Abstract
Tocilizumab is a highly effective therapeutic agent for the treatment of rheumatoid arthritis and systemic juvenile idiopathic arthritis. Furthermore, a large amount of case study data reveals that tocilizumab can be an effective therapy for not only rheumatoid arthritis but also for other mostly rare inflammatory rheumatic diseases. By blocking the interleukin-6 pathway tocilizumab can be a useful therapeutic alternative when conventional treatment fails. It is successful in treating diseases such as the adult-onset Still's disease, amyloidosis, giant cell arteritis, multiple myeloma, polymyalgia rheumatica, relapsing polychondritis, remitting seronegative symmetrical synovitis with pitting edema-syndrome, systemic lupus erythematosus, systemic sclerosis, and Takayasu arteritis. Studies underway are now recruiting patients to acquire further data on treating patients with non-rheumatic arthritis, inflammatory diseases. This review focuses on tocilizumab as a promising agent for treating rare and orphan diseases in rheumatology for which no satisfactory treatment is yet available.
Key messages
Tocilizumab has proven to be an effective and safe treatment option in patients with rheumatoid arthritis (RA) and systemic juvenile idiopathic arthritis.
Tocilizumab works in combination with disease-modifying anti-rheumatic drugs as well as in monotherapy.
Tocilizumab, blocking the interleukin-6 receptor, has promising effects on non-RA systemic, inflammatory rheumatic diseases.
Introduction
Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disease associated with a progressive synovitis causing joint pain, joint swelling, resulting in loss of function as well as in systemic effects. The disease is mediated by the effects of several cytokines, of which so far interleukin-1 (IL-1) through IL-33 have been described (Citation1), leading to systemic effects like depression, fatigue, anemia, osteoporosis, amyloidosis, cachexia, fever, and thrombocytosis.
With the implementation of the biological agents the pathogenesis of the rheumatic diseases increasingly came into the focus of clinical rheumatology. A new goal of clinical rheumatology for RA aims at lower disease activity or remission by treating to target (Citation2).
After the introduction of the tumor necrosis factor (TNF) inhibitors, T cell co-stimulation blocker, CD20-B-cell-antibody, and anti-cytokine IL-6 antibody offer an additional treatment option.
IL-6 is a pleiotropic pro-inflammatory, multi-functional cytokine produced by a variety of cell types including lymphocytes, monocytes, and fibroblasts. It was originally identified as a hepatocyte growth factor and as a B cell stimulatory factor that induces the final maturation of B cells into antibody-producing cells. The secretion of IL-6 is stimulated by IL-1β, IL-2, and TNF-α.
IL-6 is involved in various cellular processes, such as liver regeneration, hematopoiesis, and differentiation of B and T cells and neurons. Furthermore it is a migration factor and attracts T cells.
By activating osteoclast formation, IL-6 may promote erosive joint changes and osteoporosis (Citation3).
Blocking the IL-6 signaling opens up new therapeutic strategies not only for RA but also for other autoimmune inflammatory diseases such as systemic lupus erythematosus (SLE) and systemic juvenile idiopathic arthritis (sJIA).
The humanized monoclonal anti-IL-6 receptor antibody tocilizumab (TCZ) will be the focus of this article.
In the USA the therapeutic use of TCZ is indicated for the treatment of adult patients with moderately to severely active RA who have had inadequate response to one or more TNF antagonist therapies.
In the European Union, the European Medicines Agency (EMA) licensed TCZ (8 mg/kg) to treat adults (aged 18 years or over) with moderate to severe active RA in combination with methotrexate or another disease-modifying anti-rheumatic drug (DMARD) in patients who have not responded adequately to or who could not tolerate other treatments, including conventional medicines for rheumatoid arthritis (such as methotrexate (MTX)) or TNF blockers. TCZ can be used on its own in patients who cannot tolerate MTX. TCZ is also licensed to treat children from 2 years of age with active sJIA who have not responded to other treatments (non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids (GC)). It is used in combination with MTX or on its own if MTX cannot be used. The indications and approved dosages are different in the USA compared to the rest of the world. Since January 2011 in the USA TCZ is indicated for patients who have failed TNF antagonists. This applies as well for patients with moderately to severely active RA at a starting dose of 4 mg/kg every 4 weeks, with an increase to 8 mg/kg according to clinical response. In Japan and Europe, treatment with TCZ is also already indicated for sJIA and Castleman's disease. There is a growing number of case reports on positive treatment effects for single patients with different orphan diseases such as adult-onset of Still's disease (AOSD), amyloidosis, Castleman's disease, polymyalgia rheumatica (PMR), relapsing polychondritis (RP), remitting seronegative symmetrical synovitis with pitting edema (RS3PE)-syndrome, systemic sclerosis (SSc), Takayasu arteritis (TA), and giant cell arteritis (GCA), which will be reviewed in this article.
Pharmacological data
Elevated levels of IL-6 in the serum and synovial fluid of RA patients play an important role in the chronic inflammatory process and correlate positively with disease activity. TCZ is a recombinant humanized anti-IL-6 receptor monoclonal antibody that inhibits IL-6 signal transduction. TCZ binds selectively and competitively with soluble and membrane-expressed IL-6 receptors, in either blocking IL-6 signal transduction that occurs via binding directly to the membrane receptor or by the binding of the sIL-6R/IL-6 complex to gp130.
