We report for the first time a case of PJP in a tofacitinib treated RA patient that led to hypercalcemia. Physiologically, 1- alpha hydroxylation of 25-OH vitamin D occurs primarily in the proximal renal tubule in response to PTH . This step should have been inhibited fully in our patient by the low serum PTH value and the high serum calcium and normal phosphate. Extrarenal 1-alpha hydroxylation of 25-OH vitamin D occurs in macrophages driven by interferon-gamma (IFN-γ) in neoplastic, granulomatous and infectious diseases . This latter mechanism most likely explains the hypercalcemia associated with high 1,25-dihydroxyvitamin D levels.
It is postulated that in infectious diseases granuloma-forming activated macrophages can increase the conversion of 25-OH vitamin D to 1,25- dihydroxyvitamin D . Normal macrophages do not produce 1,25-dihydroxyvitamin D, but 1-alpha hydroxylation of 25-OH vitamin D can be induced in macrophages exposed to IFN-γ, which is elevated in patients with PJP as shown in a study with pediatric patients .
In general, patients with RA are at increased risk to acquire infection in comparison to non RA study subjects due to the use of immunosuppressive therapy and/or the immunomodulatory effects of RA itself . Long term safety reports regarding opportunistic infections (including PJP) among patients with RA using tofacitinib revealed a risk of infection, although the incidence rate is low and it is uncertain if this risk differs from that observed with bDMARDs [6, 7].
Recommendations on PJP prophylaxis in HIV negative patients with rheumatoid arthritis vary by author and region. A review by Wolfe et al. did not recommend PJP prophylaxis in patients with RA considering the low incidence of PJP in European and American patients .
In contrast, Mori et al. recommended short-term prophylaxis with TMP/SMX for patients with RA and newly treated with a biological and/or non-biological therapy .
A commonly encountered criterion to indicate PJP prophylaxis in non-HIV infected patients is receipt of prednisone ≥20 mg/kg/d for ≥1 month in addition to a second immunosuppressive or cytotoxic medication or a T-cell defect .
A recent study by Yukawa et al. proposes a scoring system based on usage of MTX, old age, number of immunosuppressive drugs, and dosage of prednisone, as these parameters were identified as risk factors of PJP in patients with rheumatoid arthritis . A retrospective study showed that TMP/SMX prophylaxis significantly reduced PJP incidence in patients with rheumatic diseases (especially in patients receiving high dose steroids (over 60 mg/day) . Based on this study Winthrop et al. identified following risk factors for PJP in patients treated with glucocorticoids: lymphopenia, initial glucocorticoid dose > 60 mg/day, current use of cyclophosphamide, anti TNF or rituximab use and presence of dermatomyositis, granulomatosis with polyangiitis and microscopic polyangiitis, while considering PJP prophylaxis at lower glucocorticoid doses (15 mg) when risk factor are present .
However, an international survey revealed that in 2010 of 3150 consecutive members of the American College of Rheumatology (ACR), 30% of surveyed rheumatologist reported that they never prescribed prophylaxis .
Hypercalcemia in patients with RA treated with immunosuppressive drugs in accordance with a pulmonary infection should raise high suspicion of PJP. Considering the potentially fatal courses of PJP, empirical treatment with TMP/SMX should be started in patients with sufficient clinical suspicion and should not be delayed until diagnostic procedures are performed or test results return. Evidence-based guidelines for PJP prophylaxis for the patients with autoimmune or connective tissue disease are urgently needed.