Pure red cell aplasia in a patient with rheumatoid arthritis after JAK inhibitor exposure-diagnostic challenges.

Introduction

Pure red cell aplasia (PRCA) is a syndrome characterised by normocytic anaemia and reticulocytopenia, with profound reduction or absence of erythroid precursors in the bone marrow [ 1 ]. PRCA can be classified as congenital or acquired, with the latter further subclassified as either primary or secondary [ 2 ]. PRCA secondary to rheumatoid arthritis (RA) is a rare extra-articular manifestation of this disease with variable outcomes reported following immunosuppressive treatment [ 3 ].

We report the first case of PRCA apparently masked by JAK1-inhibitor (Filgotinib) therapy in RA, in which initial reticulocyte counts were normal, leading to diagnostic delay and highlighting the need for serial monitoring in patients receiving these agents.

Case report

A 67-year-old female patient was referred to the haematology clinic with a two-month history of transfusion-dependent normocytic anaemia with recurrent hospital admissions and no evidence of gastrointestinal (GI) blood loss.

Medical history included seropositive RA, solitary sacroiliitis, interstitial lung disease, osteoporosis with previous spinal fractures and fibromyalgia. She previously had several disease modifying agents for her RA including Methotrexate, Sulfasalazine, Adalimumab, Etanercept and Abatacept. She had commenced Filgotinib a few weeks prior. The patient was wheelchair-bound due to debilitating joint disease.

Baseline blood counts on presentation were as follows: Hb 79 g/l, MCV 90 fl, MCH 31.8, WCC 9.7 × 10*9/l, Neutrophils 8.7 × 10*9/l, Lymphocytes 0.9 × 10*9/l, Eosinophils 0.1 × 10*9/l, Platelets 730 × 10*9/l, Reticulocyte count 60 × 10*9/l. Blood film examination demonstrated reactive features. Further investigations to rule out differential causes for the anaemia are summarised in Table 1 .

Bone marrow histology demonstrated hypercellular marrow with architectural disorder and some atypical megakaryocytes, as well as dyshaemopoiesis with no maturation arrest ( Fig. 1 ). On review in our multidisciplinary team (MDT) meeting, overall consensus was that features were not typical for PRCA, especially with a normal reticulocyte count, and that the anaemia could be secondary to Filgotinib. Thus, initial recommendation was to continue holding this treatment and deliver supportive care with red cell transfusions.

As expected, after holding Filgotinib, the patient had severe flares from her rheumatoid arthritis and was treated with Rituximab and Prednisolone at 9 months after her initial presentation. Despite this, she continued to have persistent, refractory transfusion-dependent anaemia ( Table 2 ).

Twelve months after initial presentation, the patient was anaemic with a new reticulocytopenia (Hb 78 g/l, Reticulocyte count 8 × 10*9/l). PRCA was considered as a potential diagnosis and, following MDT discussion, recommendation was to start Prednisolone 30 mg once daily with Ciclosporin A 50 mg twice a day.

This combination therapy was delayed due to the patient being hospitalised. However, once started, during the first month the patient managed to wean down Prednisolone by 5 mg every 7 days, and Erythropoietin injections were reduced to alternate weeks. She became transfusion-independent after four weeks and currently remains in complete remission on Ciclosporin A monotherapy ( Table 2 ).

Discussion

Acquired PRCA is characterised by severe anaemia and reticulocytopenia, with a broad differential including autoimmune disease, lymphoproliferative disorders, infections and medications ( Table 3 ) [ 2 ]. PRCA secondary to RA is rare, with only limited case reports and variable clinical presentations described [ 3 ]. Diagnosis in RA patients may be challenging due to multifactorial causes of anaemia and the potential haematological toxicities associated with DMARD therapy [ 4 ].

One plausible explanation is that our patient had evolving RA-associated PRCA from the outset, which may initially have been obscured during Filgotinib treatment. Clinical trial data have demonstrated preserved or increased haemoglobin levels during the first months of Filgotinib therapy [ 5 , 6 ]. Filgotinib selectively inhibits JAK1, whereas JAK2 is more closely associated with erythropoiesis and JAK3 with lymphocyte signalling [ 7 ]. It is therefore conceivable that preferential JAK1 inhibition may have transiently preserved erythropoietic signalling, contributing to the initially normal reticulocyte count before overt PRCA became apparent. This remains a hypothesis; larger pharmacovigilance studies are required.

