How will Bruton’s tyrosine kinase inhibitors affect rheumatoid arthritis?

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To the editor

We thank Dr. Bernal and colleagues for their interest in our article and for their report regarding arthritis in a patient treated with ibrutinib. In thinking about potential mechanisms, we turn first to the possibility that a Bruton’s tyrosine kinase inhibitor could somehow support B cell contributions to autoimmune disease. Btk-deficiency in mice profoundly depletes autoreactive B cells, while normal B cells are less affected.^1,2 This contrasts human patients who lack BTK, in whom all B cell subsets are depleted. These patients have fewer than 1% normal numbers, with failure of humoral immunity known as X-linked agammaglobulinemia (XLA).³ Interestingly, remaining B cells in these patients are more likely to have autoreactive specificities.⁴ However, these cells do not usually cause autoimmune disease, as patients do not develop autoantibodies, and there have been only rare reports of rheumatoid arthritis.⁵ Most patients do well as long as they are treated with exogenous immunoglobulins.^6,7 This correlates with murine studies regarding the role of Btk in autoimmunity, as we and others have shown that Btk-deficiency protects against multiple forms of autoimmune disease in pre-clinical models.^2,8–13 Further, we have not found evidence that Btk-deficiency might induce autoimmunity on its own, never having seen spontaneous arthritis either in Btk-deficient C57BL/6 mice, nor on the autoimmune-prone NOD background.

The effects of BTK-inhibitors, such as ibrutinib, on autoreactive B cells in patients is unknown. The effects cannot be assumed to mimic those found in XLA. For one thing, the inhibitors target only the kinase domain, leaving the adaptor domain of BTK intact. The adaptor function of BTK in mice can operate independently of the kinase function,¹⁴ and while its role in human B cells is not well-known, it could conceivably allow better B cell survival than is seen in XLA patients. Second, human patients who are given inhibitors already have established B cell populations, including autoimmune-prone and normal subsets. Whether blocking the kinase domain of BTK reduces the number of autoreactive B cells, as Btk-deficiency does in mice, or increases their relative proportion as occurs in XLA patients, is an important question that deserves study. However, if Dr. Bernal’s patient had autoimmune arthritis due to increased autoreactive B cells, she would likely have autoantibodies acting as triggers, which is not the case.

BTK is also expressed in myeloid cells, mast cells and neutrophils, which support inflammatory arthritis. The role of BTK in these cells is understudied. Some reports regarding BTK-deficient innate cells have shown decreased functions, while others have shown hyperactive qualities, indicating that BTK may sometimes have a regulatory role, supporting the authors’ cautionary advice.^15–19 As our article showed, Btk-deficiency in innate cells did not protect against autoantibody-mediated arthritis in a preclinical, serum transfer model, but neither did it increase arthritis. In the patient presented by Bernal and colleagues, a non-autoimmune inflammatory process mediated by the innate immune system is a possibility that could be supported by our study. However, most inhibitors, including ibrutinib, have been shown to suppress innate cell mediated inflammation in pre-clinical models and in vitro cellular assays.^20–23 Ibrutinib is known to have significant side effects, however, including hemorrhage, neutropenia, atrial fibrillation, infection and diarrhea, that may be due to off-target effects on other kinases including ITK, BLK, BMX, TEC, JAK3, and EGFR, to name a few.^24,25 Of note, musculoskeletal pain is also common and 11% of patients have reported arthralgias, as noted on the package insert.

New BTK-inhibitors are in development, and several are in clinical trials for treatment of rheumatoid arthritis. Some of these small molecules may have fewer off-target effects than ibrutinib. Preclinical studies using these drugs mirror those using Btk-deficient mice in showing efficacy for autoimmune disease, and there is little evidence so far from either those data or human XLA patients that targeting BTK should in itself increase the chances of autoimmune disease. Data from these studies may provide new information regarding the role of BTK in human autoreactive B cells and innate cell populations, as well as clinical outcomes. In the meantime, it may be hoped that clinicians will continue to practice vigilance in noting and reporting potential side effects, as Bernal and colleagues have done.