Brief report: genotype, phenotype, and clinical course in five patients with PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne)

Abstract

Objective: To describe the genotypes, phenotypes, immunophenotypes, and treatments of PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne), a rare autoinflammatory disease, in 5 patients.

Methods: Clinical information was gathered from medical records and through interviews with 5 patients from 4 kindreds. PSTPIP1 (CD2BP1) exon 10 and exon 11 sequencing was performed in each patient. Neutrophil granule content and cytokine levels were determined in plasma and stimulated peripheral blood mononuclear cells (PBMCs) from patients and controls.

Results: We identified 2 previously described PAPA syndrome-associated PSTPIP1 mutations, A230T and E250Q, and a novel change, E250K. Disease penetrance was incomplete, with variable expressivity. The cutaneous manifestations included pathergy, cystic acne, and pyoderma gangrenosum. Interleukin-1β (IL-1β) and circulating neutrophil granule enzyme levels were markedly elevated in patients compared to those in controls. PBMC stimulation studies demonstrated impaired production of IL-10 and enhanced production of granulocyte-macrophage colony-stimulating factor. Good resolution of pyoderma gangrenosum was achieved in 3 patients with tumor necrosis factor α (TNFα) blockade treatment.

Conclusion: This analysis of 5 patients demonstrates that mutations in PSTPIP1 are incompletely penetrant and variably expressed in the PAPA syndrome. Neutrophil granule proteins are markedly elevated ex vivo and in the plasma, and elevated levels might be compatible with a diagnosis of PAPA syndrome. TNFα blockade appears to be effective in treating the cutaneous manifestations of PAPA syndrome.

Figure 1

A, Pedigree of the family of Patients 3 and 4. Black symbols = positive for a mutation; white symbols = negative for a mutation. B, Pyoderma gangrenosum of the right forearm in Patient 3 before treatment (a) and after 15-month treatment with adalimumab (b).

Figure 2

Plasma levels of neutrophil granule enzymes and acute phase reactants in patients with PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) and control subjects. Data from 59 control subjects are shown as box plots. Each box represents the 25th and 75th percentiles, and lines inside the boxes represent the median. Whiskers represent the minimum and maximum values. Circles represent values in patients 1, 2, and 5. Samples were drawn once for each control subject and each patient. Levels of all analytes were significantly elevated in the patients. CRP = C-reactive protein; LBP = lipopolysaccharide binding protein; MMP-9 = matrix metalloproteinase 9 (neutrophil gelatinase); MPO = myeloperoxidase; HNP = human neutrophil α-defensins. *** = P < 0.005.