The IL-6 receptor is a transmembrane receptor having three domains (extracellular, intracellular, transmembrane). Signals are transduced via the JAK/STAT pathway.
In pharmacokinetic analyses no influence was seen related by age, sex, and ethnicity. While no studies have been undertaken to assess the effect of renal or hepatic impairment on the pharmacokinetic parameters of TCZ, patients with mild renal impairment (creatinine clearance at least 50 mL/min) in phase III had pharmacokinetics similar to those with normal renal function (Citation4,Citation5).
In healthy subjects administered TCZ in doses from 2 mg/kg to 28 mg/kg, absolute neutrophil counts decreased to their lowest 3 to 5 days following administration. Thereafter, neutrophils recovered towards baseline in a dose-dependent manner. RA patients demonstrated a similar pattern of absolute neutrophil counts following TCZ administration.
The elimination of TCZ is biphasic. The total clearance is concentration-dependent and equals the sum of linear and non-linear clearance. The non-linear clearance plays a major role at low TCZ concentrations. At higher TCZ concentrations, the non-linear clearance pathway is saturated and so mainly determined by the linear clearance.
Immunogenicity
A total of 2,876 patients have been tested for anti-TCZ antibodies in the controlled clinical trials. Of the 46 patients (1.6%) who developed anti-TCZ antibodies, 6 had an associated medically significant hypersensitivity reaction, of which 5 led to permanent discontinuation of treatment. In 30 patients (1.1%) who developed neutralizing antibodies, no apparent correlation to clinical response was observed. The observed incidence of antibody positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease.
For these reasons, comparison of the incidence of antibodies to TCZ with the incidence of antibodies to other products may be misleading.
Increased exposure to TCZ did not appear to result in an increase in the proportion of patients screened for anti-TCZ antibodies (HAHAs) who developed anti-TCZ HAHA and had associated allergic events or loss of clinical response.
The development of antibodies against TCZ is remarkably lower than the development of anti-adalimumab antibodies (28%), which were observed in a prospective cohort study (Citation6).
Selected case reports and main studies
An overview of the phase III study program with data on efficacy and safety of TCZ in RA has recently been published (Citation7). In the years after the introduction of TCZ, a number of studies have provided growing evidence that the principle of IL-6 receptor blockade is also working in other indications. However, most of them belong to rare diseases. shows a summary of case reports, using TCZ as a new treatment option. provides an overview of on-going studies using TCZ to treat diseases, reviewed in this article.
Table I. Case reports using TCZ.
Table II. On-going studies.
Amyloidosis
Inflammation-associated systemic serum amyloid A amyloidosis (AA amyloidosis) is a severe complication of chronic inflammatory disorders that are associated with a persisting acute phase response involving serum amyloid A protein (SAA) (Citation8). AA amyloidosis mainly affects the gastrointestinal tract and kidneys. This results in diarrhea and proteinuria, which could lead to nephrotic syndrome and finally renal insufficiency (Citation8).
There are currently data on two patients with secondary reactive amyloidosis that is associated with RA in whom TCZ treatment was initialized.
The first patient is a 50-year-old female RA patient (RA diagnosed for 12 years) with severe diarrhea, weight loss, and colon biopsy, showing marked amyloid deposits. She received TCZ (8 mg/kg) every month as treatment. Prior therapy with DMARDs (bucillamine, sulfasalazine, auranofin, leflunomide, tacrolimus, MTX) and GCs (prednisone) did not result in any amelioration of the symptoms (Citation9). Previous treatment with biological agents (etanercept, infliximab) failed to suppress disease activity. After only two TCZ infusions, diarrhea ceased and disease activity of RA improved. Serum levels of C-reactive protein (CRP) and SAA were within range again. After 3 months of TCZ a biopsy of two different parts of the colon was performed and showed no amyloid deposits.
The second case reported is that of a 53-year-old woman with RA who, despite high-dose prednisolone (60 mg) therapy and GC pulse therapy, went into a hypovolemic shock because of severe watery diarrhea associated with gastrointestinal amyloidosis (Citation10). Only 6 hours after TCZ administration, the life-threatening diarrhea lessened and vital signs stabilized the next day.
In addition to the above-described, other cases were reported by Nakamura et al., Inoue at al., and Hattori et al. These also show a promising therapeutic effect (Citation11–13).
Adult-onset Still's disease (AOSD)
AOSD is a multi-organ inflammatory disease of unknown etiology. It is characterized by frequent myalgias, arthralgias, rashes, evanescent spiking fever and sore throat, and laboratory abnormalities (leukocytosis, abnormal liver function tests, elevated acute-phase proteins) (Citation14). Various cytokines like IL-1, -6, -18, interferon-γ, and TNF are involved in the pathogenesis (Citation15).
Several cases of refractory AOSD have been reported in which TCZ dramatically reduced disease activity and thus had a GC-sparing effect.
