Blau Syndrome

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Disease Entity

Blau syndrome is a hereditary autoinflammatory disease that was first described in 1985 by Edward Blau.[1] It classically presents in childhood with the triad of granulomatous dermatitis, arthritis, and uveitis.

Etiology

Mutations in the nucleotide binding oligomerization domain containing protein 2 (NOD2) gene, housed on chromosome 16q12, have been implicated in Blau syndrome.[2] The two predominant genetic aberrations are missense mutations affecting codon 334, where arginine is replaced with tryptophan (R334W) or glutamine (R334Q).[3] This condition is typically inherited in an autosomal dominant fashion; however, sporadic mutations have been documented in patients with no previous family history of Blau syndrome.[4] In such cases, the disease may be referred to as early-onset sarcoidosis.

Epidemiology: Blau syndrome is a very rare disease. Its exact incidence and prevalence remain unknown, but available data suggests a prevalence of less than one in one million.[5] The majority of cases have been reported in Caucasians, but an increasing number of reports have emerged in other demographics.[6] There does not seem to be a gender predilection.

Pathophysiology

The NOD2 gene, formerly known as caspase recruitment domain family member 15 (CARD15), encodes the NOD2 protein, an intracellular pattern recognition receptor that is integral to innate immunity. NOD2 is primarily found in antigen-presenting cells and, under normal circumstances, facilitates an inflammatory response upon interaction with certain bacterial components.[3] This is achieved via downstream activation of nuclear factor-kappa B (NF-κB), which subsequently translocates to the cell nucleus to induce transcription of proinflammatory genes.[7] In patients with Blau syndrome, gain-of-function mutations in NOD2 lead to overactivation of NF-κB, resulting in systemic inflammation despite the absence of bacterial triggers.

Primary prevention

While there are currently no preventative measures available, genetic counseling is beneficial for families with a known history of Blau syndrome. This can assist with family planning and help avoid delays in diagnosis of affected children, enabling prompt intervention to mitigate complications of the disease.

Diagnosis

Signs and Symptoms: While a skin rash is not necessarily a ubiquitous feature of Blau syndrome, it is often the first sign of disease if it is present. In many cases, a generalized rash appears within the first year of life and manifests as discrete, erythematous papules.[8] In later stages, the dermatological findings are more variable than those seen early in the disease course; the rash may maintain its initial appearance, or the lesions may darken, coalesce, and assume a scaly texture.[9][10] Cutaneous eruptions can occur intermittently, sometimes leaving the patient with pitted scars upon resolution.[11]

           The most common feature, arthritis, tends to arise between the ages of 2 to 4 years.[8] It is typically polyarticular and symmetric, and synovial inflammation may cause the dorsal aspects of the wrist or ankle joints to appear boggy or exuberant.[12] Another characteristic finding is camptodactyly,[6] which refers to flexion contractures at the proximal interphalangeal joints of the fingers. While visually striking and capable of restricting movement, these deformities are not typically painful. Involvement of the axial skeleton is rare, as inflammation tends to be confined to more distal joints.

           Ocular involvement is almost always bilateral, and patients may present with eye pain, blurred vision, eye redness, or photophobia. On average, this feature arises slightly later than skin or joint manifestations.[13] Anterior uveitis is often observed, but the majority of patients with eye involvement actually develop panuveitis, which seemingly correlates with the duration of eye disease.[14] Recurrent inflammation leads to steady reductions in visual acuity and increases the risk of complications that further threaten sight, such as cataracts or glaucoma.[13][14]

           Beyond the classic clinical triad are a myriad of features that have been seen with variable frequency. Consistent with the autoinflammatory etiology of Blau syndrome, intermittent fevers are frequently reported.[15] Less commonly, patients may develop symptoms that reflect granulomatous infiltration of visceral organs or vasculature. Hepatomegaly, interstitial lung disease, and nephritis are examples of the former, whereas systemic hypertension, pulmonary hypertension, and large vessel vasculitis represent the latter.[15]  

History

Blau syndrome typically presents within the first decade of life with some combination of cutaneous, articular, or ocular symptoms. Given its rarity and the fact that features of the classic triad tend to arise non-simultaneously, diagnosis can be quite elusive. There is considerable overlap with several other conditions that cause similar symptoms, so it is not uncommon for an initial, isolated rash or joint pain to be misdiagnosed. If available, a positive family history is an invaluable clue that can add helpful context to the clinical picture. Once suspected, the diagnosis may be supported with biopsy demonstrating noncaseating granulomas, as well as a genetic test identifying a causative NOD2 mutation.

