of samples of involvedorgans is considered supportive of a diagnosis of sarcoidosis in the appropriate clinical presentation. The yield of transbronchial biopsy for non−caseating granulomas is 50−80% in patients withpulmonary sarcoidosis, depending on the extent of parenchymal involvement7. However, bronchoalveolar lavage (BAL) with differential cell count may also be a useful adjunct to diagnosis8.Despite frequent use of BAL in patients with sarcoidosis, no consensus has yet been achieved as to which of the cellular compartments of BAL reflect the disease stage or prognosis of newlydiagnosed pulmonary sarcoidosis. We sought to explore factors predicting the development of EN as a presenting feature of sarcoidosis and to assess the relationship between BAL lymphocytosis(BAL−l) and pulmonary disease stage in Irish patients.

MethodsWe retrospectively recorded all patients diagnosed with sarcoidosis at the Mercy University Hospital, Cork, Ireland (n=69) from January 2003 to December 2006. We hypothesized that EN wouldbe commoner in young females and that BAL lymphocytosis would predict more severe disease. Symptoms and signs at presentation were recorded in all cases. Chest radiographs and/orthoracic CT scans were reported by Consultant Radiologists and the radiological stage of sarcoidosis was determined by the study authors, depending on the presence of lymphadenopathy,interstitial involvement and fibrosis. BAL was performed by infusing 100 ml warmed sterile 0.9% saline solution into a segmental middle lobe or lingular bronchus. Collected BAL fluid was analyzedfor total and differential cell count. BAL differential cell counts were obtained from 37 patients and 66 patients had transbronchial biopsy. Pulmonary function tests (vital capacity, FEV1, anddiffusing capacity for carbon monoxide [DLCO]) were performed in 63 patients with a Jaeger Master Screen Pneumo® device (Jaeger Co., Hoechberg, Germany). Serum angiotensin convertingenzyme (ACE) was measured in 67 patients at the time of diagnosis. The Kolmogorov−Smirnov test was used to determine whether datasets were normally distributed and data were presented asmean ± standard deviation where normally distributed, median and range where not normally distributed. Statistical analysis was done by contingency table analysis and Spearman rankcorrelation using Graph Pad Instat software. Significance was assumed at p < 0.05.

ResultsForty one patients (59%) were male. Sixteen patients (23%) presented with EN. Thirty seven of 67 (55%) had ACE 60 IU/L (range 0−45 IU/L) and 20 (30%) had ACE = 90 IU/L (Table 1). Twentytwo patients of 37 (59%) had BAL−l = 20% and 9 (24%) had BAL−l = 50% (Table 1). Forty one patients of 65 (63%) had transbronchial biopsies (TBBx) that demonstrated non−caseatinggranulomas. Forty patients (58%) had stage 0 or 1 pulmonary disease and 29 (42%) had stage 2 or 3 disease.

There was an apparent bimodal distribution in age at presentation for female patients, with one group, the majority, in the classical ‘20−40 year’ age group and the second in a 45−60 yearage group. While the majority of males presented between 20 and 40 years, approximately 1/3 presented later than this with a less clear distinction between these groups compared with females(Table 2).

Patients with sarcoidosis who presented with EN were more likely to be female (p=0.042), younger (p=0.012) and have earlier stage pulmonary disease (p=0.02). There were no correlationsbetween serum ACE and granulomas on transbronchial biopsy, serum ACE and disease stage or granulomas and disease stage. BAL−l did however predict increasing disease radiological stage(p=0.042) (Figure 1).

