Acquired hemophilia A in a patient with adult‐onset Still's disease: Successful treatment with steroids

Abstract

Acquired hemophilia A (AHA) is a potentially life‐threatening hemorrhagic disorder with many etiologies. We report the first case in the literature describing the association of AHA with adult‐onset Still's disease (AOSD).

We report the first case of the literature of acquired hemophilia A associated with adult onset Still's disease, highlighting the importance of the hemostatic follow‐up in systemic diseases in order to guide management and to improve prognosis.

1. INTRODUCTION

Acquired hemophilia A (AHA) is a rare hemostatic disorder mediated by autoantibodies against endogenous factor VIII (FVIII) which typically interfere with its procoagulant function. It is a potentially fatal disease affecting patients without any previous history of bleeding. Therefore, its diagnosis must be suspected early in the presence of an isolated prolonged activated partial thromboplastin time (aPTT) not corrected by the addition of normal plasma (mixing test). It is confirmed once a reduced FVIII level is demonstrated with evidence of the presence of detectable FVIII inhibitor. ¹ Although it is mainly idiopathic, it can be associated with the postpartum period, malignancies, infections, certain drugs, and approximately in 20% of cases with autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus, and Sjögren's syndrome. ² , ³

Herein, we report, to our knowledge, the first case of a patient with adult‐onset Still's disease (AOSD) complicated by AHA, who was successfully treated by corticosteroids.

2. CASE REPORT

A 25‐year‐old Tunisian woman was referred to our internal medicine department in January 2006, due to prolonged fever, generalized fatigue, and polyarthralgia with arthritis involving the large and the small joints, which began 3 weeks before presentation. She also manifested a transient maculopapular rash occurring with the onset of fever.

Laboratory findings showed neutrophilic leukocytosis (leukocytes 20.500/mm³; PNN 19.000/mm³) and biological inflammatory syndrome (erythrocyte sedimentation rate (ESR) = 140 mm/h; C reactive protein (CRP) = 137 mg/L). Ferritin concentration was 345 μg/L. Antinuclear antibodies and rheumatoid factor were negative. Infectious and neoplastic etiologies were ruled out, as well as other inflammatory diseases. Thus, the diagnosis of AOSD was made and the patient received a high‐dose fractionated corticosteroid therapy (1 mg/kg/day of prednisone) maintained for 8 weeks with a progressive decline to 10 mg/day of prednisone for maintenance. The result was a rapid resolution of the symptoms.

One year later, she developed polyarthralgia of the large and small joints with synovitis and arthritis. X‐rays of both hands showed bilateral carpitis. Rheumatoid factor and anti‐cyclic citrullinated peptide were negative. All these findings confirm the diagnosis of AOSD in the chronic articular pattern.

The patient received methotrexate for 3 years. In response to a desire for pregnancy, it was switched to hydroxychloroquine. Unfortunately, the patient continued to have joint complaints, thereby requiring corticosteroids and non‐steroidal anti‐inflammatory drugs use.

In May 2020, at the age of 39 years old, she was admitted due to the sudden appearance of spontaneous diffuse ecchymosis extended to all four limbs (Figures 1 and 2), gingivorrhagia, and heavy menstruation.

FIGURE 1.

Large ecchymosis of the forearms at admission.

FIGURE 2.

Large ecchymosis of the lower limbs at admission.

Screening tests in hemostasis at admission revealed an isolated prolonged activated partial thromboplastin time (aPTT) (68 sec, ratio = 2,36) not corrected by mixing test. Factor VIII level was markedly reduced (<1%), while activities of factor IX and von Willebrand factor were within normal ranges. After incubation for 2 h at 37°C, the Rosner Index was 57%. Nevertheless, screening for lupus anticoagulant was negative using dilute Russell's viper venom test (DRVVT). An acquired F VIII inhibitor was suspected and quantified by the Nijmegen–Bethesda method revealing a titer of 16 BU.

Furthermore, there was no previous personal or family bleeding or clotting disorders history. In particular, no significant bleeding occurred during a cholecystectomy in 2012, a vaginal delivery in 2015, and a spontaneous abortion in 2016. All these findings confirm the diagnosis of AHA.

