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In the Clinic |

Sarcoidosis

Anthony O'Regan, MD; and Jeffrey S. Berman, MD
Ann Intern Med. 2012;156(9):ITC5-1. doi:10.7326/0003-4819-156-9-201205010-01005
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Sarcoidosis is an idiopathic granulomatous disease. Although often considered a pulmonary disease, it can affect virtually any organ with diverse and protean manifestations. However, most patients present with typical symptoms that are recognizable at the first clinical encounter. Although the cause is incompletely understood, the pathogenesis of sarcoidosis involves antigen exposure in a genetically susceptible host resulting in typical granulomatous inflammation with a prominent Th1-cell–mediated immune response, which either resolves or progresses to organ fibrosis. The identity of the antigen or antigens and the exact genetics of predisposition remain areas of intense research. The clinical course of sarcoidosis ranges from an incidental finding to a devastating, life-threatening disease. No clinical parameters allow an accurate prediction of the clinical course of sarcoidosis, although certain manifestations, such as lung fibrosis, cutaneous disease, and neurologic disease, suggest chronicity. It is benign in most cases; however, mortality seems to be increasing in the United States and England, particularly in women. Most deaths are related to pulmonary or cardiac disease.

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Grahic Jump Location
Figure 1.

A patient with lupus pernio sarcoidosis.

Violaceous plaques and nodules on the cheeks, bridge of the nose, and nares. Lesions responded to treatment with prednisone and methotrexate.

Grahic Jump Location
Grahic Jump Location
Figure 2.

Stages of sarcoidosis.

A. Stage 1. The Lofgren syndrome. A 24-year-old man presented with 1 day of bilateral symmetrical ankle swelling and pain; he also noted dusky nodules on his shins. A chest x-ray revealed bilateral hilar and right paratracheal adenopathy. Note the convex shape of the enlarged hila (arrows). B. Stage 2 pulmonary sarcoidosis. A 38-year-old man with cough, showing bilateral perihilar nodular infiltrates and bilateral hilar fullness. C. The patient initially presented with stage 2 disease with nodular interstitial lung disease and hilar fullness as shown in the x-ray. He improved with prednisone therapy. Three months after stopping prednisone the presented with fatigue and dyspnea. The chest x-ray shows stage 3 sarcoidosis with recurrence of the infiltrates, although there is no adenopathy (D). E. Stage 4 sarcoidosis. A 58-year-old man with a 30-year history of sarcoidosis, showing upper lobe fibrosis and cyst formation. Note the metallic densities in the upper-left lung, representing previous coil embolization for hemoptysis associated with aspergilloma.

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sarcoidosis in the differential diagnosis of asthenia of unknown origin in old age
Posted on May 8, 2012
oscar,m, jolobe, retired geriatrician
manchester medical society
Conflict of Interest: None Declared

Although it is true that >80% of cases of sarcoidosis present in patients aged 20-40(1), it is important to take cognisance of the presentation which appears to be typical of patients aged >65, namely, presentation with "asthenia of unknown origin"(2)(3). In France, in a retrospective study covering the 14 year period 1986-2000, 30 white patients aged >70(mean age 74) were identified in whom the presentation was characterised, in 53% of instances, by alteration in general health(asthenia and/or anorexia and/or weight loss)(2). Accessory salivary gland biopsy was positive for sarcoidosis(by showing presence of non- caseating granulomas) in 70.6 of cases, thereby proving to be an important aid to diagnosis(2). In a more recently reported study, covering the period 2002-2006, 30 French patients were identified in whom sarcoidosis was diagnosed after the age of 65. In comparison with 70 randomly selected patients in whom sarcoidosis had been diagnosed at an earlier age, the femele:male ratio was 5:1 in the former age group as opposed to 1:1 in the latter age group. Asthenia was, again a prominent feature, being significantly(p=0.012) commoner in the former than in the latter age group. The proportion of patients in whom accessory salivary gland biopsies contributed to the diagnosis was significantly(p=0.002) highrr in the former than in the latter age group although both groups were similar with regard to race and severity(3) Accordingly, in patients aged >65, sarcoidosis(along with giant cell arteritis)(4) should be included in the differential diagnosis of asthenia of unknown origin. Occult tuberculosis was also high on the differential diagnosis in the French cases(2), and rightly so in view of the non- specific presentation of "cryptic" tuberculosis(5)

