Successful tocilizumab and tacrolimus treatment in a patient with rheumatoid arthritis complicated by systemic lupus erythematosus

Introduction

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that causes various symptoms and immunological abnormalities. The standard therapy for SLE includes corticosteroids, azathioprine (AZA) and cytotoxic therapy with cyclophosphamide (CYC). However, SLE is often refractory to conventional therapeutic strategy. Mycophenolate mofetil (MMF) and anti-B cell therapy with rituximab have been shown to be efficacious for refractory cases, but they are not approved as drugs for SLE in Japan.

Tocilizumab (TCZ) is a humanized anti-interleukin-6 (IL-6) receptor antibody that neutralizes the pleiotropic actions of IL-6. Clinical trials have demonstrated the efficacy of TCZ for patients with rheumatoid arthritis (RA), Castleman's disease or juvenile idiopathic arthritis, leading to approval of TCZ for the treatment of these diseases. ¹ Several studies suggested that IL-6 may also play an important role in SLE.^2,3 Based on these findings, an open-label phase I dosage-escalation study was conducted. ⁴ This pilot study provides the first data that TCZ can effectively block IL-6 in patients with SLE. Tacrolimus (TAC) is a relatively new calcineurin inhibitor that has been increasingly used in transplant medicine. Recently, the clinical efficacy of TAC in the management of lupus nephritis has been reported. ⁵ TAC has also been successfully used in the treatment of RA, ⁶ and administration of TAC at an oral dose of 3 mg/day was approved for the treatment of lupus nephritis and RA in Japan. On the other hand, reports regarding the use of TAC for SLE patients without renal involvement are limited. ⁵

Here, we report on a patient with SLE accompanied by RA, in which arthritis and immunological abnormalities developed despite aggressive immunosuppressive therapy including high-dose steroids and intravenously administered CYC (IVCY), successfully treated with a combination of TCZ and TAC.

Case report

A 37-year-old woman was diagnosed with RA when she was 21 years old, and had been administered oral prednisolone, injectable gold and salazosulfapyridine. However, deformity of her hands gradually developed with persistent pain and joint swelling. In October 2009, she visited a nearby hospital because of prolonged high fever, in addition to polyarthralgia, and outstanding findings from laboratory examinations are summarized as follows: white blood cell (WBC) count, 5,800/µL (normal 4000–9000/µL); hemoglobin, 11.4 g/dL (normal 12.0–16.0 g/dL); platelets, 29.5 × 10⁴/µL (normal 14.0–40.0 × 10⁴/µL); C-reactive protein (CRP), 18.3 mg/dL (normal <0.3 mg/dL); rheumatoid factor (RF), 2832 IU/mL (normal <10 U/mL); RF-IgG, 8.6 (normal <2.0); anti-cyclic citrullinated peptide antibody (anti-CCP antibody), 989 U/mL (normal <4.5 U/mL). Serum complement levels were low: C3, 39 mg/dL (normal 65–135 mg/dL); C4, 4 mg/dL (normal 13–35 mg/dL); total complement activity (CH50), 12.0 U/mL (25–48 U/mL). Conversion to malignant RA was suspected, and methotrexate (MTX) was then started. In February 2010, thrombocytopenia (platelets, 6.3 × 10⁴/µl) developed. Since it cannot be denied that thrombocytopenia was induced by MTX, the drug was discontinued. Antinuclear antibodies (speckled staining pattern) showed a 2560-fold positive result (normal <20-fold), anti-Sm antibodies were 76.8 U/mL (normal <10.0 U/mL), anti-double-stranded DNA antibodies (anti-dsDNA antibody) were 160 IU/mL (normal <12 IU/mL), serum immune-complex (C1q) was 13.4 µg/mL (normal <3 µg/mL). Chest radiography revealed enlarged cardiothoracic ratio (61%), and echocardiography identified pericardial effusion. Urinalysis showed sediment containing 20–35 red blood cells (RBCs) and 0–2 WBCs per high-power field (HPF), and various types of cast without proteinuria. The patient fulfilled 5 of 11 criteria set by the American College of Rheumatology for SLE, showing renal involvement, hematological abnormality, pericarditis, positive antinuclear antibodies and anti-dsDNA antibodies. She was referred to our hospital for further examination and treatment in March 2010.

