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LetterLetter

JAK2 Specificity and Thrombosis Risk: Potential Role of Antiphospholipid Antibodies

BRUCE M. ROTHSCHILD
The Journal of Rheumatology February 2019, 46 (2) 217-218; DOI: https://doi.org/10.3899/jrheum.180722
BRUCE M. ROTHSCHILD
Indiana University School of Medicine, Muncie, Indiana; Carnegie Museum - Vertebrate Paleontology, Pittsburgh, Pennsylvania, USA.
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To the Editor:

Janus kinase (JAK) inhibitors are a relatively new addition to our tools for treatment of rheumatoid arthritis (RA)1. They are responsible for transduction of more than 38 cytokinases2, with diffuse metabolic/immunologic implications. It is those immunologic effects that have attracted evaluation for modulation as a therapeutic approach to rheumatologic disease1. Infection and gastrointestinal perforation, liver abnormalities and serum creatinine, lipid and creatine phosphokinase level elevations may complicate all JAK inhibitors, but thrombotic events appear more limited to baricitinib3. Baricitinib has shown efficacy and is approved primarily for the treatment of RA. Not all JAK inhibitors are equal. There are 4 JAK sites2. Baricitinib predominantly acts on sites 1 and 2, tofacitinib on sites 1 and 3, filgotinib on site 1, peficitinib on site 3, and upadacitinib on site 14,5.

Could baricitinib’s JAK2 inhibition (unique among currently investigated JAK inhibitors) be a clue to associated thrombotic events? Baricitinib trials suggest possible increases in thromboembolisms; tofacitinib post-marketing surveillance suggests possible increases in pulmonary thrombosis. According to the publications3,4,5, the thromboembolic risks are about 5 events per 1000 patient-years with 4 mg baricitinib daily. The general population and controls without RA have 1–4 thromboembolic events per 1000 patient-years. The rates increase in RA to 3–7 per 1000 patient-years.

JAK2 is important in hematologic cytokine induction5 and mutations are associated with myeloproliferative disease2. A possible explanation for thrombotic events with baricitinib may be modulation of platelet function in the presence of a specific risk factor. In a patient with a known autoimmune disease, one must consider an accompanying phenomenon, presence of antiphospholipid antibodies (aPL)6, especially because involvement of both arterial and venous vessels is rare when aPL are not present7.

Evaluation for presence of aPL may identify individuals at risk of thrombotic events with baricitinib and perhaps with future agents targeting type 2 JAK sites. The mean prevalence of aPL in patients with RA is 28%, although reports range from 5% to 75%. Curiously, the presence of antiphospholipid or anticardiolipin antibodies (aCL) does not appear to predict the development of thrombosis and/or thrombocytopenia in patients with RA. However, aCL in RA are associated with a higher risk for developing rheumatoid nodules. It is hypothesized that the majority of aCL identified in patients with RA have different specificities than those identified in other diseases that are associated with thrombotic events.

The presence of aPL should at the very least be assessed if thrombotic events develop in a patient receiving a JAK inhibitor, because standard treatment of thrombotic events requires modification in their presence8,9. Too few events have occurred with JAK inhibitors to be certain that these risks are significant. Longterm observational studies are needed to quantify the risks accurately and differentiate them from the underlying disease. In the interim, use of aspirin or cyclooxygenase-1–predominant nonsteroidal antiinflammatory agents with assurance of actual reduction of platelet function, unfractionated heparin, or high-dose warfarin (3.0–3.5 INR) is recommended when aPL are identified in patients who develop thromboembolic disease while receiving a JAK inhibitor.

REFERENCES

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    7. et al.
    Safety and efficacy of baricitinib through 128 weeks in an open-label, longterm extension study in patients with rheumatoid arthritis. J Rheumatol 2018;45:14–21.
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    1. Alicea-Velázquez NL,
    2. Boggon TJ
    . The use of structural biology in Janus kinase targeted drug discovery. Curr Drug Targets 2011;12:546–55.
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    1. Huizinga TW,
    2. Kay J,
    3. Harigai M,
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    Effects of baricitinib on haematological laboratory parameters in patients with rheumatoid arthritis [abstract]. Rheumatology 2018;57 Suppl 3: key075.589.
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    1. Keystone EC,
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    4. Schlichting DE,
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    Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have an inadequate response to methotrexate. Ann Rheum Dis 2015;74:333–40.
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    1. O’Shea JJ
    . Targeting the Jak/STAT pathway for immunosuppression. Ann Rheum Dis 2004;63 Suppl 2:ii67–71.
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    1. Cohen D,
    2. Berger SP,
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    4. Bloemenkamp KW,
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    . Diagnosis and management of the antiphospholipid syndrome. BMJ 2010;340:2541.
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    1. Yalavarthi S,
    2. Gould TJ,
    3. Rao AN,
    4. Mazza LF,
    5. Morris AE,
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    Release of neutrophil extracellular traps by neutrophils stimulated with antiphospholipid antibodies: a newly identified mechanism of thrombosis in the antiphospholipid syndrome. Arthritis Rheumol 2015;67:2990–3003.
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    1. Khamashta MA,
    2. Cuadrado MJ,
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    6. Hughes GR
    . The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med 1995;332:993–7.
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    1. Rothschild BM
    . Comparative antiplatelet activity of COX1 NSAIDS versus aspirin, encompassing regimen simplification and gastroprotection: a call for a controlled study. Reumatismo 2004;56:89–93.
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JAK2 Specificity and Thrombosis Risk: Potential Role of Antiphospholipid Antibodies
BRUCE M. ROTHSCHILD
The Journal of Rheumatology Feb 2019, 46 (2) 217-218; DOI: 10.3899/jrheum.180722

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JAK2 Specificity and Thrombosis Risk: Potential Role of Antiphospholipid Antibodies
BRUCE M. ROTHSCHILD
The Journal of Rheumatology Feb 2019, 46 (2) 217-218; DOI: 10.3899/jrheum.180722
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