References

(1) O'Regan A., Berman JS Sarcoidosis Ann Intern Med 2012:ITC5-2-ITC5-16

(2) Chevalet P., Clement R., Rodat O et al Sarcoidosis diagnosed in elderly subjects CHEST 2004;126:1423-1430

(3) Varron L., Cottin V., Schott A-., Broussolle C., Seve P Late-onset sarcoidosis : A comparative study Medicine 2012 : 91:137-143

(4) Martinez-Lado L., Calvino-Diaz C., Pineiro A et al Relapses and recurrences in giant cell arteritis a population study of patients with biopsy proven disease from northwestern Spain Medicine 2011;90:186-193

(5) Yu YL., Chow WH., Humphries MJ., Wong RWS., Gabriel M Cryptic miliary tuberculosis Q J Med 1986 New series 59, No 228:421-8

Conflict of Interest:

None declared

Sarcoidosis: incidence, diagnosis and treatment
Posted on May 25, 2012
Jerome M., Reich, MD, FCCP
Earle A Chiles Research Institute, Portland, Oregon
Conflict of Interest: None Declared

A number of updates to the cited sources of this sarcoidosis pr?cis seem worthwhile: 1. Incidence: The figure cited by the authors appears high. Among U.S. Whites the annual incidence is 3/100,000; among Blacks, 36/100,000.

1. Diagnosis: L?fgren's syndrome--bilateral hilar adenopathy accompanied by fever, polyarthralgia and erythema nodosum--is so distinctive that a clinical diagnosis is secure, and biopsy confirmation is deemed unnecessary. Less well known is that isolated, asymptomatic bilateral hilar lymphadenopathy (ABHL) has a positive predictive value of >99.95%; therefore one would have to submit 10,000 such patients to invasive procedures to identify, at most, five alternative diagnoses: the costs and morbidities entailed far outweigh the trivial potential benefit of an earlier alternative diagnosis which would, in any case, become evident during routine follow-up, with little potential harm from delay; not a single verified exception has been published; the British National Health Service adopted a policy of clinical diagnosis of ABHL.

2. Treatment: The prognosis of conservatively managed sarcoidosis is highly favorable. Johnston for example, furnished corticosteroid therapy solely to individuals demonstrating progressive pulmonary shadowing. It was required in only 3-percent; 5 persons experienced residual pulmonary fibrosis, which was minimal in 4; and there were no deaths attributable to sarcoidosis.

In a meta-analysis contrasting sarcoidosis mortality in population based vs. tertiary care settings, mean mortality for the former was 0.5%, one-sixth the mortality of the latter after adjustment for stage. The difference appeared to be largely ascribable to conservative management, not to adverse selection. The British Thoracic Society study, cited as an example of long term benefit of individualized intensive corticosteroid therapy, should be viewed with caution: 1) Subjects were alternately (not randomly) allocated to the intensive vs. selective treatment cohorts. 2) There was an allocation imbalance favoring the former who had a higher mean baseline diffusing capacity and half the number with stage IV. 3) The physiological difference in outcome was trivial.

The Cochrane metaanalysis of corticosteroid therapy trials, cited by the authors as showing neither benefit or harm, is also open to criticism: it included treatment of stage I (rarely indicated), inhaled corticosteroids (currently not recommended), series with clearly flawed execution, a variety of outcome measures rendering it unsuitable for metaanalysis and it did not stratify outcomes according to disease duration. A systematic review of trials limited to persons with pulmonary shadowing showed that in persons with recent onset, each of five competent controlled trials demonstrated a 2-4-fold ratio of adverse outcomes (including mortality) in corticosteroid recipients vs. controls. Its effect was neutral in intermediate duration disease and favorable in chronic progressive cases.

