Introduction

Rheumatoid arthritis (RA) is a systemic chronic autoimmune disease of unclear etiology that primarily involves the articular joints, but can also lead to several extra-articular manifestations [1–4]. Studies have reported a wide spectrum of RA disease severity among patients with human immunodeficiency virus (HIV) infection [5, 6]. Dealing with these two concurrent diseases is a great challenge for physicians, as management of RA requires the use of immunosuppressant drugs and/or corticosteroids that could potentially promote HIV virus replication and facilitate the progression of the disease [7]. Therefore, evaluation of the effectiveness and safety of anti-rheumatic drugs to control the disease progression of RA among patients with HIV infection is required to ensure that they do not interfere with the HIV infection progression [7].

Tumor necrosis factor alpha (TNF-α), which plays a vital role in host defense against intra-cellular pathogens, is a key pro-inflammatory cytokine that promotes the progression of both RA and HIV infection [8, 9]. The treatment of RA has been revolutionized by the use of biological drugs, such as anti-TNF agents [10, 11]. However, little is known about the concomitant influence of anti-TNF therapy on RA and HIV infection. A few cases have been published documenting the use of TNF-α inhibitors in patients with concurrent RA and HIV (RA–HIV) [12–14]. Therefore, the aim of our case-based review was to describe the successful treatment of a 38-year-old female patient with concomitant RA and HIV infection, who was treated with etanercept (ETN), a soluble TNF receptor (p75): FC fusion protein, following failure of treatment using standard modifying antirheumatic drugs (DMARDs) therapy. We complement our case report with a focused review of existing literature regarding the use of ETN in RA-HIV patients.

Case report

In February 2010, a 38-year-old woman presented to our rheumatology clinic for the management of her RA status. She had been diagnosed with RA 5 years previously, based on the presentation of symmetrical polyarthritis (involving the shoulders, knees, wrists, and metacarpophalangeal and proximal interphalangeal joints), morning stiffness, and positive testing results for rheumatoid factor (RF) and anti-cyclic citrullinated protein (anti-CCP). Her previous medical history was positive for asthma and surgical management of an ectopic pregnancy. At the time of presentation, her treatment included the use of hydroxychloroquine (HCQ), leflunomide (LEF) and methotrexate (MTX), with an unsatisfactory control of her RA disease severity. Physical examination revealed active synovitis of the proximal interphanlangeal and metacarpophalangeal joints, shoulders, and knees.

Routine blood analysis (Table 1) and a radiological examination were performed. Results of the initial blood tests were noticeable, with marked elevation of inflammatory factor levels, including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and interleukin 6 (IL-6). Additionally, serum RF, anti-CCP antibodies, and anti-nuclear antibodies titers were present. Routine screening results for common opportunistic infections, such as tuberculosis, was negative. Radiograph examination of both hand and knee joints revealed bilateral metacarpophalangeal joint erosions and joint space narrowing.

Table 1 Laboratory results
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Despite the utilization of optimal DMARDs, the patient’s active RA status remained unchanged, even with the addition of oral steroids tapers (15 mg/d). The severity of her RA symptoms had forced the patient to stop working, the patient reporting being depressed and intermittently stopping her medication use and frequently changing her medications. In March 2012, ETN (25 mg/week) was added to her RA drug therapy, with remarkable and rapid improvement in RA disease manifestation (Fig. 1). Over the next 2 years, the patient continued to use ETN as required.

Fig. 1
figure 1

Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) serum levels throughout the entire follow-up, pointing-up correlations with treatments, and HIV infection

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In January 2014, the patient tested positive for HIV, with a CD4+T cell count of 481/mm3 and a virus load of 20 copies/mL. Owing to the marked RA activity and seriousness of the swelling of her joints at that time, ETN (50 mg/week) was added to her treatment. In March 2014, after 10 subcutaneous infusions of ETN, the patient was deemed to be in clinical remission of RA, with no active joints identified and CRP level <8 mg/L (Fig. 1). Routine use of ETN was subsequently maintained for a period of nine months, with cessation of steroid therapy. No opportunistic infections developed over the time-period of ETN. In February 2016, the HIV infection remained stable, with a virus load <20 copies/mL and a CD4+T cell count of 516/mm3. No anti-retrovirus drugs were used throughout the biological treatment course for RA.