Puéchal et al. recently evaluated TCZ for the treatment of intractable refractory AOSD in an open study with 14 patients (Citation16). Of those 14 patients, 9 started TCZ therapy at 8 mg/kg every month, 4 patients received 8 mg/kg every fortnight, and the remaining patient started at 5 mg/kg monthly; 8 of the patients were treated in combination with MTX, 2 patients received leflunomide, and 4 of the patients received TCZ as monotherapy. TCZ was administered for 6 months. A total of 11 patients successfully completed the study, while 2 suffered from side-effects (necrotizing angiodermatitis, chest pain, and chills with the administration of TCZ) and had to withdraw; 1 patient left the study due to systemic sclerosis. Altogether, 86% of the patients responded to the therapy. At 3 months, 5 of 14 patients (36%) and at 6 months, 8 of 14 (57%) achieved remission due to the EULAR criteria (DAS 28 < 2.6). In all the patients DAS 28 improved rapidly after the TCZ administration.
Current results strongly suggest that blocking IL-6 is a promising option for the treatment of refractory AOSD. However, further long-term safety and efficacy studies are needed to confirm the effectiveness and safety of TCZ in AOSD.
Ankylosing spondylitis (AS)
AS is a systemic autoimmune disease affecting the axial skeleton and peripheral joints causing characteristic inflammatory back pain, which can lead to structural and functional impairments and a decrease in quality of life (Citation17).
Since TNF antagonists have been implemented in the therapy of AS, outcomes have improved considerably. However, up to 20% of patients do not respond adequately to the standard therapy (Citation17). This result explains the need for further exploration of therapeutical options. In a small cohort study of patients with AS, increased IL-6 was found in biopsy samples from sacroiliac joints in four of five patients (80%) (Citation18).
Hitherto are described two cases of AS patients with insufficient response to standard treatment with NSAIDs, sulfasalazine, MTX, and the available TNF antagonists (infliximab, etanercept, and adalimumab).
Henes et al. described a 36-year-old male patient with persistent disease activity despite standard treatment (Citation19). After inducing treatment with TCZ at 8 mg/kg every 4 weeks, pain was decreased at week 4 and morning stiffness halved to 30 minutes after 16 weeks. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI) and the Bath Ankylosing Spondylitis Metrology Index (BASMI) were considerably improved, and CRP decreased to normal ranges. However, magnetic resonance imaging (MRI) results did not improve.
The second case reported was the case of a 30-year-old man with a history of human leucocyte antigen-B27 (HLA-B27)-positive AS and Crohn's disease (CD) lasting more than 14 years, osteoporosis, recurrent uveitis, and psoriasis (Citation20). After treatment failure with different TNF-blocking agents, therapy with 8 mg/kg TCZ every 4 weeks was undertaken. Due to the absence of any improvement, the infusion frequency had to be increased to every 15 days. One month after the increased dosing frequency of TCZ therapy, a rapid functional and clinical improvement could be seen. Morning stiffness as well as inflammatory markers remained within normal ranges for the first 11 months.
The results with TCZ in the treatment of AS have not been very promising (Citation21) and also led to early termination of several trials in the middle of 2011.
Giant cell arteritis (GCA)
GCA as well as Takayasu arteritis (TA) is a primary systemic vasculitis. It affects mainly the aorta and its main branches, noticeable in granulomatous changes. One should note that disease activity of GCA also highly correlates with IL-6 serum levels (Citation22), as in the other diseases previously described. Granulomatous changes and inflammatory infiltration of the vessel walls of mainly the aorta and its major branches are characteristics of TA (Citation23). These pathogenic changes result in decreased arterial pulses, discrepancies in blood pressure, episodes of syncope, fever, anemia, and other symptoms (Citation24). In this chronic autoimmune-inflammatory disease we find high levels of TNF and IL-6, which eventually is the rationale for the treatment with TCZ. As well as TA, GCA is regularly treated with GCs and MTX, as a GC-sparing drug. Especially in GCA the effect of these medications unfortunately seems to be only modest (Citation25).
In a case study three GC-dependent GCA patients were treated with TCZ. Before treatment with TCZ, remissions could only be achieved with a prednisolone dose of 20 mg/day. Patients were then treated with six monthly infusions of 8 mg/kg bodyweight TCZ, which led to a dose reduction of prednisolone to 7.5 mg/day or less. Moreover, a drastic reduction of systemic inflammation was seen, with a fall in CRP and SAA. Follow-up positron emission tomography (PET) scans also showed a strong reduction in inflammation. This report allows us to conclude that inhibition of TNF (such as infliximab) is not likely to be useful in terms of GCA disease control, whereas IL-6-signaling inhibition through TCZ seems to be an emerging concept in GCA disease control (Citation26).
In the second case study, reported by Salvarani et al., three of six patients achieved complete response with TCZ (8 mg/kg/month), and one patient achieved partial remission. For the two refractory patients, taking GCs at study entry, a dose reduction to 2.5 mg/day was possible. No serious adverse events occurred during TCZ therapy. One patient showed a transient increase of liver enzymes after the second infusion. However, this patient was successfully treated with TCZ without any further elevation of liver enzymes (Citation27).
