Ellen Cahill, BA1; Sepideh Tara Rousta, MD2; Dalya Chefitz, MD3; Kristen J. Bryant, MSN, CPNP-AC4; Lakshmi Nandini Moorthy, MD, MPH5
1Rutgers Robert Wood Johnson Medical School, Piscataway, NJ
2Division of Pediatric Ophthalmology, Rutgers RobertWood Johnson Medical School, New Brunswick, NJ,Wills Eye Hospital, Philadelphia, PA
3Division of Hospital Medicine, Department of Pediatrics, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ
4The Bristol-Myers Squibb Children’s Hospital at RobertWood Johnson University Hospital, New Brunswick, NJ
5Division of Pediatric Rheumatology, Department of Pediatrics, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ
The following report presents twins with oligoarticular juvenile idiopathic arthritis (JIA), severe, recurrent uveitis, and selective IgA deficiency (SIgAD). Initial presentation, diagnostic work-up, and treatment are reviewed. Disease flare-ups as well
as complications, specifically recurrent infections, are described. JIA and JIA-associated uveitis (JIA-U), the known genetic contributions to disease development, and the risk of infections as well as the relationship between JIA and SIgAD are discussed.This case of JIA, uveitis, and SIgAD in twins lends further support to the role of genetics in disease development.This report highlights the importance of screening for JIA, and autoimmune diseases in general, in family members of patients with JIA. Additionally, the higher prevalence of immunodeficiencies such as SIgAD in this population as well as the need for immunosuppressive disease- modifying medications necessitates close monitoring for potential infections in this patient population.
- This case of juvenile idiopathic arthritis, uveitis, and selective IgA deficiency in twins lends support to the role of genetics in disease development.
- Juvenile idiopathic arthritis has been linked to several HLA and non-HLA loci including HLA-DRB1:11:03/04, DRB1:08:01, PTPN22, STAT4,TNFA and IL2RA.
- Infections present a significant risk for patients with JIA, due to both intrinsic immune defects from the disease itself and disease-modifying immunosuppressive medications
- A link exists between immunodeficiencies such as IgA deficiency and autoimmune diseases such as juvenile idiopathic arthritis, which may exacerbate the risk of infection in these patients.
Juvenile idiopathic arthritis; uveitis; IgA deficiency
We present twins with oligoarticular juvenile idiopathic arthritis (JIA), recurrent uveitis, and selective IgA deficiency (SIgAD). A discussion follows of JIA and JIA-associated uveitis (JIA-U), the known genetic contributions to disease development, and the risk of infections in this population with specific consideration given to the relationship between JIA and SIgAD.
Twin A is a 17-month old dizygotic twin male who was brought to the emergency department by his caretaker for evaluation of one-month history of left knee swelling and limping in the morning and after naps. On examination, mild swelling over the left knee with slightly decreased extension was noted. Labs were performed including complete blood count (CBC), comprehensive metabolic panel (CMP), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and Lyme titer and were notable for mildly elevated ESR at 16. X-ray of the left knee revealed soft tissue fullness questionable for joint effusion. The patient was discharged home in stable condition with recommendation to follow up with their physician. Twin A was further evaluated in the pediatric rheumatology clinic, at which time he was diagnosed with oligoarticular JIA.A steroid injection was performed to the left knee.Additional labs were ordered and notable for immunoglobulin A (IgA) < 4 mg/dL and a negative antinuclear antibody (ANA) titer, however this was repeated several months later and returned positive at 1:640.
Twin B presented at 22 months of age to the pediatric rheumatology clinic for evaluation of 4-month history of left knee stiffness, pain, and difficulty walking. He had a 30 degree flexural contracture of the left knee and synovial hypertrophy. Laboratory testing was notable for positive ANA titer at 1:640 and low IgA of 10 mg/dL.Twin B was diagnosed with oligoarticular JIA and received a steroid injection to the left knee.