Anti-erythropoietin antibody-mediated PRCA was also considered. However, the patient was already reticulocytopenic before commencing erythropoietin therapy, and the median reported onset of epoetin beta-associated PRCA is approximately 20 months [ 8 ].

Our patient did not respond to corticosteroids or Rituximab, both commonly used therapies for PRCA [ 2 ]. Increasing evidence suggests that PRCA associated with autoimmune disease may be predominantly T-cell mediated, which may explain the subsequent response to Ciclosporin A in this case [ 9 ]. Maintenance Ciclosporin A therapy has also been associated with sustained remission and improved outcomes [ 2 , 10 ].

To our knowledge, this is the first reported case suggesting possible masking of PRCA during JAK1 inhibitor therapy in RA. Clinicians should consider PRCA in patients receiving JAK inhibitors who develop refractory anaemia, even in the presence of an initially normal reticulocyte count.

Learning points

JAK1 inhibitors may transiently normalise reticulocytes in occult PRCA

Persistent transfusion-dependent anaemia in RA requires serial reticulocyte monitoring

T-cell directed immunosuppression (Ciclosporin A) is effective when steroids and Rituximab fail

Acknowledgements

None.

Conflicts of interest

Priya Sriskandarajah has received speaker fees from Celgene BMS, Novartis and Blueprint Medicines; travel fees from Jazz Pharma, Novartis and Celgene BMS; education fees from Novartis and Blueprint Medicines. All other authors had no conflicts of interest to declare.

Funding

There is no source of funding for the present case report.

Ethical approval

Not applicable.

Consent

Written informed consent for publication of the clinical course and accompanying images were obtained from the patient before the study.

Guarantor

Dr Priya Sriskandarajah.

References

1. Kala M , Das K , Baveja A . et al. Pure red cell aplasia encountered in a tertiary care Hematology laboratory: a series of nine distinctive cases . J Lab Physicians 2022 ; 15 : 316 – 20 . 10.1055/s-0042-1757584 37323590 PMC10264118

2. Means RT Jr . Pure red cell aplasia: the second hundred years . Am J Med Sci 2023 ; 366 : 160 – 6 . 10.1016/j.amjms.2023.06.009 37327996

3. Kuang S , Yap ES , Wang DA . et al. Case reports 001. Pure red cell aplasia: a rare and challenging extra-articular manifestation of rheumatoid arthritis . Rheumatology 2017 ; 56 : ii49 – 95 . 10.1093/rheumatology/kex062

4. Molteni E , Adinolfi A , Bondi V . et al. Novel insights into the management of rheumatoid arthritis: one year in review 2024 . Clin Exp Rheumatol 2024 ; 42 : 947 – 60 . 10.55563/clinexprheumatol/166dsf 38743447

5. Traves PG , Murray B , Campigotto F . et al. JAK selectivity and the implications for clinical inhibition of pharmacodynamic cytokine signalling by filgotinib, upadacitinib, tofacitinib and baricitinib . Ann Rheum Dis 2021 ; 80 : 865 – 75 . 10.1136/annrheumdis-2020-219012 33741556 PMC8237188

6. Takeuchi Y , Konishi M , Hirabayashi H . et al. AB0492 Anemia in patients with rheumatoid arthritis treated with jak inhibitors . Ann Rheum Dis 2023 ; 82 : 1440 – 1 . 10.1136/annrheumdis-2023-eular.1076

7. Kim ES , Keam SJ . Filgotinib in rheumatoid arthritis: a profile of its use . Clin Drug Investig 2021 ; 41 : 741 – 9 . 10.1007/s40261-021-01055-0 PMC8613087 34304373

8. McKoy JM , Stonecash RE , Cournoyer D . et al. Epoetin-associated pure red cell aplasia: past, present, and future considerations . Transfusion. 2008 ; 48 : 1754 – 62 . 10.1111/j.1537-2995.2008.01749.x 18482185 PMC2730535

9. Abkowitz JL , Kadin ME , Powell JS . et al. Pure red cell aplasia: lymphocyte inhibition of erythropoiesis . Br J Haematol 1986 ; 63 : 59 – 67 . 10.1111/j.1365-2141.1986.tb07495.x 3085703

10. Sawada K , Hirokawa M , Fujishima N . et al. PRCA collaborative study group. Long-term outcome of patients with acquired primary idiopathic pure red cell aplasia receiving cyclosporine a. a nationwide cohort study in Japan for the PRCA collaborative study group . Haematologica. 2007 ; 92 : 1021 – 8 . 10.3324/haematol.11192 17640861