26th February 2025

Other rare autoinflammatory disorders

Behçet’s syndrome

This is a rare autoinflammatory disorder characterised by oral and genital ulcers and increased thrombotic risk. It is more common in males of Middle Eastern origin and is associated with HLA B51. The diagnosis is clinical as there is no clear diagnostic test, although a positive pathergy test is suggestive (insertion of a needle causes formation of a papule or pustule at the insertion site).

Clinical features include:

• Oral ulcers are often the first sign of disease. These are generally painful and may prevent eating.
• Genital ulcers are the most specific feature of Behçet’s, particularly if they heal with scarring, as few other conditions do this. They are most commonly found on the scrotum in men and vulva in women.
• There can be a wide range of thrombotic manifestations, from DVT to cerebral venous sinus thrombosis. Pulmonary artery aneurysms are relatively common and are rarely seen in other conditions.
• Up to 75% of patients have skin involvement, which varies from an acneiform rash to erythema nodosum.
• Uveitis is relatively common and can be the presenting feature.
• Gastrointestinal involvement mimicking IBD can be seen due to bowel ulceration.

Management depends on the specific organ involved. Oral and genital ulcers can be treated with topical steroids or oral colchicine. If this is not sufficient, DMARDs such as azathioprine and anti-TNF alpha agents such as infliximab can be used.

Relapsing polychondritis

This is a rare autoinflammatory disorder which causes immune-mediated destruction of cartilage.

Clinical features include:

• Auricular cartilage is the most commonly affected, followed by nasal cartilage.
• Episcleritis and anterior scleritis commonly co-exist.
• Seronegative asymmetric polyarthritis affecting the small joints is a common presenting symptom.
• Laryngotracheal cartilage is affected in up to 50% and can present with cough, hoarseness or stridor. Other respiratory manifestations include recurrent lower respiratory tract infections.
• Cardiac involvement is the second most common cause of mortality after respiratory causes. Aortic regurgitation secondary to aortic root dilatation is the most common cardiac feature.
• Other systems, such as the kidneys, GI tract, and CNS can be involved, but this is rarer.

Treatment varies widely, from NSAIDs and colchicine to biologics such as anti-TNF agents, depending on severity.

Familial Mediterranean fever (FMF)

This is an autosomal recessive disease caused by a mutation in the MEFV gene, which encodes the pyrin protein. Diagnosis is by genetic testing.

It is most common in Mediterranean populations. Onset is generally in childhood, with 90% of patients experiencing an attack before the age of 20.

Episodes of fever and serositis characterise the disease. These can occur at a varying frequency and generally last up to 72 hours. Symptoms will depend on the site of inflammation; for example, abdominal pain mimicking an acute abdomen can occur with peritonitis and chest pain can be caused by pericarditis or pleuritis. Arthritis is also a common symptom. This is generally monoarticular, affecting the large joints.

Treatment is with oral colchicine. This helps to prevent flares and decrease the risk of the development of complications such as amyloidosis. IL-1 inhibitors such as anakinra and canakinumab are starting to be used in colchicine-refractory cases.

Adult-onset Still’s disease (AOSD)

AOSD is the term for systemic juvenile idiopathic arthritis when seen in a patient over 16 years old.

It typically presents with daily fevers, a salmon-coloured maculopapular rash and arthritis. The rash is usually non-pruritic and flares with episodes of fever. Joint involvement can initially be in an oligoarticular pattern but progresses to a more severe polyarthritis. Sore throat, lymphadenopathy and splenomegaly may also be found.

There is no definitive diagnostic test. ESR and CRP are markedly raised, and there is a neutrophilic leucocytosis. Elevated ferritin is very common and likely represents an acute phase response. Typically, antibodies are negative.

Mild-to-moderate disease is treated with NSAIDs once other causes are excluded. If patients do not respond to NSAIDs, either glucocorticoids or biologic therapy are initiated. Biologic therapy is usually with IL-1 inhibitors such as anakinra or canakinumab.

IgG4-related disease

This is a heterogeneous disease characterised by inflammation and fibrosis. Many of the subtypes were considered separate entities until it became clear that lesions shared histological findings of abundant IgG4-positive plasma cells.

Patients are usually constitutionally well; fever or elevated CRP suggest another disease process. There can be single or multi-organ involvement at diagnosis, and disease progression is variable.

There are four different phenotypes that have been recognised recently:

• Pancreatobiliary: diabetes, exocrine insufficiency, sclerosing cholangitis and autoimmune pancreatitis.
• Head and neck limited: orbital involvement, sinusitis, thyroiditis, cranial nerve palsies and hearing loss. This tends to affect younger women of Asian origin.
• Retroperitoneal: sequelae of retroperitoneal fibrosis, including hydronephrosis, aortitis, and compression of various structures.
• Mikulicz’s (systemic): enlargement of the lacrimal and salivary glands with xerostomia and xerophthalmia, with any of the other features previously described.

Treatment is generally with glucocorticoids, then biologic agents such as rituximab to maintain remission.

Amyloidosis

Amyloidosis encompasses a group of multisystemic diseases caused by abnormal protein folding and deposition in tissues, known as amyloid deposits. These accumulate faster than they can be cleared away and, therefore, build up within organs and tissues, interfering with structure and function. Multiple different proteins can be involved, and the clinical presentation can differ depending on the subtype.

Subtypes of amyloidosis

Classification is based on the precursor protein:

Table 8 Clinical features and associations of amyloidosis subtypes

There are also other genetic forms of amyloidosis which will not be discussed here.

Diagnosis and management of amyloidosis

Histological confirmation is required to establish a diagnosis. With Congo red stain, the sample appears red under normal light and apple green under polarised light microscopy.

Management is tailored toward the clinical manifestations and treating the underlying causative disorder.

References

• Yazici H, Seyahi E, Hatemi G, Yazici Y. Behçet syndrome: a contemporary view. Nature Reviews Rheumatology. 2018 Jan 3;14(2):107–19
• Clunie GPR, Wilkinson N, Nikiphorou E, Deepak Jadon. Oxford handbook of rheumatology. Oxford: Oxford University Press; 2018
• Lanzillotta M, Mancuso G, Della-Torre E. Advances in the diagnosis and management of IgG4 related disease. BMJ. 2020 Jun 16;369:m1067
• Stone JH, Zen Y, Deshpande V. IgG4-Related Disease. New England Journal of Medicine. 2012 Feb 9;366(6):539–51
• Alghamdi M. Familial Mediterranean fever, review of the literature. Clinical Rheumatology. 2017 Jun 18;36(8):1707–13
• Kingdon J, Roscamp J, Sangle S, D’Cruz D. Relapsing polychondritis: a clinical review for rheumatologists [Internet]. Academic.oup.com. 2017 Nov 6 [cited 2022 Feb 24];57(9):1525–32. Available from: https://academic.oup.com/rheumatology/article/57/9/1525/4596655
• Mandl LA. Clinical Manifestations and Diagnosis of Adult-Onset Still’s Disease [Internet]. O’Dell JR, editor. UpToDate. 2022 [cited 2022 Mar 1]. Available from: https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-adult-onset-stills-disease
• Khan MF. Amyloidosis. Postgraduate Medical Journal [Internet]. 2001 Nov 1 [cited 2022 Mar 1];77(913):686–93. Available from: https://pmj.bmj.com/content/77/913/686
• Smith EL. Clinical manifestations and diagnosis of Behçet syndrome. [Internet]. Merkel PA, Ramirez Curtis M, editors. UpToDate. 2022 [cited 2022 Mar 2]. Available from: https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-behcet-syndrome