At 29 months of age, the twins were referred to ophthalmology due to high risk of uveitis, at which time examination revealed asymptomatic, severe bilateral anterior and posterior uveitis with optic neuritis and evidence of synechiae and band keratopathy.The patients were sent to the emergency department to be admitted for treatment. Upon admission, the patients were placed on atropine ointment, dexamethasone/ neomycin/polymyxin B eye drops, and prednisolone eye drops. On hospital day 2, the twins were started on methotrexate and infliximab.They were discharged in stable condition on eye drops, oral prednisolone, and methotrexate and began treatments with adalimumab every other week. Given the presentation of arthritis and uveitis in twins, the patients were tested for Blau syndrome, and were negative for the NOD2 mutation.
Over the next several years, the twins had several flares of arthritis and uveitis despite treatment with methotrexate and adalimumab, with Twin B having more recurrences of left knee arthritis and requiring more ophthalmic management due to recurrent uveitis. Interestingly,Twin A had initially presented with more band keratopathy and severe iris synechiae, but went on to have fewer bouts of uveitis while on systemic medications. It is hypothesized that he had more severe silent uveitis prior to diagnosis, but was more responsive to treatment.The patients continued to receive steroid eye drops for uveitis as well as naproxen and steroid injections for arthritis.They were switched from adalimumab to infliximab due to recurrence of uveitis on adalimumab. Both patients were admitted to the hospital several times for fever and vomiting, and were diagnosed with adenovirus and influenza on multiple occasions.Twin A was evaluated for recurrent otitis media, and was diagnosed with eczema as well as iron deficiency anemia.Twin B was diagnosed with obstructive sleep apnea and underwent adenotonsillectomy. Both patients were treated for recurrent methicillin-resistant staphylococcus aureus (MRSA) abscesses. Both Twin A and Twin B’s IgA levels were re-tested and noted to be < 6 mg/dL, meeting criteria for diagnosis of SIgAD. At six years of age at present, Twin A’s JIA and uveitis are currently in remission on methotrexate weekly and infliximab every 6 weeks. Twin B has had persistent left knee arthritis and uveitis, however is improving on methotrexate weekly and infliximab every 4 weeks.
JIA is one of the most common pediatric rheumatic diseases, with a prevalence of approximately 4 in 1,000 children.1 JIA encompasses a heterogeneous set of 7 conditions consisting of arthritis before age 16 for more than 6 weeks duration and of unknown etiology.2 According to the International League of Associations for Rheumatology classification, oligoarticular JIA is defined as arthritis affecting up to 4 joints during the first six months of disease.3
Uveitis is the most common extraarticular manifestation of JIA, occurring in 10-20% of children with JIA.4,5 Uveitis is often asymptomatic, chronic, and relapsing in this population, and can lead to serious complications including vision loss, cataracts, band keratopathy, synechiae, and cystoid macular edema .4-7 Therefore, screening and early detection are extremely important in patients with JIA at risk of uveitis. Several studies have investigated risk factors associated with the development of JIA-associated uveitis (JIA-U). Researchers have found 65-90% of patients with chronic uveitis to be ANA positive.8 Additional risk factors for JIA-U include younger age at disease onset, shorter disease duration, oligoarticular subtype, female gender, rheumatoid factor (RF) negativity, and anti-cyclic citrullinated peptide (anti-CCP) negativity.1,5,9-13 One study found that patients with JIA-U were diagnosed with JIA at a median age of 2.8 and with uveitis at a median age of 4.8.6 Based on these identified risk factors, both
the American Academy of Pediatrics and the American College of Rheumatology/Arthritis Foundation recommend uveitis screening every 3 months for patients with oligoarticular JIA who are ANA positive with disease onset before age 6 and of less than 4 years in duration.5,7,8