TCZ seems to be a highly promising therapy for large-vessel vasculitis (LVV). Patients with GCA, as well as TA, showed a marked response to TCZ, as described in a recent publication by Unizony et al. (Citation28).
Fibrinogen and SAA levels as well as all mentioned clinical symptoms normalized after one month. It is of note that the ulcerative colitis also improved under the TCZ treatment.
The initial level of IL-6 of 1720 pg/mL decreased to 114 pg/mL after 46 weeks and to 13.6 pg/mL after 137 weeks. No antibodies against TCZ could be detected at any time during the long-term treatment (> 5 years). A dose reduction for prednisolone from 30 mg/day to first 17.5 mg/day and finally 7.5 mg/day could also be accomplished (Citation29).
Kaly et al. also recently reported on outstanding treatment success in other non-organ-specific autoimmune diseases, such as polymyositis, graft-versus-host disease, Behcet's syndrome, spondyloarthropathies, and TNF-receptor-associated periodic syndrome, with TCZ as well (Citation30).
Polymyalgia rheumatica (PMR)
PMR is a chronic inflammatory disorder that manifests itself with aching and morning stiffness in the shoulders, neck, and pelvic girdles (Citation31). Overproduction of IL-6 seems to play a major role in the pathogenesis of PMR (Citation32). Furthermore, it has been shown that IL-6 correlates with disease activity (Citation32). Hagihara et al. reported one case of a 65-year-old woman with morning stiffness, aching of the shoulders, and myalgias in the upper limbs. Serum levels of CRP were highly elevated. Therapy of 20 mg/day prednisone decreased disease activity. However, when prednisone was tapered to 10 mg/day the disease flared up. Only after one injection of TCZ at 8 mg/kg every month, serum CRP and SAA levels normalized and the pain in the shoulders and pelvic girdle decreased. Morning stiffness disappeared after five infusions of TCZ, and remission was achieved according to the PMR-Activity Score (PMR-AS) criteria (Citation33).
Relapsing polychondritis (RP)
Recurrent inflammation and cartilage destruction of ears and nose are the main characteristics of RP. GCs, immunosuppressive and cytotoxic drugs, have only limited therapeutic index in this rare disease, due to drug resistance and acute airway destruction (Citation34).
It was reported in a letter that TCZ was given to two patients with elevated levels of IL-6, since conventional treatment and also newer treatment options like TNF-α and IL-1 antibodies have shown only poor amelioration.
In case 1 a 29-year-old female patient, who was diagnosed with RP in 2005, showed a decreasing CRP under the treatment of infliximab (3 mg/kg) and MTX (10 mg/week). However, elevating CRP and worsening symptoms were seen after dose reduction of prednisolone. Bronchial airway thickening also persisted under infliximab.
An injection of TCZ (8 mg/kg) was then given monthly, starting in June 2007; 9 months later, subjective symptoms (visual analogue scale) had markedly improved. Moreover CRP remained under 0.04 mg/dL and serum matrix metalloproteinase-3 (MMP3) decreased from 215 to 64–155 ng/mL. After 1 year of treatment with TCZ bronchial widening was seen and prednisolone could be reduced from 15 mg/day to 10 mg/day.
Case 2 involved a 52-year-old male who was admitted in 2006 due to dyspnea and polyarthritis. Costochondral lesions, airway narrowing, and serum autoantibody for type II collagen titer of 2476 U/mL led to RP diagnosis.
Treatment with prednisolone and MTX kept the disease activity stable until September 2007, when a disease relapse occurred. Due to the elevated IL-6 level, TCZ treatment was started at a dose of 8 mg/kg from September 2007 onward. MMP3 decreased from 783–1080 ng/mL to 364–621 ng/mL and joint pain normalized after treatment for 5 months. In addition, CRP, SAA, and the autoantibody to type II collagen titer decreased. Due to the reduction in respiratory symptoms a dose reduction of prednisolone was possible from 15 mg/day to 10 mg/day.
This study for the first time demonstrated the ameliorative effect of tocilizumab on symptoms caused by PR (Citation35).
Remitting seronegative symmetrical synovitis with pitting edema-syndrome (RS3PE-syndrome)
RS3PE-syndrome is an inflammatory disease seen mainly in elderly male patients. RS3PE-syndrome was first described by McCarty et al. in 1985 and is characterized by bilateral pitting edema of the hands and a symmetrical polyarthritis of sudden onset (Citation36). Although the etiology of RS3PE-syndrome is still unclear, it could be shown that IL-6 is involved in the development of the disease (Citation37).
Tanaka et al. were the first to report an ameliorative effect of TCZ. This involved a 51-year-old female patient resistant to GC treatment (Citation38). The patient presented with elevated serum levels of IL-6 (7.8 pg/mL), CRP (0.95 mg/dL), SAA (55 mg/mL), and MMP3 (636 ng/mL). Morning stiffness lasted for 4 hours, and gallium-citrate scintigraphy showed uptake in the bilateral shoulders (Citation38). After the initiation of TCZ (8 mg/kg) every 4 weeks, a remarkable suppression of clinical symptoms was observed, and CRP as well as SAA normalized for the first time. Serum MMP3 levels decreased. As the patient developed a cholecystitis, treatment had to be stopped and disease activity flared up again.