Physical examination

Possible ophthalmological findings:[13][14][15]

·       Decreased visual acuity

·       Conjunctival injection

·       Granulomatous uveitis (anterior, intermediate, posterior, or panuveitis)

·       Anterior chamber cells

·       Aqueous flare

·       Busacca nodules

·       Nummular corneal opacities

·       Mutton fat keratic precipitates

·       Band keratopathy

·       Posterior synechiae

·       Cataracts

·       Optic disc pallor

·       Optic disc edema

·       Peripapillary nodules

·       Macular edema

·       Retinal vascular sheathing

·       Multifocal choroiditis

·       Retinal detachment

·       Elevated intraocular pressure (IOP)

Possible dermatological findings:[15]

·       Discrete millimetric papules

·       Tan-colored, scaling rash

·       Ichthyosiform rash

·       Lichenoid (flat-topped) lesions

·       Erythema nodosum

·       Leukocytoclastic vasculitis

·       Firm subcutaneous nodules

·       Pitted scars

Possible rheumatological findings:[15]

·       Non-tender, exuberant joint swelling

·       Flexion contractures of proximal interphalangeal joints (camptodactyly)

·       Hypertrophic tenosynovitis

·       Synovial cysts

·       Reduced range-of-motion

Diagnostic procedures

·       Optical coherence tomography (OCT) may be utilized to characterize the extent of ocular disease.

·       Skin or synovial biopsy may be obtained, which will reveal noncaseating granulomas. Of these two options, skin biopsy is less invasive and has demonstrated higher accuracy.[12]

·       Next generation sequencing may be performed to test for causative NOD2 mutations, which will confirm the diagnosis.

Laboratory tests

Other etiologies of dermatitis, arthritis, uveitis, recurrent fever, and granulomatous disease should be excluded. Depending upon patient history and physical examination, consider the following studies:

·      Complete blood count (CBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum angiotensin-converting enzyme (ACE), antinuclear antibody (ANA), anti-neutrophilic cytoplasmic antibody (ANCA), rheumatoid factor (RF), anti-dsDNA antibody, Lyme disease serology, RPR/VDRL, human leukocyte antigen (HLA) testing, tuberculin skin test, pathergy skin test

Differential diagnosis

Juvenile idiopathic arthritis, Yao syndrome, sarcoidosis (juvenile and adult forms), rheumatoid arthritis, systemic lupus erythematosus, vasculitis, tuberculosis, Lyme disease, syphilis, reactive arthritis, Behcet’s disease

Medical therapy

There are no formal guidelines for the treatment of Blau syndrome, but management involves a multidisciplinary effort to maintain quality of life and prevent long-term complications. Symptomatic relief during acute flares may be achieved with the use of nonsteroidal anti-inflammatory drugs or high-dose corticosteroids.[13] Importantly, only the latter are capable of slowing disease progression. Corticosteroids also have utility during quiescent periods, albeit at lower doses. The prolonged need for corticosteroids, coupled with the frequency of refractory symptoms, often necessitates the use of immunosuppressants such as methotrexate, mycophenolate mofetil, or azathioprine.

Some evidence has demonstrated that in patients with Blau syndrome, serum levels of tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) are higher than those seen in healthy controls.[16] For this reason, the use of monoclonal antibodies to target these cytokines has become a point of interest; however, varying degrees of efficacy have been reported in the literature.[13][17][18] Due to conflicting results and the relatively sparse amount of data available, it is difficult to ascertain the true therapeutic benefit of these agents.

Surgery

Although medical management is the cornerstone of treatment for patients with Blau syndrome, operative intervention is warranted in certain scenarios. With regard to ocular disease, some inflammatory sequelae (e.g., cataracts) should be addressed surgically. With regard to rheumatological disease, patients may opt to undergo joint fusion procedures due to severe, unrelenting arthritis.

Complications and Prognosis

Due to the propensity to impair vision and potentially cause blindness, ocular manifestations of Blau syndrome pose the greatest threat to quality of life. In a cohort of patients described by Rosé et al., complications of uveitis with anterior segment involvement included cataracts in 55% of patients, elevated IOP in 36%, and band keratopathy in 23%. Involvement of the posterior segment resulted in optic atrophy in 14%, macular edema in 14%, and retinal detachment in 9% of patients.[15]

           Chronic joint inflammation and resultant deformities also predispose patients to a decline in daily functioning and general well-being. When assessed using a Health Assessment Questionnaire (HAQ) or Childhood Health Assessment Questionnaire (CHAQ), 59% of patients with Blau syndrome reported some degree of impairment in functional capacity. Roughly half of these patients attested to a negative impact on their global well-being, as well.[15]

References

1.    Blau EB. Familial granulomatous arthritis, iritis, and rash. J Pediatr. 1985 Nov;107(5):689-93. doi: 10.1016/s0022-3476(85)80394-2.