Discussion

In this case, we describe the successful use of ETN to treat a patient with severe RA and concomitant HIV infection. Although the patient had been resistant to optimal DMARDs, the addition of ETN produced rapid and remarkable improvements in the patient’s RA disease status (Figs. 1, 2), with benefits maintained over the 30-month follow-up period. Her HIV disease status remained stable without use of any anti-retrovirus agents, with no development of opportunistic infections or adverse effects.

Fig. 2
figure 2

DAS 28 scores and CD4+ lymphocytes (mm−3) during the treatment of RA with etanercept

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Over the past decades, the treatment of RA has significantly evolved with the introduction of several biological anti-TNF therapies, providing excellent symptomatic remission in many patients with RA. ETN, one of the most widely utilized anti-TNF medications, has been proven to be effective and relatively safe in several clinic studies [15, 16]. Since the comorbid occurrence of RA and HIV infection is rare, the effectiveness and safety of ETN in these patients has only been reported in a few case reports and thus remains unclear. To best of our knowledge, a retrospective review of the published literature was performed by searching the PubMed and MEDLINE databases using the key words “rheumatic arthritis,” “HIV” and “etanercept” (period 2000–2016). Only articles available in English were reviewed. Except for 4 irrelevant articles, the remaining 3 case reports were included in this review (summarized in Table 2).

Table 2 Reported cases of RA concomitant with HIV, treated with TNF inhibitors
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Kaur et al. [12] described the case for a 44-year-old man with a long history of RA, with concomitant HIV, HBV and HCV infection. Highly active anti-retrovirus therapy (HAART) was used because of the low absolute CD4 count (299/mm3) at first presentation in 1999. With progression of the severity of the active arthritis and poor outcomes with DMARDs, TNF antagonists were added to the patient’s drug therapy. The patient developed an allergic reaction after three infusions of infliximab, which required discontinuation of this drug. The patient was subsequently treated using ETN (50 mg/week), with a good clinical response of RA symptoms, with CD4 count increasing to 530/mm3 and HIV virus replications decreasing to <50 copies/mL. No opportunistic infections or adverse events were reported.

In 2008, Cepeda et al. described the outcomes of two patients with RA and HIV who were treated with ETN for at least a 12-month period [13]. An excellent response to ETN was identified in both cases, with no opportunistic infections reported, with no anti-retrovirus treatment required in one patient. The absolute CD4 count and HIV virus load were closely monitored throughout the treatment, with no evidence of HIV progression or deterioration in CD4 count.

Finally, De Nardo et al. [14] reported on ETN treatment for a woman with RA and HIV (CD4 >500 cells/mm3, virus load <50 copies/mL). Again, a dramatic improvement in RA disease status was reported within 2 weeks of treatment onset. However, this patient did progress to septic shock and multiple organ failure after receiving a seasonal influenza vaccine, with adjuvant, 2 weeks after onset of ETN treatment. Despite plasma exchange, the patient’s clinical condition deteriorated rapidly, with diagnosis of acute respiratory distress syndrome and kidney failure. The patient was intubated, with hemodialysis and antibiotic therapy initiated. The patient survived the acute episode and her condition gradually improved.

