Successful treatment of interstitial pneumonitis with anakinra in a patient with adult-onset Still’s disease

Abstract

A 29-year-old African woman with active adult-onset Still’s disease (AOSD) that developed at the end of 2018 presented to our hospital in September 2019 with pleuritic right-sided pain and respiratory insufficiency of almost a month’s duration, which had failed to respond to high-dose corticosteroid and antibiotic treatment. A thoracic CT revealed right pleural effusion, multiple consolidations and pulmonary collapse. Besides pulmonary symptoms, the patient had arthralgia, fever, a salmon-coloured rash, leucocytosis and rising inflammatory markers. After an AOSD flare diagnosis was established, intravenous methylprednisolone and painkillers were administered. Due to the severity of the pleural effusion and the lack of response to previous treatments, subcutaneous anakinra was started. Two days after the first dose the patient had almost fully recovered. The success of this case points out the potential effectiveness of anakinra in the prevention of a pulmonary failure and the treatment of a severe intermittent polycyclic pattern of AOSD.

Background

The term adult-onset Still's disease (AOSD) was first used by Bywaters in 1971,¹ in order to describe a series of adult patients who had features similar to children with systemic juvenile idiopathic arthritis (JIA) and did not fulfil the criteria for classic rheumatoid arthritis (RA).² This disease is an uncommon systemic inflammatory disorder of unknown aetiology and its main symptoms are spiking fever, arthralgia or arthritis, an evanescent salmon maculopapular rash and leucocytosis with neutrophil predominance.^3–5 AOSD can be divided into three main patterns,³ but the intermittent polycyclic pattern seems to be related to a worse prognosis and to the need for more aggressive treatment.⁵ Serum ferritin levels are usually used to establish an AOSD diagnosis,⁶ although the Yamaguchi criteria have the highest sensitivity for the disease.⁷

Initial therapeutic decisions are based on the extent and severity of the disease and whether it is characterised by arthritis or by systemic signs of inflammation.⁸ First-line treatment consists of non-steroidal anti-inflammatory drugs and corticosteroids; however, they are rarely effective, with symptom control achieved in only 20% of patients.⁹ Nevertheless, patients with serious visceral involvement may achieve a quicker response with high-dose intravenous methylprednisolone.⁹ Second-line treatment involves immunomodulatory agents as methotrexate, which effectively controls acute AOSD and allows steroid dose sparing.^{10 11} Third-line agents are used in patients who have not responded adequately to previous treatments. The potential effectiveness of biological agents targeting interleukin-1 (IL-1) makes anakinra a suitable candidate.¹² The evidence regarding the potential use of anakinra for AOSD treatment is principally derived from observational studies and clinical experience.3 4 8 13–17

We present a case of intermittent polycyclic pattern and severe AOSD flare with interstitial pneumonitis and pleural effusion that improved dramatically with anakinra treatment; the patient has since been in remission.

Case presentation

A 29-year-old African woman was in London when she presented to a hospital at the end of 2018 with fever, headache, odynophagia, rash and arthralgias. With the exception of breast implants, further review of her medical, social and family history were unremarkable. After several possible diagnoses were dismissed, the final one pointed to AOSD, even though autoimmunity studies were incomplete at the time she left hospital.

On 5 January 2019, she presented to our hospital with polyarthralgia, malaise, mild hepatitis, flaking dermatitis and urinary incontinence, among other conditions. During admission, microbiologic screening (HIV, hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex virus (HSV), cytomegalovirus (CMV), Epstein-Barr virus (EBV) and enterovirus) and autoimmunity studies (antinuclear antibodies (ANA), anti-DNA antibodies, antineutrophil cytoplasmic autoantibodies (ANCA), anti-citrullinated protein antibodies, normal-high complement, and normal rheumatoid factor) were all negative. Blood results showed raised serum lactate dehydrogenase (LDH) of 336 U/L, raised ferritin of 2892 ng/mL, and raised C-reactive protein (CRP) of 166 mg/L. There was also leucocytosis and decreasing haemoglobin values. On 11 January, the patient was discharged with a prescribed daily dose of 40 mg of prednisone; she followed this treatment until May, when she started feeling asymptomatic and decided to discontinue prednisone. However, in July, she restarted steroid therapy because of the arthralgia.