Systemic juvenile idiopathic arthritis (sJIA)
Juvenile idiopathic arthritis (JIA) is comprised of a heterogeneous group of several diseases characterized by a present arthritis of unknown etiology that manifests itself before the age of 16 years and persists for at least 6 weeks, while excluding other known conditions. Systemic JIA, formerly called Still's disease, is a subset of JIA involving patients with intermittent fever, rash, and arthritis; sJIA is the rarest type of JIA, representing 10%–20% of all JIAs.
Excessive IL-6 production seems to be of major importance in the pathogenesis of JIA (Citation39). So far treatment of sJIA remains a challenging task as treatment options are limited and unsatisfactory. The treatment of sJIA with TCZ, with or without concomitant MTX, has been approved by the Federal Drug Administration (FDA) since April 2011 and by the EMA since August 2011. According to the package insert, the recommended dosing for TCZ in sJIA patients weighing less than 30 kg is 12 mg/kg and in those greater than 30 kg, 8 mg/kg at 2-week intervals.
Efficacy and safety of TCZ in patients with systemic juvenile idiopathic arthritis (sJIA)—TENDER
Study design: TENDER is a global phase III study evaluating the efficacy, safety, pharmacokinetics, and pharmacodynamics of TCZ in sJIA. Patients with active sJIA and inadequate response to systemic GCs and NSAIDs are represented in this study. In the first phase, children aged 2–17 were randomized to receive placebo or TCZ every other week. In the second part all patients (n = 88) received open-label TCZ (Citation40). The average age of the patients in the study was 9.5 years, with an average disease duration of 5 years. Most children were presented with very active disease, including fevers in approximately half of the population, and an average of 19 swollen joints.
The long-term extension data from week 104 was presented at EULAR 2012 (Citation41).
Efficacy: After the first dose of TCZ, CRP levels and erythrocyte sedimentation rate (ESR) decreased rapidly and remained so through week 52. At 12 weeks, 85% of the participants receiving TCZ achieved the primary end-point, compared with 24% of children receiving placebo. The proportions of patients achieving efficacy end-points were similar across all TCZ exposure quartiles.
Safety: A greater TCZ exposure was not accompanied by an increased incidence of adverse events. Upper respiratory tract infections, headache, nasopharyngitis, and diarrhea belonged to the most frequent side-effects in the study. The most commonly reported infections included pneumonia, gastroenteritis, chicken-pox, and ear infections; these were more frequently seen in TCZ-treated patients.
Systemic lupus erythematosus (SLE)
SLE is a chronic autoimmune inflammatory disease, affecting joints, skin, kidneys, lungs, nervous system, and other organs of the body. It has been described that multiple cytokines—amongst them IL-6—are involved in the pathogenesis of SLE and play an important role in the regulation of disease activity (Citation42).
An open-label phase I dosage escalation study has been undertaken to collect preliminary data and assess both the clinical and immunologic efficacy of TCZ in patients with mild-to-moderate SLE (Citation43). A total of 16 patients were allocated to receive either 2 mg/kg (group 1; n = 4), 4 mg/kg (group 2; n = 6), or 8 mg/kg (group 3; n = 6) of TCZ given every other week with a total of seven infusions. Illei et al. were also the first to investigate the safety of TCZ in patients with SLE and yield evidence for the acceptable safety profile and an immunologic and clinical benefit for patients with SLE.
Already a single dose of TCZ resulted in a prompt significant decrease of all acute-phase reactants, particularly ESR, fibrinogen, and CRP. At the end of the study, immunoglobulin G levels had significantly decreased, while no change in the anti-double-stranded Deoxyribonucleic acid (dsDNA) antibodies could be identified. Disease activity measured by the systemic lupus activation measure (SLAM) and SLE disease activity index (SLEDAI) scores improved significantly. The mean number of swollen joints improved from 7.7 at baseline to 1.1 at the end of the treatment period. Prednisone dosage could successfully be tapered to an average of 7.5 mg/day in the patients taking either 15 or 20 mg/day at baseline visit.
Overall, the infusions were well tolerated. Although mild adverse events occurred in all participating patients, none of the patients had to withdraw from the study. Two serious adverse events have been reported, both of them taking place in the same patient.
A slight increase in the serum levels of aspartate aminotransferase (AST), total cholesterol, high density lipoprotein (HDL-) and low density lipoprotein (LDL-) cholesterol as well as of triglycerides was detected at an early treatment period.
Both physician's and patient's global assessment decreased significantly in group 1 and 2, while there was no such change found in group 3.
Systemic sclerosis (SSc)
SSc is a chronic inflammatory disease affecting the connective tissue and hence results in fibrotic changes of the skin as well as the internal organs. Although the etiology remains unclear, it has been shown several times that IL-6 is involved in the pathogenesis of SSc and correlates with disease activity (Citation44,Citation45).