Etiologic diagnosis of this AHA was then retained. No drug use was incriminated and there was no context of recent pregnancy or abortion. Moreover, the patient had no current or past history of malignancies or dermatological diseases. The physical examination and the thoraco‐abdomino‐pelvic CT scan did not show any malignant process. However, echo‐mammography revealed a breast nodule classified ACR 4. A biopsy was indicated, but given the context of AHA, it was postponed after 1 month following the improvement of coagulation tests. Surprisingly, the patient presented an outbreak of her Still's disease. She presented persistent fever, polyarthralgia, and arthritis of the large joints. Moreover, laboratory data were consistent with findings of systemic inflammatory process as it showed markedly elevated acute phase reactants with a serum CRP concentration of 150 mg/L and an ESR of 130 mm/h. In addition, we found neutrophilic leukocytosis: leukocytes 15,530/mm³, PNN 12,000/mm³, and elevated serum ferritin levels. Based on the clinical findings and the laboratory results, the diagnosis of AHA related to AOSD was established. High‐dose corticosteroid therapy (oral prednisone at a dose of 1 mg/kg/day) was rapidly initiated with strict clinical and biological monitoring.

Good clinical evolution was achieved with a progressive but complete resolution of the bruises (Figures 3 and 4). After 7 weeks of treatment, the aPTT was 36.7 s (ratio = 1.22), the FVIII activity reached 17%, and the FVIII inhibitor disappeared. The mammary biopsy was then performed without significant bleeding. The histology showed a fibrocystic breast disease.

FIGURE 3.

Regression of the ecchymosis in the forearms after 3 weeks.

FIGURE 4.

Regression of the ecchymosis in the lower limbs after 6 weeks.

Subsequently, the patient was discharged home on corticosteroid therapy with a gradually reduced dose by 5 mg/day every week, until the dose of 10 mg/day is achieved. Daily calcium and vitamin D supplementation was also indicated.

After a 7‐month follow‐up with regular clinical and hematological monitoring, the patient did not relapse. Her aPTT reached 27 s (ratio 0.9). The FVIII inhibitor was not detected and the FVIII activity had a normal value.

3. DISCUSSION

We have described an original observation of AHA associated to AOSD.

AHA occurs with an incidence of approximately 1.5 cases per million each year and represents predominantly a pathology of the elderly (median age of onset range: 64–78 years). ⁴ , ⁵ , ⁶ A small peak age in the incidence was reported in women, related to pregnancy. ¹ In fact, AHA appears to be more frequent in the age between 20 and 40 years in women than men. Nevertheless, except for this range of age, it affects both sexes equally. Our patient was 39 years old when she was diagnosed with AHA.

Although the production of FVIII inhibitor remains idiopathic in about half of the cases, we believe that it is associated in our present case with Still's disease. AOSD is a rare multisystemic autoinflammatory disorder of unknown etiology typically characterized by high spiking fever, polyarthritis, evanescent skin rash, sore throat, neutrophilic leukocytosis, and hyperferritinemia. It is a rheumatic condition with a heterogeneous clinical presentation that is encountered in adults, typically between 16 and 35 years.

In fact, our patient has been following up for an AOSD referring to Yamaguchi criteria. ⁷ It was evolving over 14 years, in its chronic articular pattern. Interestingly, the development of AHA was associated with an AOSD flare. Nevertheless, the other causes of AHA were excluded particularly drug use, pregnancy, infections, and malignancies. In particular, autoimmune diseases are the most commonly associated etiology to AHA. ² Acquired FVIII inhibitor has already been associated to a wide variety of autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, dermatomyositis but never in AOSD. ³ , ⁸ We believe that this case provides evidence that AOSD should be added as one of the causes of AHA.

Notably, AHA is a serious condition that can lead to severe hemorrhagic complications. Its pathogenesis involves a decrease in factor VIII activity, related to the spontaneous appearance of neutralizing immunoglobulin G (IgG) autoantibodies against this coagulation factor, which results in a tendency to excessive bleeding. ⁹ , ¹⁰

Most FVIII acquired inhibitors display a non‐linear inactivation pattern (type II) and they do not totally inactivate FVIII in vitro. ¹⁰ Thus, the Bethesda assay may not be able to estimate the real potential of the autoantibody. ² , ¹¹

Clinically, hemorrhage is acute and spontaneous in the majority of patients. AHA is characterized by subcutaneous bleeds, hemorrhages into muscles or soft tissues, and mucous membranes (e.g., epistaxis, gastrointestinal and genitourinary bleeds, retroperitoneal hematomas). However, hemarthrosis, a typical feature of congenital hemophilia A, is infrequent. ¹² AHA may have dramatic manifestations, such as cerebral hemorrhage or bleeding induced by trauma, surgery, or other invasive procedures. Fatal hemorrhage can occur up to 5 months after presentation if the disease‐causing inhibitor is not eradicated. ⁶ Therefore, AHA is considered as a life‐threatening bleeding disorder that is associated with a high mortality rate more than 20%. ²

