Monogenic disorders causing systemic lupus erythematosus represent a small subset of cases. Type-1 interferonopathies, like spondyloenchondrodysplasia with immune dysregulation constitute an important functional category of monogenic lupus. Apart from autoimmune disorders, neurological and skeletal abnormalities are additional manifestations observed in this disorder. A young female presented with seizures due to acute hemorrhagic stroke secondary to malignant hypertension. On evaluating the cause for hypertension, there was evidence of glomerulonephritis and multiple autoantibodies positivity including dsDNA. A diagnosis of lupus was made based on clinical and laboratory findings. Kidney biopsy revealed mesangial proliferative glomerulonephritis with predominant IgA deposits favouring IgA nephropathy. Additional features in the form of short stature with vertebral abnormalities and bilateral basal ganglia calcification led to evaluation of Type-1 interferonopathies. Sanger sequencing identified a novel compound heterozygous variants c.550C>T (p.Q184*) in exon 3 and c.740T>G (p.L247R) in exon 4 of ACP5 gene. Parents were found to be carriers of the variants in ACP5 gene. Management included antihypertensive agents and symptomatic therapy. On follow-up, there was complete resolution of glomerulonephritis and normalization of blood pressure. This case report documents the classic phenotype comprising autoimmune, skeletal, and neurological abnormalities in spondyloenchondrodysplasia with immune dysregulation with a novel variant on Sanger sequencing in an Indian patient. This report also highlights the rare coexistence of IgA nephropathy in monogenic lupus.

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BackgroundMethotrexate (MTX) is the first-line therapy for rheumatoid arthritis (RA), but nearly 30% of RA patients do not respond to it. Methotrexate acts by enhancing the level of adenosine, which gets converted to inosine by the enzyme adenosine deaminase (ADA). We studied whether ADA gene polymorphism and serum levels of total ADA are associated with responsiveness to MTX.MethodsTwo hundred seven disease-modifying antirheumatic drug–naive active RA patients (DAS28-ESR [Disease Activity Score–28 for rheumatoid arthritis with erythrocyte sedimentation rate] ≥3.2) satisfying the European League Against Rheumatism (EULAR)/American College of Rheumatology 2010 criteria were enrolled. Genotyping was done in all patients, and in a subset (n = 59), blood was collected at baseline and at 2 months of MTX treatment for serum total ADA estimation by ELISA. Response at 4 months was assessed by EULAR criteria, and patients were classified as responders or nonresponders. The correlation of baseline clinical parameters, ADA gene polymorphism, and serum total ADA levels with EULAR response was sought.ResultsAfter 4 months of MTX monotherapy, 172 patients (83.1%) were classified as responders and 35 (16.9%) as nonresponders. Except DAS28-ESR (6.1 [5.43–6.84] in responders vs 5.6 [4.77–6.21] in nonresponders, p = 0.02), other baseline parameters (age, disease duration, ESR, and C-reactive protein level) were similar between responders and nonresponders. Single nucleotide polymorphisms in ADA gene, baseline serum ADA levels (10.52 ± 5.37 ng/mL in responders vs 12.28 ± 5.14 ng/mL in nonresponders), or change in ADA levels after 2 months of MTX therapy did not show any association with MTX response (p = 0.73, p = 0.34, p = 0.55, respectively). Adenosine deaminase genotype did not affect the blood ADA level.ConclusionsNo association was seen between ADA single nucleotide polymorphism rs244076 as well as serum ADA level and response to MTX therapy.

Background Despite methotrexate (MTX) being the first line therapy for RA,30% of patients do not respond to MTX. Methotrexate acts by increasing adenosine levels which lead to anti-inflammatory effects. Adenosine deaminase (ADA) enzyme converts adenosine to inosine thus reduces levels of adenosine. Thus, ADA levels and single nucleotide polymorphism (SNP) in ADA gene may affect the treatment effect of MTX. Our objective was to study if genetic polymorphism in ADA gene and baseline serum ADA levels in patients with RA is associated with methotrexate response. Methods 207 DMARD naïve active RA (DAS28 ESR ≥3.2) patients satisfying EULAR/ACR 2010 criteria were enrolled. Genotyping was done in all patients (n = 207) by TaqMan 5' nuclease assay. In a subset of patients(n = 59) blood sample was collected at baseline and 2 months for ADA estimation by ELISA. Ethical approval and written informed consent was taken. Oral MTX was initiated at dose of 15mg/week, escalated 5mg every month till the patients had DAS28 < 2.6 or a maximum dose of 25 mg/week was reached. At 4 months based on EULAR response patients were classified as responders or non-responders. Using a Chi-squared test, SNPs were associated with response to methotrexate therapy. Baseline clinical parameters and serum ADA levels were correlated with EULAR response. Results Among 207 patients (177females) mean age was 41.49± 12.14 years and median disease duration 24 (40) months.172 patients (83.1%) were responders and 35 (16.9%) non-responders. 197 (95.16%) patients were seropositive (RF and/or ACCP+). With regard to SNP in ADA gene,47.8% were AA,42.5% AG and 9.7% were GG genotype. Mean DAS 28 CRP was 4.76 ± 1.05 and median DAS 28 ESR was 6.00 (1.38). Mean serum baseline ADA was 10.82 ±5.33 pg/dl. Except DAS28ESR (p = 0.02), other baseline parameters like age, disease duration, ESR, CRP, DAS 28 CRP were similar between responders and non-responders. SNPs in ADA gene were not associated with EULAR response (p = 0.475). Baseline ADA levels (10.52 ± 5.37 vs 12.28 ± 5.14; p = 0.34) 2 month ADA levels (p = 0.34) and change in ADA level from baseline at 2 months, i.e. delta ADA (p = 0.55) did not show any association with MTX response. Mean ADA level was similar between the 3 genotypes of ADA(p = 0.736) Comparison of parameters between methotrexate responders and non-responders Conclusion ADA gene polymorphism and serum ADA levels do not affect response to methotrexate. Disclosures H. Gangadharan Nair: Grants/research support; Indian Rheumatology Association Research grant. A. Singh: None. S. Majumder None. A. Aggarwal None.