An explanation advanced to account for these findings is that corticosteroid therapy in recent onset sarcoidosis impairs resolution. Absent compelling symptoms, current guidelines favor intervention in persons with pulmonary shadowing exhibiting progressive pulmonary impairment (with no reference to duration of unresolved pulmonary shadowing). , Swigris et al. reported a sarcoidosis mortality increase of 50% in females and 30% in males in the past two decades. More pervasive intervention is a possible explanation for this secular change.

References

1. O'Regan A, Berman JS. Sarcoidosis. Ann Intern Med. 2012 May 1;156(9):ITC51

2. Reich JM, Johnson RE. Estimated incidence of clinically identified sarcoidosis in a Northwest United States population. Sarcoidosis Vasc Diffuse Lung Dis 1996;13:173-77

3. Reich JM, Brouns MC, O'Connor EA, Edwards MJ. Mediastinoscopy in patients with presumptive stage I sarcoidosis: a risk/benefit, cost/benefit analysis. Chest 1998;113:147-53

4. Johnston RN. Pulmonary sarcoidosis after ten to twenty years. Scott Med J 1986; 31(2):72-78

5. Reich JM. Mortality of intrathoracic sarcoidosis in referral vs. population-based settings: influence of stage, ethnicity, and corticosteroid therapy. Chest 2002;121:32-39

6. Gibson GJ, Prescott RJ, Muers MF et al. British Thoracic Society sarcoidosis study: effects of long term corticosteroid treatment. Thorax 1996; 51:238-47

7. Paramothayan S, Jones PW. Corticosteroid therapy in pulmonary sarcoidosis: a systematic review. JAMA 2002; 287(10):1301-1307

8. Reich JM. Adverse long-term effect of corticosteroid therapy in recent-onset sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2003; 20(3):227-234

9. Hunninghake GW, Costabel U, Ando M, et al. ATS, ERS, WASOG. Statement on sarcoidosis. Am J Respir Crit Care Med 1999;160:736-55

10. Wells AU, Hirani N. Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. Thorax 2008; 63(Supp V):V1-V58

11. Swigris JJ, Olson AL, Hule TJ, Fernandez-Perez ER, Solomon J, Sprunger D, Brown KK. Sarcoidosis mortality in the United States 1988- 2007. Am J Respir Crit Care Med 2011;183:1524-1530

Conflict of Interest:

None declared

Sarcoidosis: incidence, diagnosis and treatmen
Posted on July 19, 2012
Jerome M. Reich, MD, FCCP
Earle A Chiles Research Institute, Portland, Oregon
Conflict of Interest: None Declared

A number of updates to the cited sources of this sarcoidosis pr?cis seem worthwhile:1. Incidence: The figure cited by the authors appears high. Among U.S. Whites the annual incidence is 3/100,000; among Blacks, 36/100,000.

1. Diagnosis: Lofgren's syndrome--bilateral hilar adenopathy accompanied by fever, polyarthralgia and erythema nodosum--is so distinctive that a clinical diagnosis is secure, and biopsy confirmation is deemed unnecessary. Less well known is that isolated, asymptomatic bilateral hilar lymphadenopathy (ABHL) has a positive predictive value of ca. 99.95%; therefore one would have to submit 10,000 such patients to invasive procedures to identify, at most, five alternative diagnoses: the costs and morbidities entailed far outweigh the trivial potential benefit of an earlier alternative diagnosis which would, in any case, become evident during routine follow-up, with little potential harm from delay; not a single verified exception has been published; the British National Health Service adopted a policy of clinical diagnosis of ABHL.