In August 2019, while in Equatorial Guinea, she presented to a hospital with fever, mild hepatitis and pleuritic right-sided pain, which improved with levofloxacin and corticosteroid therapy for 10 days.

Nevertheless, on 10 September she presented to our hospital again with recurrent fever of 39°C and pleuritic right-sided pain. She also had respiratory insufficiency, mild hepatitis and, as shown in figure 1, high levels of serum LDH. In addition, rising inflammatory markers (figure 2) and leucocytosis (figure 3) with neutrophil predominance of 18 700/μL were found in blood tests.

Figure 1.

Serum lactate dehydrogenase (LDH) follow-up levels during the last admission and after discharge.

Figure 2.

C-reactive protein (CRP) follow-up levels during the last admission and after discharge.

Figure 3.

Leucocytes follow-up levels during the last admission and after discharge.

Odynophagia, a salmon-coloured rash on the neck and neckline, urinary incontinence, and wrist, hand and knee arthralgia were found on physical examination of the patient. The thoracic CT showed segmental atelectasis, pleural effusion and presumed pneumonia.

During her hospital stay, the symptoms did not abate with the use of painkillers, corticosteroids and antibiotics (which were not stopped until 26 September, due to the presumed community-acquired pneumonia). Oxygen saturation continued dropping to 88% and the patient developed anaemia, as shown in figure 4, so transfusions of red blood cells were given on 18 September.

Figure 4.

Haemoglobin follow-up levels during the last admission and after discharge.

The patient continued to have high-spiking fevers and developed acromioclavicular joint arthralgia and arthritis. In addition, serum ferritin levels increased to 39 728 ng/mL, as shown in figure 5.

Figure 5.

Ferritin follow-up levels during the last admission and after discharge.

The final diagnosis pointed to an interstitial pneumonitis and respiratory insufficiency in the context of an AOSD flare.

Investigations

Pulmonary manifestations are signs of severe AOSD, as well as other systemic symptoms, but they can also be secondary to infection.

A breast MRI was done to rule out a possible complication of breast implants, which could have explained the badly controlled immune disorder.

Atypical pneumonia was dismissed, because during the previous admission levofloxacin was unsuccessfully administered, as well as tuberculosis and a viral infection due to negative interferon-gamma release assay (IGRA) results and negative PCR results, respectively. Aspergillosis and Pneumocystis jirovecii pneumonia were also dismissed after negative galactomannan results and negative beta-D-glucan assay results, respectively.

With all this information and according to the Yamaguchi criteria,⁷ the only diagnosis that properly fitted was interstitial pneumonitis secondary to a severe AOSD flare.

Treatment

Following the first diagnosis, the patient was treated with intravenous methylprednisolone, ceftriaxone and levofloxacin during all her previous admissions. After she was discharged, treatment continued with 20 mg of prednisone per day.

When the patient presented to our hospital in September 2019, she was initially treated with 60 mg intravenous methylprednisolone, painkillers and ceftriaxone. However, her inflammatory markers did not improve, as shown in figures 1, 2 and 5, and she suffered from high temperature spikes reaching 39°C; so ceftriaxone was replaced by meropenem until Pneumocystis jirovecii pneumonia and other infectious causes were dismissed.

Once the diagnosis was established, a therapeutic plan of 3 days with 500 mg of pulsed intravenous methylprednisolone, 10 mg of methotrexate per week, and a daily dose of 100 mg of anakinra was started. Anakinra treatment was prescribed at this point in consideration of the severe stage of the disease, despite previous treatments, and based on previous case reports of successful anakinra treatment.^{12 14–24}

Methotrexate administration was started at the same time as anakinra, as the effectiveness of methotrexate takes 2–3 weeks to appear following its first dose; in this way, the effectiveness of methotrexate should already be established by the time the administration of anakinra was stopped.

Two days after the first subcutaneous injection of anakinra was administered (on 28 September), the patient was practically asymptomatic.

She discontinued anakinra on 25 October and has been in remission ever since.

Outcome and follow-up

Symptoms began to decrease 2 days after the first dose of anakinra was administered. The dyspnoea and arthralgia disappeared, and the oxygen saturation increased up to normal levels. The effectiveness of anakinra was also observed in the evolution of the serum parameters after its administration (figures 1–5).