On physical examination at admission to our hospital, polyarthritis and ulnar deviation and swan neck deformity of the fingers were observed. RA was diagnosed by the presence of morning stiffness, polyarthritis, radiographic changes and a positive test for RF. Disease Activity Score in 28 joints (DAS 28)-erythrocyte sedimentation rate (ESR) was 7.36. The Steinbrocker classification for this patient was stage IV and class III. She had no history of butterfly rash, photosensitivity, alopecia, oral ulcers or Raynaud’s phenomenon. She was diagnosed with SLE coexisting with RA. Although the complication of lupus nephritis was suggested, a nephrologist declined to perform a renal biopsy because of thrombocytopenia (platelets, 2.3 × 10⁴/µl at the time). She was initially administered intravenous corticosteroid (methylprednisolone, 500 mg/day, 3 consecutive days) followed by oral corticosteroid (prednisolone, 50 mg/day) (Figure 1). urine casts and pericardial effusion disappeared and platelet count moderately increased; however, prominent immunologic abnormalities persisted. Furthermore, discoid lesions appeared and polyarthralgia was rapidly exacerbated during dose reduction of prednisolone (40 mg/day at the time), so IVCY therapy (500 or 750 mg/body) was started on 18 May 2010. Although discoid lesions disappeared, none of the other clinical and laboratory parameters were resolved. Therefore, TAC (2 mg/day) was introduced on 31 August 2010. IVCY therapy was stopped due to adverse effects of alopecia on 16 September 2010. Polyarthralgia slightly improved after introduction of TAC, but its comprehensive therapeutic effect was obviously inadequate. Since trough serum concentration of TAC was relatively low (6.2 ng/dL), we attempted to increase its dosage. However, she developed severe diarrhea with escalating TAC dose, so we were forced to maintain its original dosage. Therefore, we decided to introduce a combination therapy with IL-6 blocking agents after obtaining informed consent from the patient on 15 October 2010. Because some reports suggested that TNF-alpha inhibitors have the potential to exacerbate SLE, ⁷ we selected the additional treatment with TCZ. Complete relief of joint symptoms occurred and DAS28 reached remission criteria after the initiation of TCZ therapy. Furthermore, increased serum levels of anti-dsDNA antibodies and immune-complex rapidly improved. Although thrombocytopenia and decreased serum complement levels gradually aggravated with tapering the dosage of prednisolone, they also tended to improve. Oral corticosteroid was mildly tapered, but the dose of TAC and TCZ has been unchanged. The disease activity has been totally suppressed by this regimen for six months without any complications including infection.

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Figure 1

Clinical course. ANA: antinuclear antibody; anti-dsDNA antibody: anti-double-stranded DNA antibody; CH50: total complement activity; CRP: C-reactive protein; IC: immune-comple; IVCY: intravenously administered cyclophosphamide; mPSL: methylprednisolone.

Discussion

We experienced a Japanese patient with refractory overlap syndrome of SLE and RA. The coexistence of RA and SLE has been reported, ⁸ and proven treatment regimens seem to be needed to treat both RA and SLE. In our case, corticosteroids, salazosulfapyridine and IVCY were ineffective, and it was difficult to use MTX because of thrombocytopenia derived from SLE. The patient responded to TAC therapy by showing partial improvement of joint symptoms, but her immunological manifestations were not controlled. After the initiation of combination therapy with TCZ, that not only obtained a complete remission of RA, surprisingly, the serum levels of SLE markers including anti-dsDNA antibodies and immune-complex dramatically decreased. Our report suggests the possibility that this combination therapy is effective in treating SLE as well as RA.

SLE is a potentially fatal autoimmune disease characterized by a recurring pattern of remission and flare. The prognosis has improved with better therapeutic options, but an appreciable subset of SLE patients fails to achieve optimal disease control. There is a clear unmet need for better and targeted therapies in SLE. IL-6 is a cytokine with multiple biological activities, and it has prominent effects on both B cells and T cells. The efficacy of treatment with TCZ – a monoclonal antibody against the IL-6 receptor – has been demonstrated in completed phase III studies of RA. Serum IL-6 levels of SLE patients were found to be elevated ² and IL-6 blockade was shown to prevent the onset and progression of SLE in murine models. ³ Therefore, TCZ can be expected to become a novel drug for SLE. Recently, the results of an open-label, phase I study of TCZ in patients with SLE was published, showing a decrease in disease activity, the anti-dsDNA antibody level, and the frequency of circulating plasma cells. ⁴ The serum CH50 level of our patient was also elevated by the combination therapy, but it remained subnormal. TCZ has been shown to lower complement levels independently of disease activity, ⁴ so the CH50 level should not be used as a marker of lupus activity.

TAC is a relatively new type of medication and has immunosuppressive effects through specifically inhibiting the calcineurin pathway in T cells. It has been approved for RA and refractory lupus nephritis in Japan. A recent report from Japan also successfully treated 10 SLE patients with TAC without renal involvement. ⁹ Suzuki et al. evaluated the efficacy of TAC in SLE, focusing especially on various lupus manifestations and found it to be effective. ¹⁰ Therefore, it was suggested that TAC acted synergistically with TCZ for the treatment of SLE and RA in our case. Although neutropenia, abnormal liver function tests, alteration in lipid metabolism, and especially infection were concerns, ⁴ these adverse effects were not seen in our patient.

In conclusion, this is the first report to describe that TCZ in combination with TAC, shows dramatic effectiveness in the treatment of not only RA but also SLE. We believe that we have to bear in mind that TCZ, even without combining with TAC, is one of several treatment options in selected cases of refractory SLE, especially accompanied with a condition resembling RA, and that further investigations will be required to establish its efficacy and safety.