Löfgren's Syndrome

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Löfgren's syndrome is a subtype of acute sarcoidosis involving:[1] 

  • Hilar lymphadenopathy
  • Erythema nodosum
  • Joint symptoms
  • Fever

It is named after Swedish researcher, Sven Löfgren (1910-1978), who worked on sarcoidosis in the 1940s and 1950s.

Patients with Löfgren's syndrome generally have a good prognosis, are unlikely to develop chronic disease (sarcoidosis is considered chronic when symptoms last for more than three years) and most patients with Löfgren's can expect a self-limiting illness and spontaneous remission.[2] As with other forms of sarcoidosis, aetiology is unknown - the interaction of an unidentified environmental trigger and a genetically susceptible host is likely. 'A case-control etiologic study of sarcoidosis' (ACCESS) - a large US-based case-control study - failed to find any single environmental or occupational causative factor.[3][4]

What differentiates individuals who develop Löfgren's syndrome from other forms of sarcoidosis is also unclear: the effects of different polymorphisms in the the CR2 gene on chromosome 3 are being investigated, one particular haplotype of which appears to be associated with an increased risk of Löfgren's syndrome.[5][6]

  • Incidence varies widely around the world, with some populations (notably the Irish and Nordic people) more prone to developing Löfgren's syndrome.
  • In Europe and the USA, sarcoidosis initially presents with Löfgren's syndrome in 10% of patients.[7] 
  • A study in Catalonia suggested an incidence of 0.65 per 100,000 per annum. It is much rarer in other areas of the world, such as Japan.[8] 

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Risk factors

  • Strong female predominance.
  • Young to middle-age (mean age of onset - 35 years).
  • There is a strong association with human leukocyte antigen (HLA)-DRB1 alleles. The association with HLA-DRB1*03 is particularly striking and is a very strong marker for a good prognosis.[9][10] 
  • Seasonality - presentation is more common in spring months (northern hemisphere).[11] 

Symptoms

  • Arthralgia.
  • Cough or dyspnoea.
  • Fever or malaise.

Signs

  • Erythema nodosum.
  • Periarticular ankle inflammation/bilateral ankle arthritis.
  • Bilateral Achilles tendonitis (rare).[12]
  • Uveitis.

Presentation appears to differ between men and women, with a predominance of erythema nodosum amongst women and bilateral ankle arthritis in men.[13]

Löfgren's syndrome needs to be distinguished from other causes of:

Investigations indicating active sarcoidosis include:[1] 

  • CXR (abnormalities include mediastinal lymphadenopathy or pulmonary infiltration).
  • Gallium-67 scan may be used when CXR is normal; shows increased hilar or paratracheal uptake).
  • Lung function tests (decreased forced vital capacity).
  • Serum calcium level (may be elevated).
  • Serum angiotensin-converting enzyme (may be increased).
  • Lymph node biopsy.
Always remember to perform CXR in those presenting with periarticular ankle signs.

The ankle arthritis may best be demonstrated by MRI scan.[15]

  • Once Löfgren's syndrome can be confidently diagnosed, the patient can be reassured that the condition is benign and normally self-limiting.
  • Routine biopsy is not required to confirm the diagnosis unless there are atypical features.
  • Management is supportive - eg, non-steroidal anti-inflammatory drugs for arthralgia.
  • Prednisolone may be required for more severe cases.
  • Follow-up should continue until any hilar lymphadenopathy has resolved.

Prognosis is usually very good, typically resolving within one year. In a minority, disease remains active (8%) or relapses (6%), sometimes after a long period.[1] Good prognostic markers include:

  • Normal serum angiotensin-converting enzyme levels at diagnosis.
  • Particular HLA types - being HLA-DRB1*03 negative increases the risk of non-resolving disease.[16]

