Alopecia Areata Following the Use of Belimumab in a Patient with Systemic Lupus Erythematosus and Arthritis Who Responded Well to Baricitinib: A Case Report

Introduction

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that has a relapsing and remitting course. Complement is commonly used as a marker of disease activity in SLE. In active disease, serum complement levels are usually reduced. There are many clinical manifestations, ranging in severity from mild to life-threatening [1]. The cornerstone of SLE treatment includes hydroxychloroquine and adjunct medications, such as corticosteroids, immunosuppressants, and biologics [2,3]. However, maintaining remission in SLE is difficult, and distinguishing between disease manifestations and medication adverse effects poses a significant challenge.

Conducting research on SLE is a challenging task. There was a composite outcome measure in all studies that did not focus on 1 or a few manifestations. From this perspective, the overall improvement in disease activity cannot be directly attributable to an improvement in a single manifestation. The heterogeneity of the disease, with different pathogenic mechanisms for clinical manifestations, is an essential part of this difficulty. The treating physician can follow the appropriate recommendations for management and carefully select patients with lupus for a particular drug. Unexpectedly, a significant adverse effect may develop, and off-label drug use may control this adverse effect and other lupus manifestations.

We report a standard case of a lupus patient with hair loss and arthritis who initially responded well to belimumab but unfortunately developed progressive alopecia areata (AA) to complete hair loss from her body, as alopecia totalis (AT) and alopecia universalis (AU). The use of baricitinib resulted in a significant improvement in her AA, and unexpectedly, lupus-related arthritis responded as well. The patient provided consent for the publication of her case and associated images.

Case Report

A 54-year-old female patient from Saudi Arabia presented to the Rheumatology Clinic at Dr. Soliman Fakeeh Hospital in August 2019 with generalized fatigue, tiredness, and significant hair loss, which rated at 50%, indicating a severe condition based on the Severity of Alopecia Tool (SALT) score, with no evidence of anxiety or mood disorders. Additionally, she had oligoarthrities for the past 2 years, reported as tenderness in multiple joints without swelling, heat, or redness, involving a total of 4 joints. Furthermore, non-scarring annular patches of hair loss were noted on the right temporal scalp (Figure 1A, 1B). Laboratory investigations revealed a C-reactive protein level of 7.1 mg/L (reference range: <5 mg/L), positive antinuclear antibodies and anti-double-stranded deoxyribonucleic acid (anti-ds DNA). The rest of her laboratory findings were unremarkable. A diagnosis of SLE was established. Therefore, she was started on conventional therapies including hydroxychloroquine 200 mg twice daily and azathioprine 50 mg twice daily. A few months later, during her follow-up appointments, mucocutaneous findings progressed, with worsening arthritis symptoms. Therefore, we decided to start 600 mg intravenous (i.v.) belimumab in addition to her current medications. At the next follow-up, she showed significant improvement in her symptoms. This improvement persisted during the subsequent visits, and the patient expressed satisfaction with the progress (Figure 2A, 2B). However, after a few months, she began experiencing gradual deterioration with symptoms including increased fatigue, tiredness, and significant hair loss, again affecting most of her scalp, eyelashes, and eyebrows. This observation was documented during more than 1 clinical visit. She was assessed by a dermatology service, and her condition was labeled AA based on the pattern of hair loss, as shown in Figure 3A–3D. Initially, we suspected that this might be related to lupus disease activity. However, the patient started on topical prednisolone injections and showed a satisfactory response at the beginning. During her treatment course, she unexpectedly started to lack a response to her medications as she developed AT and AU. Thus, methotrexate was initiated instead of azathioprine, and the belimumab dose was increased to 800 mg i.v. A few months later, in January 2021, hair loss progressed to AU (Figure 4A–4D). The possibility of adverse drug reactions from belimumab had been raised. Consequently, the administration of belimumab was ceased, while maintaining the previous management approach. One month after discontinuing belimumab, the patient experienced gradual hair growth with systemic and local steroid injections. Over the following few months, we attempted to gradually taper her prednisone, but without major success in terms of her symptoms. The addition of mycophenolate mofetil (MMF) 2000 mg/day instead of methotrexate did not seem to help over a period of approximately 5 months. We tried to re-challenge her with belimumab, but this resulted in losing the gain that was achieved before, only after 2 doses of belimumab in the re-challenge phase. Following a detailed discussion with our colleagues in the Dermatology Department, we decided to discontinue belimumab and MMF and start baricitinib at 4 mg daily, while maintaining hydroxychloroquine. One month after starting baricitinib, the patient exhibited a discernible initiation of improvement in her AU, and during subsequent follow-up visits, she started regaining nearly all her hair (Figure 5A, 5B). Her joint symptoms improved significantly, without any joint pain or tenderness on physical examination. We were able to gradually taper the prednisone to complete the treatment. Her most recent serology in March 2024 showed normal C-reactive protein levels and negative anti-ds DNA serology. The patient remained on baricitinib 4 mg and hydroxychloroquine.