Figure 1: Bronchoalveolar lavage lymphocyte percentage compared with worsening chest radiograph stage in patients with pulmonary sarcoidosis

DiscussionIn Ireland, patients with sarcoidosis who present with EN tend to be younger, female and have early stage pulmonary disease. Higher percentages of lymphocytes in BAL fluid appear to predictincreasing radiological disease stage in Irish patients with sarcoidosis. The clinical manifestations of sarcoidosis differ in different parts of the world8,9. It is unclear whether these differences arisefrom genetic factors, environmental factors or a combination thereof. Prior studies emphasize disease onset between the ages of 20 and 40 years10. However, in the ACCESS study,approximately one−third of the recruited patients were 50 years of age or older5. A bimodal age occurrence has been observed, with the second peak seen in patients over 50 years11. The datafrom our series demonstrate a bimodal age distribution in females that is less apparent in males. About 80−90% of patients with sarcoidosis have pulmonary involvement and 25% will have one ormore cutaneous manifestations12. Women are significantly over represented among patients with acute sarcoidosis with EN. Our data show that EN as an initial presentation of sarcoidosis iscommoner in women in Ireland, consistent with data from other countries.

Clinical variables associated with poorer prognosis in previous studies include black race, onset of disease after the age of 40, symptoms that last for more than six months, the absence of EN,splenomegaly, involvement of more than three organ systems and stage III pulmonary disease13. As this study was not a longitudinal study, it is impossible to comment on prognostic indicators.However, there was no correlation between age at presentation and disease stage, which is associated with poorer prognosis in patients with sarcoidosis. The presence of BAL lymphocytosis,combined with other typical features such as bihilar lymphadenopathy, elevated serum ACE and erythema nodosum, may be helpful in differentiating sarcoidosis from other causes of interstitiallung disease14,15. However, BAL lymphocytosis may also be seen in hypersensitivity pneumonitis, idiopathic pulmonary fibrosis, beryllosis, amiodarone pneumonitis and pulmonary Langerhanscell histiocytosis. In a recent study of patients with interstitial lung disease, the likelihood for sarcoidosis increased from 33.7 to 68.1% when lymphocyte numbers were 30−50% and granulocytenumbers were low in BAL16. While there have been reports of attenuated BAL lymphocytosis in smokers with sarcoidosis compared with nonsmokers, we were unable to demonstrate suchdifferences.

"Early" or active sarcoidosis is characterized by an increase in the total numbers of BAL cells recovered, increased numbers of lymphocytes, and an elevated CD4/CD8 T−lymphocyte ratio.However, although once thought to be highly predictive of a diagnosis of sarcoidosis, more recently, the BAL lymphocyte CD4/CD8 ratio has proven less useful (and was not available to ourgroup). The relationship of BAL lymphocytosis to increasing radiographic stage has not, to our knowledge, been demonstrated previously and may be unique to Irish patients. Furthermore, itsuggests that BAL fluid analysis may be of most use in patients with interstitial pulmonary involvement and less useful in those with stage 1 radiographic disease. A recent study from Swedenconcluded that patients who presented with EN compared with those who presented with ankle inflammation without EN were identically strongly associated with HLA−DRB1*0301/DQB1*0201,with 60 (69.0%) and 44 (69.8%) patients having this particular HLA type in the EN−positive and EN−negative groups, respectively. Such patients recovered to the same degree, that is, at almost100%1. Linkage disequilibrium, the nonrandom association between two or more alleles, exists for HLA−DRB1*0301 and DQB1*020117. A clear association for DQB1*0201 with reduced risk ofdisease progression has been previously reported and also found to be associated with Löfgren's syndrome in patients in the United Kingdom18.

This study had some limitations. The data would have been complemented by HLA analysis in patients. However, the cost−benefit of such analysis in routine clinical practice is uncertain. That is, itis unclear whether there is a clinical benefit to HLA studies in patients with sarcoidosis who present with EN or whether presentation with EN alone is sufficient to predict a favourable prognosis.Secondly, although the relationship of BAL lymphocytosis to increasing radiographic stage was statistically significant, the correlation was weak, suggesting that further study with higher numbersof patients might be of value. The authors were also surprised by the male preponderance among the study population. Male preponderance would contradict many international studies in patientswith sarcoidosis as well as being contrary to the anecdotal experience of the authors. We suspect that this male preponderance was a sporadic event within the period of this study rather thanreflecting a true male preponderance in patients with sarcoidosis in Ireland. However, it is also possible that Irish females with erythema nodosum, particularly those taking the oral contraceptivepill, may be less likely to be referred for work−up and that males may be more likely to be referred for work−up and diagnosed with sarcoidosis.