It is hypothesized that JIA is a complex disorder involving both genetic and environmental influences.14,15 Several sibling and twin reports have supported the role of genetics in disease development.14,16-20 Studies in monozygotic twins have found concordance rates between 25-40% and it has been estimated that siblings of those with JIA have a 15-30 fold higher risk of developing the disease.15,21 In the largest twin study to date, of 14 pairs of twins, 13 were concordant for disease onset and course, and 12 were concordant for ANA presence or absence.15 In this study, the first twin developed disease on average 5.5 months before the second twin.15 More broadly, studies have revealed an elevated risk of autoimmune disease in family members of patients with JIA.15,22 Candidate gene studies, genotype arrays, and genome wide association studies have found both human leukocyte antigen (HLA) and non-HLA loci to be associated with the development of oligoarticular JIA and JIA-U.15 Oligoarticular JIA has been associated with HLA- DRB1:11:03/04 and DRB1:08:01.15,23 Non-HLA loci associated with JIA include PTPN22, a lymphoid protein tyrosine kinase that negatively regulates T cells, STAT4, which has been implicated inT cell differentiation,TNFA gene, which encodesTNF-alpha, and IL2RA, the interleukin (IL)-2 receptor.15,24 In terms of
JIA-U, HLA-DRB1:11 has been found to be associated with an increased risk of uveitis in patients with oligoarticular JIA. Importantly, these alleles are common in the general population.15 Therefore, more research is needed to understand genetic risk factors predisposing patients to JIA. Additionally, environmental insults such as infections, trauma, and stress have been implicated in JIA, however more research is needed to fully understand environmental contributions to disease.2,9,24
Infections present a significant risk for patients with JIA, due to both intrinsic immune defects from the disease itself and disease-modifying immunosuppressive medications.25 JIA involves chronic inflammation and activation of both the innate and adaptive immune system, specifically leading to excess TNF- alpha, IL-1, and IL-6.25 These immunologic disturbances have been hypothesized to predispose patients to infection.25 Additionally, immunosuppressive treatments increase the risk of upper respiratory infections, urinary tract infections, and herpes zoster virus.26 Interestingly, the twins were found to have SIgAD. IgA is the most abundant immunoglobulin in the body and SIgAD is the most common primary immunodeficiency.27 Patients with SIgAD may be asymptomatic or may be at an increased risk of mucosal infection (e.g., pneumonia, recurrent otitis, fungal infections), atopic disease (e.g., allergies, asthma, rhinitis, and atopic dermatitis), and autoimmune disease.28,29 Specifically, between 25.5 and 31.7% of individuals with SIgAD have an autoimmune condition and approximately 2.7% of patients with JIA have IgA deficiency.28 Several proposed mechanisms exist linking SIgAD to autoimmune disease. It has been hypothesized that certain HLA genes predispose patients to both SIgAD and autoimmune disease.28 Others have argued that an undiscovered monogenic mutation predisposes patients to both conditions.28 Other researchers have hypothesized that low IgA predisposes patients to mucosal pathogens, increasing the number of sensitized antigens and placing patients at higher risk of autoimmune disease due to the possibility of molecular mimicry.28 More research is needed to fully understand the risk of infection in patients with JIA and SIgAD, as well as determine the role of screening, vaccination, and prophylactic treatment.
In summary, we present twins with oligoarticular JIA diagnosed before age two, recurrent uveitis, and selective IgA deficiency. Although additional research is necessary to understand the etiology of JIA and the roles of genetics and the environment in disease development, reports such as this support a clear genetic component to JIA and JIA-U. Given that musculoskeletal complaints are common amongst children and uveitis is typically asymptomatic in this patient population, it is important for physicians to consider JIA as a differential diagnosis and refer patients promptly to a pediatric rheumatologist if there is a concern, especially in those with a family history of JIA or autoimmune disease. Additionally, practitioners should consider the risk of recurrent infections in these patients given the association between immunodeficiencies such as SIgAD and autoimmune disease as well as the immunosuppressive effects of disease-modifying medications.
- Foeldvari I. Ocular involvement in juvenile idiopathic arthritis: classification and treatment. Clin Rev Allergy Immunol. 2015;49(3):271-277.
- Prakken B, Albani S, Martini A. Juvenile idiopathic arthritis. Lancet. 2011;377(9783):2138-2149.
- Petty RE, Southwood TR, Manners P, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004;31(2):390-392.
- Conti G, Chirico V, Porcaro F, et al. Frequency and identification of risk factors of uveitis in juvenile idiopathic arthritis: a long-term follow-up study in a cohort of italian children. J Clin Rheumatol. 2019.
- Angeles-Han ST, Pelajo CF,Vogler LB, et al. Risk markers of juvenile idiopathic arthritis-associated uveitis in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. J Rheumatol. 2013;40(12):2088-2096.