Currently, there is only one report on treating patients suffering from SSc with TCZ (Citation46). Both patients had been suffering from severe spreading skin sclerosis despite recommended immunosuppressant treatment (prednisolone, cyclosporine) prior to the TCZ administration. Patient 1 is a man, suffered from skin sclerosis continuing to spread from his hands to his forearms, upper arms and feet, and a decrease in renal function was accompanied by an increase in blood pressure. Urine analysis was positive for protein and occult blood, and plasma levels of renin were increased. His disease showed positive anti-nuclear antibodies (ANAs) and went along with esophageal involvement.
Patient 2, a 57-year-old male, was positive for anti-topoisomerase I, as well as ANAs. Due to a pulmonary fibrosis the patient suffered from dyspnea. In both patients, skin evaluation (modified Rodnan total skin score (mRTSS) and z-score from the Vesmeter hardness) showed an increased hardness of the skin. None of the patients showed marked elevation of CRP or serum IL-6.
During the administration of TCZ at 8 mg/kg every 2 weeks for 6 months, the skin of both patients softened and consequently led to an improvement in the patients’ joint mobility. In histological analysis a decrease of collagen fiber bundles could be observed, while skin thickness did not change.
Although fibrotic changes of the skin regressed, no marked changes in the involvement of the internal organs could be traced.
Takayasu arteritis (TA)
It was reported that a 20-year-old female patient with diagnosed TA and ulcerative colitis in 1996 (at the age of 15) was treated with an initial prednisolone dose of 60 mg/day.
After treatment with cyclosporine A and cyclophosphamide a prednisolone reduction to 30 mg/day was possible, but followed by reoccurring symptoms. Other medical treatment (high-dose methylprednisolone, daily doses of oral azathioprine and mycophenolate mofetil or MTX together with oral GCs) did also not result in full disease control.
Due to left cervical and chest pain, episodes of syncope, discrepancies in blood pressure, a loss of 5 kg in 1 month, elevated serum CRP level of 126 mg/L, marked thickening of the wall of the ascending aorta, the three main branches, and the descending aorta, as well as stenosis of the left subclavian artery in September 2001, TCZ treatment was considered.
Following a single TCZ dose of 4 mg/kg the serum CRP decreased to 26 mg/L within 1 week. After 3 weeks the serum CRP was completely normalized. TCZ was given once a week to once every 2 weeks after the sixth dose of the drug, maintaining a dose of 4 mg/kg per infusion. Following this dosing schedule a TCZ blood concentration was provided, so that TA activity was sufficiently suppressed. After the 26th treatment (46 weeks after the start of treatment), the TCZ dose was increased from 4 mg/kg to 8 mg/kg in order to extend the infusion interval from 2 to 3 weeks.
Addendum: additional new promising indications
There are currently additional, new indications in non-strictly autoimmune inflammatory diseases in preclinical stages. One example, currently under investigation, is multiple myeloma (MM).
MM is an incurable clonal B cell malignancy with terminally differentiated plasma cells. It is the second most common hematologic malignancy in the USA (Citation47). During the last decade the number of therapeutical options has increased remarkably as signaling pathways in which myeloma cells are involved are better understood and thereby more potential therapeutical targets have been uncovered. Involved in various interactions of myeloma cells, IL-6 is one of those targets. IL-6 is secreted by myeloma cells and their microenvironment, which then results in proliferation of myeloma cells (Citation47). TCZ has been reported to be a promising agent in a murine MM model by Yoshio-Hoshino et al. (Citation48) and is currently under investigation for treating MM.
Conclusion
In addition to the extensively reported success of IL-6 antibody, TCZ, in treating patients with RA, this review shows promising outcomes for patients suffering from various rare, non-RA rheumatic diseases which up to now have been refractory to existing therapeutic options.
Due to comparable pathological mechanisms of RA and non-RA systemic inflammatory rheumatic diseases, such as AOSD, GCA, PMR, RP, SLE, and other rare conditions, TCZ showed a remarkable improvement in disease activity in combination with MTX, as well as when given as monotherapy.
The case reports on these various, non-RA systemic inflammatory rheumatic diseases have shown not only amelioration of laboratory parameters, but also improvement of clinical symptoms. TCZ was well tolerated by all treated patients. Side-effects were barely reported.
In spite of the limited number of patient experiences that we have reported here, the results on TCZ treatment show promising results. However, this advancement in treatment needs further investigation in larger patient populations.
Case reports per se contain a reporting bias, which could potentially overestimate the positive effects and underscore the side-effects. Case reports should always be interpreted with caution as the example of the treatment of spondyloarthropathies showed. Randomized clinical trials had to be terminated early, because the primary end-point was not reached.
Declaration of interest: R. A. has received research grants and honoraria from the Speakers bureau from ROCHE. T. M.: None.
References
- McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 2007;7:429–42.
- Felson DT, Smolen JS, Wells G, Zhang B, van Tuyl LH, Funovits J, et al. American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Arthritis Rheum. 2011;63:573–86.
- Kotake S, Sato K, Kim KJ, Takahashi N, Udagawa N, Nakamura I, et al. Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation. J Bone Miner Res. 1996;11:88–95.