We conclude that one quarter of patients with sarcoidosis in Ireland present with EN. These patients are more likely to be young females with early stage radiological disease. Despite widevariations in the clinical presentation and course of sarcoidosis globally, the consistency of EN as a favourable prognostic feature is striking, as is the consistency of age distribution atpresentation.

Correspondence: T O’ConnorDepartment of Respiratory Medicine, Mercy University Hospital, Grenville Place, CorkTel: +353 21 4271971Fax: +353 21 4276341Email: terryoconnor@eircom.net

References1. Grunewald J, Eklund A. Sex−specific manifestations of Löfgren's syndrome. Am J Respir Crit Care Med 2007;175:4−5.2. Yanardag H, Pamuk ON, Karayel T. Cutaneous involvement in sarcoidosis: analysis of the features in 170 patients. Respir Med 2003;97:978−82.3. Fernandez−Faith E, McDonnell J. Cutaneous sarcoidosis: differential diagnosis. Clin Dermatol 2007;25:276−87.4. Löfgren S, Lundback H. The bilateral hilar lymphoma syndrome; a study of the relation to age and sex in 212 cases. Acta Med Scand 1952;142:259–264.5. Baughman RP, Teirstein AS, Judson MA, et al. Case Control Etiologic Study of Sarcoidosis (ACCESS) research group. Clinical characteristics of patients in a case control study of sarcoidosis.Am J Respir Crit Care Med 2001;164:1885−1889.6. Kremer JM. Histologic findings in siblings with acute sarcoid arthritis: association with the B8, DR3 phenotype. J Rheumatol 1986;13:593−7.7. Shorr AF, Torrington KG, Hnatiuk OW. Endobronchial biopsy for sarcoidosis: a prospective study. Chest 2001;120:109−14.8. Hunninghake GW, Costabel U, Ando M, et al. ATS/ERS/WASOG statement on sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1999;16:149−73.9. Siltzbach LE, James DG, Neville E, et al. Course and prognosis of sarcoidosis around the world. Am J Med 1974;57:847−852.10. James DG. The many faces of sarcoidosis. The Thome Villar Memorial Lecture. Sarcoidosis 1990;7:1−8.11. Hillerdal G, Nou E, Osterman K, Schmek el B. Sarcoidosis: epidemiology and prognosis A 15−year European study. Am Rev Respir Dis 1984;130:29−32.12. Hunninghake GW, Gilbert S, Pueringer R, et al. Outcome of the treatment for sarcoidosis. Am J Respir Crit Care Med 1994;149: 893−898.13. Newman LS, Rose CS, Maier LA. Sarcoidosis. N Engl J Med 1997;336:1224−34.14. Drent M, Mansour K, Linssen C. Bronchoalveolar lavage in sarcoidosis. Semin Respir Crit Care Med 2007;28:486−95.15. King TE Jr. Clinical advances in the diagnosis and therapy of the interstitial lung diseases. Am J Respir Crit Care Med 2005;172:268−79.16. Welker L, Jörres RA, Costabel U, Magnussen H. Predictive value of BAL cell differentials in the diagnosis of interstitial lung diseases. Eur Respir J 2004;24:1000−6.17. Iannuzzi MC, Baughman RP. Reverse Phenotyping in Sarcoidosis. Am J Respir Crit Care Med 2007;175:4−5.

Characteristics of patients presenting with erythema nodosum and sarcoidosis 1

18. Sato H, Grutters JC, Pantelidis P, et al. HLA−DQB1*0201: a marker for good prognosis in British and Dutch patients with sarcoidosis. Am J Respir Cell Mol Biol 2002;27:406–412.

Comments:<br>OtherReferences:

Acknowledgement:

Characteristics of patients presenting with erythema nodosum and sarcoidosis 2