Further reading & references

  1. Byun CW, Yang SN, Yoon JS, et al; Lofgren's Syndrome-Acute Onset Sarcoidosis and Polyarthralgia: A Case Report. Ann Rehabil Med. 2013 Apr;37(2):295-9. doi: 10.5535/arm.2013.37.2.295. Epub 2013 Apr 30.
  2. Mana J, Marcoval J; Skin manifestations of sarcoidosis. Presse Med. 2012 Jun;41(6 Pt 2):e355-74. doi: 10.1016/j.lpm.2012.02.046. Epub 2012 May 9.
  3. Newman LS, Rose CS, Bresnitz EA, et al; A case control etiologic study of sarcoidosis: environmental and occupational risk factors. Am J Respir Crit Care Med. 2004 Dec 15;170(12):1324-30. Epub 2004 Sep 3.
  4. Rossman MD, Kreider ME; Lesson learned from ACCESS (A Case Controlled Etiologic Study of Sarcoidosis). Proc Am Thorac Soc. 2007 Aug 15;4(5):453-6.
  5. Spagnolo P, Renzoni EA, Wells AU, et al; C-C chemokine receptor 2 and sarcoidosis: association with Lofgren's syndrome. Am J Respir Crit Care Med. 2003 Nov 15;168(10):1162-6. Epub 2003 Jul 25.
  6. Valentonyte R, Hampe J, Croucher PJ, et al; Study of C-C chemokine receptor 2 alleles in sarcoidosis, with emphasis on family-based analysis. Am J Respir Crit Care Med. 2005 May 15;171(10):1136-41. Epub 2005 Mar 4.
  7. Kobak S, Yalcin M, Sever F, et al; Sarcoidosis Presenting as Lofgren's Syndrome with Myopathy. Case Rep Rheumatol. 2013;2013:125251. doi: 10.1155/2013/125251. Epub 2013 Apr 3.
  8. Ohta H, Tazawa R, Nakamura A, et al; Acute-onset sarcoidosis with erythema nodosum and polyarthralgia (Lofgren's syndrome) in Japan: a case report and a review of the literature. Intern Med. 2006;45(9):659-62. Epub 2006 Jun 1.
  9. Grunewald J; HLA associations and Lofgren's syndrome. Expert Rev Clin Immunol. 2012 Jan;8(1):55-62. doi: 10.1586/eci.11.76.
  10. Darlington P, Gabrielsen A, Sorensson P, et al; HLA-alleles associated with increased risk for extra-pulmonary involvement in sarcoidosis. Tissue Antigens. 2014 Apr;83(4):267-72. doi: 10.1111/tan.12326.
  11. Sipahi Demirkok S, Basaranoglu M, Dervis E, et al; Analysis of 87 patients with Lofgren's syndrome and the pattern of seasonality of subacute sarcoidosis. Respirology. 2006 Jul;11(4):456-61.
  12. Ortiz V, Holgado S, Olive A, et al; Achilles tendinitis as the presentation form of Lofgren's syndrome. Clin Rheumatol. 2000;19(2):169-70.
  13. Grunewald J, Eklund A; Sex-specific manifestations of Lofgren's syndrome. Am J Respir Crit Care Med. 2007 Jan 1;175(1):40-4. Epub 2006 Oct 5.
  14. Kumar G, Kumar N; All red is not always bacterial cellulitis: a case of Lofgren's syndrome. WMJ. 2010 Feb;109(1):31-3.
  15. Anandacoomarasamy A, Peduto A, Howe G, et al; Magnetic resonance imaging in Lofgren's syndrome: demonstration of periarthritis. Clin Rheumatol. 2007 Apr;26(4):572-5. Epub 2006 Aug 2.
  16. Grunewald J, Eklund A; Lofgren's syndrome: human leukocyte antigen strongly influences the disease Am J Respir Crit Care Med. 2009 Feb 15;179(4):307-12. Epub 2008 Nov 7.

Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical conditions. EMIS has used all reasonable care in compiling the information but make no warranty as to its accuracy. Consult a doctor or other health care professional for diagnosis and treatment of medical conditions. For details see our conditions.

Original Author:
Dr Chloe
Current Version:
Peer Reviewer:
Prof Cathy Jackson
Document ID:
2396 (v22)
Last Checked:
24/11/2014
Next Review:
23/11/2019