2.    Miceli-Richard C, Lesage S, Rybojad M, et al. CARD15 mutations in Blau syndrome. Nat Genet. 2001 Sep;29(1):19-20. doi: 10.1038/ng720.

3.    Caso F, Costa L, Rigante D, et al. Caveats and truths in genetic, clinical, autoimmune and autoinflammatory issues in Blau syndrome and early onset sarcoidosis. Autoimmun Rev. 2014 Dec;13(12):1220-9. doi: 10.1016/j.autrev.2014.08.010.

4.    Matsuda T, Kambe N, Ueki Y, et al. Clinical characteristics and treatment of 50 cases of Blau syndrome in Japan confirmed by genetic analysis of the NOD2 mutation. Ann Rheum Dis. 2020 Nov;79(11):1492-1499. doi: 10.1136/annrheumdis-2020-217320.

5.    Yi Yong C, Mukhtyar C, Armon K. Blau syndrome treated with sequential biologics. Rheumatol Adv Pract. 2018;2(Suppl 1):rky034.028. doi:10.1093/rap/rky034.028

6.    Sfriso P, Caso F, Tognon S, et al. Blau syndrome, clinical and genetic aspects. Autoimmun Rev. 2012 Nov;12(1):44-51. doi: 10.1016/j.autrev.2012.07.028.

7.    Negroni A, Pierdomenico M, Cucchiara S, Stronati L. NOD2 and inflammation: current insights. J Inflamm Res. 2018;11:49-60. doi:10.2147/JIR.S137606.

8.     Caso F, Galozzi P, Costa L, et al. Autoinflammatory granulomatous diseases: from Blau syndrome and early-onset sarcoidosis to NOD2-mediated disease and Crohn's disease. RMD Open 2015;1:e000097. doi: 10.1136/rmdopen-2015-000097.

9.    Poline J, Fogel O, Pajot C, et al. Early-onset granulomatous arthritis, uveitis and skin rash: characterization of skin involvement in Blau syndrome. J Eur Acad Dermatol Venereol. 2020 Feb;34(2):340-348. doi: 10.1111/jdv.15963.

10.  Schaffer JV, Chandra P, Keegan BR, Heller P, Shin HT. Widespread Granulomatous Dermatitis of Infancy: An Early Sign of Blau Syndrome. Arch Dermatol. 2007;143(3):386–391. doi:10.1001/archderm.143.3.386

11.  Rosé CD, Wouters CH, Meiorin S, et al. Pediatric granulomatous arthritis: an international registry. Arthritis Rheum. 2006 Oct;54(10):3337-44. doi: 10.1002/art.22122.

12.  Kuye IO, Adisa M, Nazarian RM, Arvikar SL, Smith GP. Granulomatous skin involvement in a patient with an unusual NOD2 mutation. Australas J Dermatol. 2017 May;58(2):142-144. doi: 10.1111/ajd.12441.

13.  Suresh S, Tsui E. Ocular manifestations of Blau syndrome. Curr Opin Ophthalmol. 2020 Nov;31(6):532-537. doi: 10.1097/ICU.0000000000000705.

14.  Sarens IL, Casteels I, Anton J, et al. Blau syndrome-associated uveitis: preliminary results from an international prospective interventional case series. Am J Ophthalmol. 2018 Mar;187:158-166. doi: 10.1016/j.ajo.2017.08.017.

15.  Rosé CD, Pans S, Casteels I, et al. Blau syndrome: cross-sectional data from a multicentre study of clinical, radiological and functional outcomes, Rheumatology, Volume 54, Issue 6, June 2015, Pages 1008 1016, https://doi.org/10.1093/rheumatology/keu437

16.  Aróstegui JI, Arnal C, Merino R, et al. NOD2 gene-associated pediatric granulomatous arthritis: clinical diversity, novel and recurrent mutations, and evidence of clinical improvement with interleukin-1 blockade in a Spanish cohort. Arthritis Rheum. 2007 Nov;56(11):3805-13. doi: 10.1002/art.22966.

17.  Vitale A, Rigante D, Lucherini OM, et al. Biological treatments: new weapons in the management of monogenic autoinflammatory disorders. Mediators Inflamm. 2013;2013:939847. doi: 10.1155/2013/939847.

18.  Nagakura T, Wakiguchi H, Kubota T, et al. Tumor necrosis factor inhibitors provide longterm clinical benefits in pediatric and young adult patients with Blau syndrome. J Rheumatol. 2017 Apr;44(4):536-538. doi: 10.3899/jrheum.160672.

19.  Wouters CH, Maes A, Foley KP, Bertin J, Rose CD. Blau syndrome, the prototypic auto-inflammatory granulomatous disease. Pediatr Rheumatol Online J. 2014 Aug 6;12:33. doi: 10.1186/1546-0096-12-33.