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- Hilar lymphadenopathy
- Erythema nodosum
- Joint symptoms
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. 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.
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.
- 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.
- 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.
- 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.
- Seasonality - presentation is more common in spring months (northern hemisphere).
- Cough or dyspnoea.
- Fever or malaise.
- Erythema nodosum.
- Periarticular ankle inflammation/bilateral ankle arthritis.
- Bilateral Achilles tendonitis (rare).
Presentation appears to differ between men and women, with a predominance of erythema nodosum amongst women and bilateral ankle arthritis in men.
Löfgren's syndrome needs to be distinguished from other causes of:
- Erythema nodosum - eg, infection (Streptococcus spp., tuberculosis (TB), mycoplasma); drugs, inflammatory bowel disease, non-Hodgkin's lymphoma, Behçet's disease.
- Hilar lymphadenopathy - lymphoma, TB and lung cancer need to be excluded, particularly where lymphadenopathy is not symmetrical.
- Pyrexia of unknown origin.
Investigations indicating active sarcoidosis include:
- 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.
The ankle arthritis may best be demonstrated by MRI scan.
- 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. 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.
Further reading & references
- Judson MA; The management of sarcoidosis by the primary care physician. Am J Med. 2007 May;120(5):403-7.
- Turchin I, Nguyen K, Menard HA; Cough, fever, joint pain and tender nodules: what is your call? CMAJ. 2008 Jan 15;178(2):151-2.
- Sven Halvar Löfgren; whonamedit.com
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Grunewald J; HLA associations and Lofgren's syndrome. Expert Rev Clin Immunol. 2012 Jan;8(1):55-62. doi: 10.1586/eci.11.76.
- 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.
- 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.
- 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.
- 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.
- Kumar G, Kumar N; All red is not always bacterial cellulitis: a case of Lofgren's syndrome. WMJ. 2010 Feb;109(1):31-3.
- 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.
- 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.
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Dr Colin Tidy
Prof Cathy Jackson