NLRP1-associated autoinflammation with arthritis and dyskeratosis M08.3

Grandemange S et al (2016)

NLRP1-associated autoinflammation with arthritis and dyskeratosis syndrome (NAIAD) is a very rare (<10 patients are known with the first description in 2016) monogenic autoinflammatory disease characterized by skin lesions (urticarial exanthema (?), verrucous lesions of the skin), arthritis, recurrent fever of 3-4 days and increased acute phase reactants. This disease was first reported in 2016.

Childhood and adolescence

The disease is characterized by diffuse hyperkeratotic skin changes, signs of autoinflammation and autoimmunity with urticarial exanthema and painful arthritides. One patient was diagnosed with severely impaired left ventricular function with complete left bundle branch block during an exacerbation of the disease (Garrelfs MR et al. 2019). The cardiac dysfunction proved to be rapidly reversible after the administration of high-dose methylprednisolone.

Molecular screening can be used to detect homozygous and heterozygous mutations in NLRP1 (c.2176C > T; p.Arg726Trp/ c.3641C > G, p.Pro1214Arg). The patients diagnosed to date showed elevated systemic levels of caspase-1 and interleukin 18, suggesting involvement of the NLRP1 inflammasome. Cytokine profiling shows elevated levels of IL6, IL10 and IL18.

Symptomatic. Corticosteroids, acitretin, etanercept or anakinra.

Inflammasomes are multiprotein complexes that recognize pathogens and trigger biological mechanisms for infection control. The nucleotide-binding oligomerization domain-like receptor (NLR), which contains a PYRIN domain 1 (NLRP1), NLRP3 and NLRC4, plays a key role in this innate immune system by assembling directly in inflammasomes and regulating inflammation. Mutations in NLRP3 and NLRC4 are associated with inherited autoinflammatory diseases, while polymorphisms or mutations in NLRP1 are associated with autoimmune diseases such as vitiligo, rheumatoid arthritis and familial keratosis lichenoides chronica.

A 22-year-old woman, first child of unrelated healthy parents, with a 17-year-old healthy younger sister presented with episodic fever with abdominal pain that persisted over a 6-year period. The fever recurred every month and persisted for a week. Painful lower abdominal pain accompanied the fever episodes, which lasted about 6 hours per day, with no other gastrointestinal symptoms.

During the first three years, the patient suffered from recurrent generalized urticaria, and for the last 8 months she had been suffering from polyarthritis of the small and large joints of the upper and lower extremities. Under therapy with corticosteroids, hydroxychloroquine 200 mg/day and methotrexate 15 mg/week, the arthritic symptoms improved. Results: We identified a novel disease in three patients from two unrelated families with diffuse skin dyskeratosis, autoinflammation, autoimmunity, arthritis and a high proportion of B-cells in the junction. Another patient was reported who was diagnosed with severely impaired left ventricular function with complete left bundle branch block during an exacerbation of the disease (Garrelfs MR et al. 2019). The cardiac dysfunction proved to be rapidly reversible after the administration of high-dose methylprednisolone.

The laboratory tests revealed increased acute phase reactions (erythrocyte sedimentation rate [ESR]: 105 mm/h, C-reactive protein [CRP]: 12 mg/L). Serum aspartate aminotransferase and serum alanine aminotransferase were elevated by 1.5 and 2 times the upper normal limit, respectively. Creatine phosphokinase was normal, antinuclear antibodies (ANA), rheumatoid factor and anti-cyclic citrullinated peptide antibodies were absent. (Sureja NP et al. (2022

1. Grandemange S et al. (2016) A new autoinflammatory and autoimmune syndrome associated with NLRP1 mutations: NAIAD (NLRP1-associated autoinflammation with arthritis and dyskeratosis). Ann Rheum Dis 76:1191-1198.
2. Garrelfs MR et al. (2019) Transient left bundle branch block and left ventricular dysfunction in a patient with NLRP1-associated autoinflammation with arthritis and dyskeratosis syndrome. Cardiol Young 29:435-438.
3. Harapas CR et al (2018) An Update on Autoinflammatory Diseases: Inflammasomopathies. Curr Rheumatol Rep 20:40.
4. Sureja NP et al. (2022) Autoinflammation with Arthritis and Dyskeratosis an Inflammasomopathy. Case Report and Review of Literature. Indian Journal of Rheumatology 17: 65-68