Discussion

We reported a case of a female patient with longstanding SLE with notable hair loss and oligoarthritis throughout the course of her disease. The patient underwent a step-by-step treatment approach, initially receiving hydroxychloroquine and azathioprine. However, her symptoms worsened over time, necessitating the addition of belimumab to her regimen. Initial improvement was maintained for a while, but later, the patient experienced gradual deterioration, including the development of gradual hair loss over the scalp, ultimately affecting her entire body, as AU. Concerns about an adverse reaction to belimumab prompted its discontinuation along with MMF, and the patient was switched to baricitinib, while continuing hydroxychloroquine in addition to local measures and systemic steroid therapy. After 1 month of baricitinib treatment, the patient showed significant improvement in alopecia and arthritis. Her lupus was in remission until the time of this report.

Belimumab was the first biological therapy approved for SLE treatment. It is included in the current European Alliance for Associations of Rheumatology recommendations for the management of SLE [4]. In our report, we observed that the patient developed worsening AA after significant initial improvement with belimumab treatment. Our initial thought focused on lupus disease activity, but ongoing deterioration let us to stop belimumab. The AA as a manifestation could be related to synergistic effect between belimumab and her current treatment. This assumption was questioned when her AA worsened again after re-challnege with belimumab, since the patient was exposed to 3 different drugs while she was on belimumab (azathioprine, methotrexate, and MMF). Secondary failure is a well-reported phenomenon following use of biological drugs. This would explain the initial improvement of the patient’s condition following the use of belimumab and then lack of efficacy. Several phase III trials have demonstrated the effectiveness of belimumab as targeted biotherapy for SLE [5]. AA or any other paradoxical induction of adverse effects of autoimmunity was never reported in these trials, as outlined by others [6]. In a recent case series [6], belimumab was discontinued in 2 out of 3 patients who developed AA following the use of belimumab, but they did not re-challenge these patients with belimumab to further confirm a true relationship with AA. We re-challenged our patient with belimumab, which unfortunately worsened her AA further. We reached a more confident stage in making a clinical decision to permanently stop belimumab in our patient. We were less likely to consider AA as a part of an SLE disease flare in this patient. This was despite the association between AA and SLE [7].

Belimumab is an anti-B-lymphocyte stimulator monoclonal antibody that affects B cells as well as the T cell lineage [8]. Blocking the B-lymphocyte stimulator has been associated with reduced CD4+ and CD8+ T-cell counts and increased regulatory T-cell activity, suggesting a potential protective effect and lower risk of AA induction. However, it is important to note that belimumab, despite primarily targeting B cells, also influences CD4+ follicular T-helper (TFH) cells [9,10]. Consequently, impairment of TFH cells in certain patients could potentially lead to the autoreactivity of CD8+ T cells. Therefore, belimumab can contribute to the development of AA [8]. Further research is required to fully understand the mechanisms and potential links between belimumab and AA induction.

Baricitinib (JAK 1 and 2 inhibitors), a recently approved medication for certain autoimmune disorders, have shown promising results in various studies. In a trial focusing on patients with severe AA [11], continuous therapy with oral baricitinib for >52 weeks resulted in increased regrowth of scalp hair, eyebrows, and eyelashes. The clinical response was more pronounced at a dose of 4 mg than at 2 mg. Additionally, another trial involving patients with severe AA [12] demonstrated that oral baricitinib was more effective than placebo in promoting hair regrowth at 36 weeks in 2 phase III studies. However, the effectiveness of baricitinib in treating SLE remains unclear. An interesting finding in our case was the significant effectiveness of baricitinib in improving the arthritis. A systematic review and meta-analysis of randomized controlled trials [13] revealed that a dosage of 2 mg did not provide clinical benefits in SLE, whereas a dosage of 4 mg significantly reduced disease activity at week 24, as measured by the SRI-4 response. However, this difference was not maintained at week 52. Previous meta-analyses [14,15] have shown similar findings. Overall, further research is needed to evaluate the steroid-sparing effect and long-term efficacy of 4 mg baricitinib in patients with SLE.

There is a gap in lupus research, as the outcome is usually a composite measure of disease activity. However, this measure does not meticulously specify the degree of improvement in a particular clinical domain. Baricitinib research in lupus has shown promising results in phase II trials [11]; however, the results were not replicated in phase III trials [10]. Our case provides insight into future studies on SLE by focusing on specific outcomes rather than composite outcomes. Therefore, a new approach to research on lupus is recommended. Baricitinib might be a good drug for highly selected patients with lupus, particularly those with AA and arthritis.

Conclusions

Here, we report a case of lupus with arthritis and significant hair loss. The patient’s symptoms initially improved with belimumab treatment; however, this response was not maintained. Significant hair loss in the form of AA and AU developed while she was on belimumab and recurred with re-challenge. Following the discontinuation of belimumab, our patient showed significant hair growth with improvement in arthritis with the use of baricitinib. It is important to further investigate the effectiveness of baricitinib in managing lupus by focusing on 1 or 2 domains as outcome measures.