After the patient was discharged on 4 October, she continued without symptoms with a maintenance dose of 10 mg methotrexate per week, 30 mg prednisone per day and 100 mg anakinra per day. Due to good tolerance, the weekly dose of methotrexate was increased to 15 mg.

Three weeks later, on 25 October 2019, the patient stopped taking anakinra and maintained the corresponding doses of methotrexate and prednisone. The latest analysis revealed normal haemoglobin, leucocytes, platelets, CRP, LDH and ferritin levels; she continued in remission during her 7 months follow-up and no adverse effects have been detected throughout this period.

Discussion

Some autoinflammatory diseases, such as AOSD, have been shown to be related to inappropriate IL-1 production.²⁵

Ruscitti et al ²³ performed a meta-analysis of 19 studies that included a total of 417 patients in order to determine the effectiveness of biological drugs in the treatment of AOSD; researchers estimated that 85% of patients clinically responded to treatment and 66% reached complete remission. They also proposed anakinra as a suitable option in refractory systemic AOSD due to highly expressed IL-1 in patients with mainly systemic manifestations.

Anakinra is an immunosuppressive drug that competitively inhibits IL-1 receptors, thus neutralising the biological activity of IL-1 and, therefore, reducing inflammation; its effectiveness has previously been reported in the treatment of several diseases such as RA, cryopyrin-associated periodic syndromes, JIA and AOSD.^{22 26}

The first effective use of anakinra in AOSD was reported by Rudinskaya et al ²⁷ in 2003. Between 2005 and 2013, six case series12 15 18 28–30 and one prospective randomised open label trial¹⁶ were published with data from a total of 92 AOSD patients. The observed rate of complete remission ranged from 50–100%. In addition, corticosteroid therapy could be reduced or even stopped in the majority of patients. This is particularly important in young patients who are more affected by short-term and long-term adverse effects of glucocorticoid treatment. In the present case, corticosteroids were successfully tapered from 30 mg to 15 mg in a 4 month period.

On the other hand, and particularly in refractory AOSD, treatment with anakinra has also been shown to be effective. In 2015, Ortiz-Sanjuán et al ²¹ analysed data from 41 surveyed patients with AOSD, who had previously responded inadequately to corticosteroids and to at least one disease-modifying antirheumatic drug, and who were finally treated with anakinra. The conclusions were that anakinra was associated with a rapid and maintained clinical and laboratory improvement in most patients from their series. In the present case, treatment with anakinra resulted in a remarkable reduction of pleural effusion and the interstitial pneumonitis disappeared. Serum ferritin levels decreased 2 days after the first dose of anakinra was administered, as well as LDH, CRP, leucocytes and platelets levels.

In the present case, a particularly intensive approach was chosen to treat interstitial pneumonitis and pleural effusion in the context of an intermittent polycyclic pattern of AOSD that was unresponsive to conventional treatment; the prevention of pulmonary failure was the reason for administering anakinra for 28 days at a daily dose of 100 mg. It was also the selected treatment due to its high effectiveness in neutralising IL-1 in patients with highly active systemic disease, as in our case, rather than in patients with joint involvement.^{21 23 30}

Based on previously published investigations and the present study, anakinra could be considered as first-line therapy in refractory systemic AOSD. In addition, in severe cases, such as the one described here, early treatment with this biologic drug in monotherapy could represent an important benefit for the patient, as previously mentioned by Sota et al ²⁰

In conclusion, this was a complex case of AOSD in which the patient underwent multiple treatments, including glucocorticoids for a long time and antibiotics among others, always with poor long-term efficacy and a continuous need for intravenous high-dose glucocorticoids. To the best of our knowledge, this is the first reported case of the successful treatment with anakinra of interstitial pneumonitis and pleural effusion associated to refractory AOSD. Further investigations should be carried out.

Learning points.

• New commercial drugs for the treatment of rheumatoid arthritis have superseded the use of anakinra for this specific pathology; however, this biological drug has been shown to be highly effective in the treatment of adult-onset Still disease (AOSD).

• The successful treatment with anakinra of a case of interstitial pneumonitis and pleural effusion associated to refractory systemic AOSD points to its potential use as first-line therapy in severe pulmonary cases.

Data availability statement

All data relevant to the study are included in the article.

Ethics statements

Patient consent for publication

Obtained.