- Nishimoto N, Kishimoto T. Humanized antihuman IL-6 receptor antibody, tocilizumab. Handb Exp Pharmacol. 2008;181:151–60.
- Frey N, Grange S, Woodworth T. Population pharmacokinetic analysis of tocilizumab in patients with rheumatoid arthritis. J Clin Pharmacol. 2010;50:754–66.
- Roche. RoACTEMRA [summary of product charcteristics] prescribing information. Welwyn Garden City: Roche Registration Limited, January 2009.
- Alten R. Tocilizumab: a novel humanized anti-interleukin 6 receptor antibody for the treatment of patients with rheumatoid arthritis. Ther Adv Musculoskelet Dis. 2011;3:133–49.
- Lachmann HJ, Goodman HJ, Gilbertson JA, Gallimore JR, Sabin CA, Gillmore JD, et al. Natural history and outcome in systemic AA amyloidosis. N Engl J Med. 2007;356:2361–71.
- Nishida S, Hagihara K, Shima Y, Kawai M, Kuwahara Y, Arimitsu J, et al. Rapid improvement of AA amyloidosis with humanised anti-interleukin 6 receptor antibody treatment. Ann Rheum Dis. 2009;68:1235–6.
- Sato H, Sakai T, Sugaya T, Otaki Y, Aoki K, Ishii K, et al. Tocilizumab dramatically ameliorated life-threatening diarrhea due to secondary amyloidosis associated with rheumatoid arthritis. Clin Rheumatol. 2009;28:1113–6.
- Nakamura T. Amyloid A amyloidosis secondary to rheumatoid arthritis: pathophysiology and treatments. Clin Exp Rheumatol. 2011;29:850–7.
- Inoue D, Arima H, Kawanami C, Takiuchi Y, Nagano S, Kimura T, et al. Excellent therapeutic effect of tocilizumab on intestinal amyloid a deposition secondary to active rheumatoid arthritis. Clin Rheumatol. 2010;29:1195–7.
- Hattori Y, Ubara Y, Sumida K, Hiramatsu R, Hasegawa E, Yamanouchi M, et al. Tocilizumab improves cardiac disease in a hemodialysis patient with AA amyloidosis secondary to rheumatoid arthritis. Amyloid. 2012; 19:37–40.
- Efthimiou P, Paik PK, Bielory L. Diagnosis and management of adult onset Still's disease. Ann Rheum Dis. 2006;65:564–72.
- Chen DY, Lan JL, Lin FJ, Hsieh TY. Proinflammatory cytokine profiles in sera and pathological tissues of patients with active untreated adult onset Still's disease. J Rheumatol. 2004;31:2189–98.
- Puechal X, DeBandt M, Berthelot JM, Breban M, Dubost JJ, Fain O, et al. Tocilizumab in refractory adult Still's disease. Arthritis Care Res (Hoboken). 2011;63:155–9.
- Braun J, Sieper J. Ankylosing spondylitis. Lancet. 2007;369:1379–90.
- Francois RJ, Neure L, Sieper J, Braun J. Immunohistological examination of open sacroiliac biopsies of patients with ankylosing spondylitis: detection of tumour necrosis factor alpha in two patients with early disease and transforming growth factor beta in three more advanced cases. Ann Rheum Dis. 2006;65:713–20.
- Henes JC, Horger M, Guenaydin I, Kanz L, Koetter I. Mixed response to tocilizumab for ankylosing spondylitis. Ann Rheum Dis. 2010;69:2217–8.
- Brulhart L, Nissen MJ, Chevallier P, Gabay C. Tocilizumab in a patient with ankylosing spondylitis and Crohn's disease refractory to TNF antagonists. Joint Bone Spine. 2010;77:625–6.
- Kiltz U, Heldmann F, Baraliakos X, Braun J. Treatment of ankylosing spondylitis in patients refractory to TNF-inhibition: are there alternatives?Curr Opin Rheumatol. 2012;24:252–60.
- Salvarani C, Cantini F, Boiardi L, Hunder GG. Laboratory investigations useful in giant cell arteritis and Takayasu's arteritis. Clin Exp Rheumatol. 2003;21(6 Suppl 32):S23–8.
- Arend WP, Michel BA, Bloch DA, Hunder GG, Calabrese LH, Edworthy SM, et al. The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis. Arthritis Rheum. 1990;33:1129–34.
- Miller DV, Isotalo PA, Weyand CM, Edwards WD, Aubry MC, Tazelaar HD. Surgical pathology of noninfectious ascending aortitis: a study of 45 cases with emphasis on an isolated variant. Am J Surg Pathol. 2006;30:1150–8.
- Jover JA, Hernandez-Garcia C, Morado IC, Vargas E, Banares A, Fernandez-Gutierrez B. Combined treatment of giant-cell arteritis with methotrexate and prednisone. a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2001;134:106–14.
- Schafer VS, Zwerina J. Biologic treatment of large-vessel vasculitides. Curr Opin Rheumatol. 2012;24:31–7.
- Salvarani C, Magnani L, Catanoso M, Pipitone N, Versari A, Dardani L, et al. Tocilizumab: a novel therapy for patients with large-vessel vasculitis. Rheumatology (Oxford). 2012;51:151–6.