Consistent with the above results, our patient had an excellent response to ETN, despite her positive HIV infection status, with reduced joint swelling and decreased acute-phase inflammation markers (Fig. 1), progressing to complete clinical remission of her RA status (Fig. 2). The HIV infection was stable and no anti-retrovirus drugs were required, with no incidence of opportunistic infection or adverse effects. Additionally, it was reported that anti-TNF therapies, including ETN, can be successfully used for the treatment of HIV-associated arthritis in patients with a stable HIV infection status and CD4+ lymphocyte counts [17]. Other studies have confirmed the effectiveness and safety of using ETN for the management of psoriasis and psoriasis-related arthritis in patients with HIV infection, over long-term follow-up [18–20]. Therefore, TNF-alpha antagonists can provide an effective and safe treatment option for RA in patients with a positive HIV infection status, and may, in fact, attenuate the progression of the HIV infection. The mechanisms underlying the effect of TNF-alpha antagonists on the HIV infection remain unclear.

Previous studies have suggested that TNF-α promotes HIV propagation, ultimately leading to the acquired immuno-deficiency syndrome (AIDS) [21]. High TNF-α levels are typically present throughout all stages of HIV infection, with the highest levels detected during presence of concomitant opportunistic infection. Therefore, excessive TNF-α production may aggravate HIV disease status, amplify the loss of immune capacity and, ultimately, result in clinical manifestations of AIDS [22]. A prospective cohort study further reported elevations in serum TNF-α levels in patients treated with anti-retrovirus agents, with levels increasing with progression of the infection status [23]. In vitro studies have also reported that TNF-α promotes the expression of HIV protein through the nuclear factor kappa beta (NF-κB) signaling pathways [24]. HIV-related proteins, such as Gp120 and Nef, further promote the expression of TNF-α via common pathways, which ultimately augment virus propagation and cause apoptosis of uninfected bystander immune cells [9, 25].

Several clinical studies have suggested that anti-TNF therapy could improve the disease status of HIV/AIDs [26–29]. In a randomized trial, ETN was used in six patients with HIV infection who were on a highly active antiretroviral therapy (HAART), with a virus load <5000 copies/mL. Absolute CD4 counts remained stable, with no serious complications attributable to the use of ETN reported [26]. Based on this evidence, strategies to inhibit TNF-α in HIV patients may, theoretically, be of clinical significance.

Considering the critical role of TNF-α in the progressive elimination of intracellular pathogens, anti-TNF therapies may increase the risk of serious opportunistic infections [30, 31]. Several infections have been reported in association with anti-TNF therapies, including bacterial, viral, fungal, and parasitic infections [32]. The development of active tuberculosis among patients on anti-TNF therapies is a serious concern [33]. Due to compromised immune function, HIV-positive patients frequently present with atypical extrapulmonary manifestations or disseminated diseases, which increase the difficulty of effectively managing the HIV infection [34]. Therefore, the use of TNF antagonists should be carefully considered in patients who are at risk for tuberculosis, particularly those who are HIV-positive. Consistent with published guidelines, at-risk patients should undergo routine tuberculosis screening, which, for our patient, were consistently negative [33]. Furthermore, it was suggested that anti-TNF therapies were effective and safe to use in patients with rheumatic disease in whom the underlying HIV infection is stable (restricting use of anti-TNF in patients with a CD4 count <200/mm3 and viral loading <6000 copies/mL at the beginning of the therapy) [13]. Closely monitoring HIV viral load, as well as CD4 count, is of great importance, especially in HIV-infected patients on immune suppressive drugs, such as anti-TNF therapies.

Based on our case review, we propose that anti-TNF therapy is a viable alternative for the treatment of RA in patients with HIV infection who are not responding to conventional DMARDs, as long as the underlying HIV infection status is stable. Awareness of the therapeutic potential of anti-TNF therapies and of potential adverse effects is necessary for an optimal use of anti-TNF in this clinical population [32]. Close monitoring of clinical parameters of HIV infection status, with judicious use of antiretroviral agents, should be considered. Moreover, patients should be screened for latent tuberculosis before implementing anti-TNF therapy. Further clinical studies are needed to provide definitive evidence regarding the effectiveness and safety of anti-TNF agents for RA in patients with HIV.

Written informed consent was obtained from the patient for publication of this report.