- Angeles-Han ST, McCracken C,Yeh S, et al. Characteristics of a cohort of children with juvenile idiopathic arthritis and JIA- associated uveitis. Pediatr Rheumatol Online J. 2015;13:19.
- Angeles-Han ST, Ringold S, Beukelman T, et al. 2019 American College of Rheumatology/Arthritis Foundation guideline for the screening, monitoring, and treatment
of juvenile idiopathic arthritis-associated uveitis. Arthritis Rheumatol. 2019;71(6):864-877.
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- Grassi A, Corona F, Casellato A, Carnelli V, Bardare M. Prevalence and outcome of juvenile idiopathic arthritis- associated uveitis and relation to articular disease. J Rheumatol. 2007;34(5):1139-1145.
- Heiligenhaus A, Minden K, Föll D, Pleyer U. Uveitis in juvenile idiopathic arthritis. Dtsch Arztebl Int. 2015;112(6):92- 100, i.
- Tappeiner C, Klotsche J, Sengler C, et al. Risk factors and biomarkers for the occurrence of uveitis in juvenile idiopathic arthritis: data from the inception cohort of newly diagnosed patients with juvenile idiopathic arthritis Study. Arthritis Rheumatol. 2018;70(10):1685-1694.
- Vitale AT, Graham E, de Boer JH. Juvenile idiopathic arthritis-associated uveitis: clinical features and complications, risk factors for severe course, and visual outcome. Ocul Immunol Inflamm. 2013;21(6):478-485.
- RobazziTC, Rios G, Castro C.Two pairs of brothers with juvenile idiopathic arthritis (JIA): case reports. Rev Bras Reumatol. 2015;55(1):75-78.
- Hersh AO, Prahalad S. Immunogenetics of juvenile idiopathic arthritis: a comprehensive review. J Autoimmun. 2015;64:113- 124.
- Julián K,Terrada C, Quartier P, Lehoang P, Bodaghi B. Uveitis related to juvenile idiopathic arthritis: familial cases and possible genetic implication in the pathogenesis. Ocul Immunol Inflamm. 2010;18(3):172-177.
- Baum J, Fink C. Juvenile rheumatoid arthritis in monozygotic twins: a case report and review of the literature. Arthritis Rheum. 1968;11(1):33-36.
- Prahalad S, Ryan MH, Shear ES,Thompson SD, Glass DN, Giannini EH.Twins concordant for juvenile rheumatoid arthritis. Arthritis Rheum. 2000;43(11):2611-2612.
- Moroldo MB,Tague BL, Shear ES, Glass DN, Giannini EH. Juvenile rheumatoid arthritis in affected sibpairs. Arthritis Rheum. 1997;40(11):1962-1966.
- Rosenberg AM, Petty RE. Similar patterns of juvenile rheumatoid arthritis within families. Arthritis Rheum. 1980;23(8):951-953.
- QianY, Acharya NR. Juvenile idiopathic arthritis-associated uveitis. Curr Opin Ophthalmol. 2010;21(6):468-472.
- Prahalad S, Shear ES,Thompson SD, Giannini EH, Glass DN. Increased prevalence of familial autoimmunity in simplex and multiplex families with juvenile rheumatoid arthritis. Arthritis Rheum. 2002;46(7):1851-1856.
- Tugal-Tutkun I, Quartier P, Bodaghi B. Disease of the year: juvenile idiopathic arthritis-associated uveitis–classification and diagnostic approach. Ocul Immunol Inflamm. 2014;22(1):56-63.
- Macaubas C, Nguyen K, Milojevic D, Park JL, Mellins ED. Oligoarticular and polyarticular JIA: epidemiology and pathogenesis. Nat Rev Rheumatol. 2009;5(11):616-626.
- Aeschlimann FA, Chong SL, Lyons TW, et al. Risk of serious infections associated with biologic agents in juvenile idiopathic arthritis: a systematic review and meta-analyses. J Pediatr. 2019;204:162-171.e163.
- CecchinV, Zannin ME, Ferrari D, et al. Longterm safety and efficacy of adalimumab and infliximab for uveitis
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- Odineal DD, Gershwin ME.The epidemiology and clinical manifestations of autoimmunity in selective IgA deficiency. Clin Rev Allergy Immunol. 2020;58(1):107-133.
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