Outstandingly, the severity of bleeding events does not correlate with the factor VIII level nor does it reflect the strength of the autoantibody. ⁶ Furthermore, the aPTT is not useful in predicting the risk of fatal bleeding. Based on a study performed by the European Acquired Hemophilia Registry (EACH2) on 501 patients, the diagnosis of AHA was triggered in most cases (89.0%) by a bleeding symptom that led to further hemostatic laboratory tests and confirmation of the autoimmune disease. In 48 patients (9.6%), the diagnosis was based on a prolonged aPTT. No bleeding events were reported in 33 of these cases, whereas bleeding occurred only after diagnosis in 15 patients. ¹³

Since delays in diagnosis may lead to mortality, AHA must be promptly considered by cooperative management decisions and attributed to its cause in order to begin appropriate treatment as soon as possible. ⁵ The diagnosis was evoked in our patient by the recent onset of extensive ecchymosis and confirmed by isolated prolonged aPTT in the presence of FVIII inhibitor. All interfering agents that may resemble circulating inhibitors and differential diagnosis were excluded. The FVIII autoantibody titer was measured by the Nijmegen–Bethesda method, the dilution of patient plasma closest to a 50% inhibition of FVIII in normal pooled plasma was selected.

The newest international recommendations of AHA were published by Tiede et al. in 2020. ¹¹ The first‐line hemostatic treatment with bypassing agents, involving recombinant activated factor VII (rFVIIa), activated prothrombin complex concentrate (APCC), or recombinant porcine FVIII (rpFVIII), is required especially in cases of massive and critical bleeding regardless of the inhibitor titer and residual FVIII activity, or before invasive procedures. Immunosuppressive therapy (IST) to eradicate FVIII autoantibodies should be simultaneously and immediately initiated for all the patients with AHA after diagnosis confirmation to minimize the risk of serious hemorrhages. The choice of the IST can be determined using prognostic markers (FVIII activity, inhibitor titer).

Steroids alone for 3–4 weeks are recommended for patients with FVIII:C ≥ 1 IU/dL and inhibitor titer ≤20 BU at baseline. Steroids combined with rituximab or a cytotoxic agent for first‐line therapy are indicated in patients with FVIII <1 IU/dL or inhibitor titer >20 BU.

The most commonly used immunosuppressive strategy, which leads to complete remission in about up to 80% of patients, includes corticosteroids (prednisone 1–2 mg/kg/day for 4–6 weeks) or in combination with cyclophosphamide (1–2 mg/kg per day for a maximum of 5 weeks). ¹⁴

In our case, even though FVIII:C was less than 1% at baseline, corticosteroids alone were a relevant alternative for simultaneously managing AHA and AOSD. This therapy was sufficient to get an early clear‐cut reduction of the inhibitor level. Bypassing agents were not required given the absence of active severe bleeding. The most likely explanation for the rapid reduction of antiFVIII titer is the high corticosteroid sensitivity of AOSD. ¹⁵

Given the risk of relapse of the inhibitor in about 20% of cases after complete remission, long‐term follow‐up commonly with the aPTT and factor VIII autoantibody levels is recommended in all patients with AHA. Additionally, patients should be aware of this possible hemostatic disorder and seek urgent medical care in case of unusual bleeding symptoms so that relapse can be identified early. ⁵ , ⁶

4. CONCLUSION

To our knowledge, AHA associated with AOSD has never been described. The purpose of this observation is to highlight the importance of a rapid diagnosis of such a rare disease, often misdiagnosed or even unrecognized. This is not only important for a better understanding of the pathogenesis of the diseases, but also to guarantee an earlier diagnosis. In AOSD as in other autoimmune diseases, hemostatic follow‐up is very important to ensure a better therapeutic management and to avoid life‐threatening complications.

AUTHOR CONTRIBUTIONS

Chifa Damak: Resources. Donia Chebbi: Conceptualization; resources; writing – original draft. Faten Frikha: Resources. Ikram El Ahmer: Conceptualization; resources; writing – original draft. imen krichen: Resources; supervision; validation. Choumous Kallel: Resources; supervision; validation. Mouna Snoussi: Resources. Raida Ben Salah: Resources. Sameh Marzouk: Resources; supervision; validation. Zouhir Bahloul: Resources; supervision; validation.

CONFLICT OF INTEREST STATEMENT

The authors have no conflict of interest to declare.

CONSENT

Written informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy.

ETHICS STATEMENT

Published with the consent of the patient.

Chebbi D, Marzouk S, Krichen I, et al. Acquired hemophilia A in a patient with adult‐onset Still's disease: Successful treatment with steroids. Clin Case Rep. 2023;11:e7105. doi: 10.1002/ccr3.7105

DATA AVAILABILITY STATEMENT

All data is available.