- Unizony S, Arias-Urdaneta L, Miloslavsky E, Arvikar S, Khosroshahi A, Keroack B, et al. Tocilizumab for the treatment of large-vessel vasculitis (giant cell arteritis, takayasu arteritis) and polymyalgia rheumatica. Arthritis Care Res (Hoboken). 2012;64:1720–9.
- Nishimoto N, Nakahara H, Yoshio-Hoshino N, Mima T. Successful treatment of a patient with Takayasu arteritis using a humanized anti-interleukin-6 receptor antibody. Arthritis Rheum. 2008;58:1197–200.
- Kaly L, Rosner I. Tocilizumab - a novel therapy for non-organ-specific autoimmune diseases. Best Pract Res Clin Rheumatol. 2012;26:157–65.
- Hagihara K, Kawase I, Tanaka T, Kishimoto T. Tocilizumab ameliorates clinical symptoms in polymyalgia rheumatica. J Rheumatol. 2010;37: 1075–6.
- Cutolo M, Montecucco CM, Cavagna L, Caporali R, Capellino S, Montagna P, et al. Serum cytokines and steroidal hormones in polymyalgia rheumatica and elderly-onset rheumatoid arthritis. Ann Rheum Dis. 2006;65:1438–43.
- Leeb BF, Rintelen B, Sautner J, Fassl C, Bird HA. The polymyalgia rheumatica activity score in daily use: proposal for a definition of remission. Arthritis Rheum. 2007;57:810–5.
- Rapini RP, Warner NB. Relapsing polychondritis. Clin Dermatol. 2006;24:482–5.
- Kawai M, Hagihara K, Hirano T, Shima Y, Kuwahara Y, Arimitsu J, et al. Sustained response to tocilizumab, anti-interleukin-6 receptor antibody, in two patients with refractory relapsing polychondritis. Rheumatology (Oxford). 2009;48:318–9.
- McCarty DJ, O’Duffy JD, Pearson L, Hunter JB. Remitting seronegative symmetrical synovitis with pitting edema. RS3PE syndrome. JAMA. 1985;254:2763–7.
- Oide T, Ohara S, Oguchi K, Maruyama M, Yazawa M, Inoue K, et al. Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome in Nagano, Japan: clinical, radiological, and cytokine studies of 13 patients. Clin Exp Rheumatol. 2004;22:91–8.
- Tanaka T, Hagihara K, Shima Y, Narazaki M, Ogata A, Kawase I, et al. Treatment of a patient with remitting seronegative, symmetrical synovitis with pitting oedema with a humanized anti-interleukin-6 receptor antibody, tocilizumab. Rheumatology (Oxford). 2010;49:824–6.
- Kim KH, Kim DS. Juvenile idiopathic arthritis: diagnosis and differential diagnosis. Korean J Pediatr. 2010;53:931–5.
- De Benedetti F, Brunner H, Ruperto N, Calvo I, Cuttica R, Malattia C, et al. Efficacy and safety of Tocilizumab (TCZ) in patients (PTS) with systemic juvenile idiopathic arthritis (sJIA): TENDER 52-week data. Ann Rheum Dis. 2011;70(Suppl 3):67.
- De Benedetti F, Brunner H, Ruperto N, Kenwright A, Devlin C, Calvo I, et al. Efficacy and safety of Tocilizumab (TCZ) in patients with systemic juvenile idiopathic arthritis (sJIA): 2-year data from TENDER, a phase 3 clinical trial. Ann Rheum Dis. 2012;71(Suppl 3):425.
- Kishimoto T. IL-6: from laboratory to bedside. Clin Rev Allergy Immunol. 2005;28:177–86.
- Illei GG, Shirota Y, Yarboro CH, Daruwalla J, Tackey E, Takada K, et al. Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study. Arthritis Rheum. 2010;62:542–52.
- Matsushita T, Hasegawa M, Hamaguchi Y, Takehara K, Sato S. Longitudinal analysis of serum cytokine concentrations in systemic sclerosis: association of interleukin 12 elevation with spontaneous regression of skin sclerosis. J Rheumatol. 2006;33:275–84.
- Stuart RA, Littlewood AJ, Maddison PJ, Hall ND. Elevated serum interleukin-6 levels associated with active disease in systemic connective tissue disorders. Clin Exp Rheumatol. 1995;13:17–22.
- Shima Y, Kuwahara Y, Murota H, Kitaba S, Kawai M, Hirano T, et al. The skin of patients with systemic sclerosis softened during the treatment with anti-IL-6 receptor antibody tocilizumab. Rheumatology (Oxford). 2010;49:2408–12.
- Katzel JA, Hari P, Vesole DH. Multiple myeloma: charging toward a bright future. CA Cancer J Clin. 2007;57:301–18.
- Yoshio-Hoshino N, Adachi Y, Aoki C, Pereboev A, Curiel DT, Nishimoto N. Establishment of a new interleukin-6 (IL-6) receptor inhibitor applicable to the gene therapy for IL-6-dependent tumor. Cancer Res. 2007;67:871–5.