2. Treatment: The prognosis of conservatively managed sarcoidosis is highly favorable. Johnston for example, furnished corticosteroid therapy solely to individuals demonstrating progressive pulmonary shadowing. It was required in only 3-percent; 5 persons experienced residual pulmonary fibrosis, which was minimal in 4; and there were no deaths attributable tosarcoidosis. In a meta-analysis contrasting sarcoidosis mortality in population based vs. tertiary care settings, mean mortality for the former was 0.5%, one-sixth the mortality of the latter after adjustment for stage. The difference appeared to be largely ascribable to conservative management, not to adverse selection. The British Thoracic Society study, cited as an example of long term benefit of individualized intensive corticosteroid therapy, should be viewed with caution:

1) Subjects were alternately (not randomly) allocated to the intensive vs.selective treatment cohorts.

2) There was an allocation imbalance favoringthe former who had a higher mean baseline diffusing capacity and half the number with stage IV.

3) The physiological difference in outcome was trivial. The Cochrane metaanalysis of corticosteroid therapy trials, cited bythe authors as showing neither benefit or harm, is also open to criticism:it included treatment of stage I (rarely indicated), inhaled corticosteroids (currently not recommended), series with clearly flawed execution, a variety of outcome measures rendering it unsuitable for metaanalysis and it did not stratify outcomes according to disease duration. A systematic review of trials limited to persons with pulmonary shadowing showed that in persons with recent onset, each of five competentcontrolled trials demonstrated a 2-4-fold ratio of adverse outcomes (including mortality) in corticosteroid recipients vs. controls. Its effect was neutral in intermediate duration disease and favorable in chronic progressive cases.

An explanation advanced to account for these findings is that corticosteroid therapy in recent onset sarcoidosis impairs resolution. Absent compelling symptoms, current guidelines favor intervention in persons with pulmonary shadowing exhibiting progressive pulmonary impairment (with no reference to duration of unresolved pulmonary shadowing). , Swigris et al. reported a sarcoidosis mortality increase of 50% in females and 30% in males in the past two decades. More pervasive intervention is a possible explanation for this secular change.

References

1. O'Regan A, Berman JS. Sarcoidosis. Ann Intern Med. 2012 May 1;156(9):ITC51

2. Reich JM, Johnson RE. Estimated incidence of clinically identified sarcoidosis in a Northwest United States population. Sarcoidosis Vasc Diffuse Lung Dis 1996;13:173-77

3. Reich JM, Brouns MC, O'Connor EA, Edwards MJ. Mediastinoscopy in patients with presumptive stage I sarcoidosis: a risk/benefit, cost/benefit analysis. Chest 1998;113:147-53

4. Johnston RN. Pulmonary sarcoidosis after ten to twenty years. Scott Med J 1986; 31(2):72-78

5. Reich JM. Mortality of intrathoracic sarcoidosis in referral vs. population-based settings: influence of stage, ethnicity, and corticosteroid therapy. Chest 2002;121:32-39

6. Gibson GJ, Prescott RJ, Muers MF et al. British Thoracic Society sarcoidosis study: effects of long term corticosteroid treatment. Thorax 1996; 51:238-47

7. Paramothayan S, Jones PW. Corticosteroid therapy in pulmonary sarcoidosis: a systematic review. JAMA 2002; 287(10):1301-1307

8. Reich JM. Adverse long-term effect of corticosteroid therapy in recent-onset sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2003; 20(3):227-234

9. Hunninghake GW, Costabel U, Ando M, et al. ATS, ERS, WASOG. Statement on sarcoidosis. Am J Respir Crit Care Med 1999;160:736-55

10. Wells AU, Hirani N. Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. Thorax 2008; 63(Supp V):V1-V58

11. Swigris JJ, Olson AL, Hule TJ, Fernandez-Perez ER, Solomon J, Sprunger D, Brown KK. Sarcoidosis mortality in the United States 1988-2007. Am J Respir Crit Care Med 2011;183:1524-1530

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