Tocilizumab for the treatment of adult-onset Still's disease.

ABSTRACT Introduction: Adult-onset Still´s disease (AOSD) is a systemic inflammatory condition that affects mainly young people. The clinical course consists of two distinctive patterns: one with a predominance of systemic symptoms and another manifested by progressive chronic polyarthritis. Glucocorticoids remain the mainstay in the treatment of AOSD. However, biologic therapies are often required to achieve clinical remission and allow glucocorticoid discontinuation. Areas covered: The review summarizes the main retrospective and prospective studies, and case series on the use of the anti-interleukin (IL)-6 receptor tocilizumab in AOSD. Expert opinion: Since IL-6 serum levels are highly increased in both active systemic and polyarticular phenotypes, IL-6 blockade was considered to be a plausible therapeutic option for the management of AOSD. Tocilizumab, the only anti-IL-6-receptor antagonist currently available for AOSD, has proved to be effective for the management of refractory AOSD patients, including those with life-threatening complications. Nevertheless, there are some reports describing patients who are refractory to any therapy. Future research should focus on the identification of prognostic biomarkers that help us to tailor an individualized treatment for each type of patient and in the search of new disease activity indices that help us to monitor the response to the therapy more closely.


Introduction
Adult-onset Still´s disease (AOSD) is a systemic inflammatory disease of unknown origin affecting mainly young people with an estimated annual incidence between 0.16 and 0.4/100,000 persons worldwide [1-3]. It is slightly more common in women [4,5], and there is a bimodal age distribution, with a peak between 15  AOSD is clinically characterized by daily high spiking fever, evanescent salmoncolored maculopapular rash, arthritis, musculoskeletal symptoms and neutrophilic leukocytosis. Other common manifestations include: sore throat, lymphadenopathy, A c c e p t e d M a n u s c r i p t pulmonary infiltrates, pleuritis, pericarditis, abdominal pain and hepatosplenomegaly [3,12,13]. As the result of a systemic inflammatory response, patients with AOSD present elevation of acute-phase reactants (APR), such as the erythrocyte sedimentation rate (ESR) and the C-reactive protein (CRP), marked leukocytosis with neutrophilia, anemia and thrombocytosis. Serum ferritin levels are particularly increased (classically more than 5 times above the upper limit of normal) and it may be a good biomarker of disease activity [3,13]. AOSD is also associated with a reduction in the glycosylated ferritin fraction, so that the combination of serum ferritin levels higher than 1000 µg/L with a glycosylated fraction <20% has been found to have a high specificity for a diagnosis of the disease [14,15]. Due to the low incidence of the disease, the treatment of AOSD remains largely empirical, mainly based on case reports and small retrospective case series, and not on controlled studies. Non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids (GC) represent the first line therapy, particularly for musculoskeletal manifestations and fever, with response rates between 20% and 60% [3,12,24].
Tocilizumab (TCZ), a humanized anti-IL-6R antibody that binds to both the membranebound and soluble form of IL-6R, is an effective biologic agent for the treatment of AOSD. Data from retrospective studies and case series demonstrate the efficacy of TCZ in monotherapy or combined to DMARDs for refractory AOSD, both in patients with the CAD and the SP patterns and for some life-threatening complications of the disease [30][31][32][33]. In the present review, we have focused on the use of TCZ for the treatment of AOSD. Data on the efficacy and safety of TCZ for AOSD therapy are discussed.
A c c e p t e d M a n u s c r i p t

Areas covered
Glucocorticoids are the cornerstone of treatment of AOSD. However, they are effective in only 60% of patients with AOSD [3,13]. They  Anti-IL1 agents, especially anakinra (ANK) and canakinumab, are especially useful in the SP of the disease. ANK has recently been approved by the European Medical Agency (EMA) for their use in AOSD [38]. Although the anti-IL-6R TCZ has not approved for the use of in AOSD therapy yet, it is commonly use in AOSD as off-label treatment. In this regard, the daily clinical practice supports the use of TCZ in patients with AOSD. Tumor necrosis factor (TNF) blocking drugs are currently considered as a second line of biologic therapy in patients with the CAD pattern [3,28,38].

Unmet needs of currently available therapies in AOSD management
The diagnosis of AOSD is usually made by the exclusion of other systemic diseases.
Most clinicians use the criteria proposed by Yamaguchi

Introduction to the compound
IL-6 is a pleiotropic pro-inflammatory cytokine produced by a number of cells including T-and B-cells, monocytes and fibroblasts. IL-6 is involved in different physiological processes such as T-cell activation, induction of immunoglobulin secretion, induction of hepatic acute phase protein synthesis and stimulation of hemopoiesis. This cytokine has been implicated in the pathogenesis of a broad spectrum of diseases including inflammatory diseases, osteoporosis and neoplasia. IL-6 is also a pivotal cytokine involved in the pathogenesis of AOSD, reason why it was considered as an important target for the treatment of this disease. Moreover, IL-6 serum levels are markedly increased in both the active SP as well as in the active CAD phenotype  TCZ is a humanized anti-IL-6R antibody that binds to both soluble and membranebound IL-6 receptors (sIL-6R and mIL-6R), inhibiting sIL-6R and mIL-6R-mediated signaling. TCZ is available for intravenous (IV) infusion and subcutaneous (SC) injections. Due to the extensive experience with TCZ in rheumatoid arthritis (RA), many of the pharmacological data that we will present in the following paragraphs are based on studies in patients with RA.

Clinical indications
The excellent data in terms of clinical efficacy and safety of TCZ in the treatment of RA and other rheumatic diseases supported the use of TCZ in AOSD patients who were refractory to GC, conventional DMARDs, and other biologic agents including anti-TNF-α agents and IL-1 blocking agents [44]. Its use was also supported by results from  Table 2 shows the main approved and off-label indications for the use of TCZ nowadays.

Pharmacodynamics
TCZ interferes not only with the pathological effects of IL-6, but also with its physiological effects at multiple levels. Rapid decreases in CRP, ESR and serum amyloid A (SAA) were observed in RA patients undergoing TCZ therapy. Decreases in the levels of CRP to within normal ranges are seen as early as week 2, with decreases maintained during the treatment [47].
Consistent with the effect on ARP, TCZ administration was associated with reduction in platelet count within the normal range. TCZ also decreases the IL-6 driven effect on hepcidin production, leading to an increase of hemoglobin levels due to improvement of iron availability.
The absolute neutrophil count decreased to their lowest levels 3 to 5 days after starting the administration in healthy subjects who received TCZ at doses between 2 and 28 mg/kg. Thereafter, neutrophils recovered towards baseline in a dose dependent manner.
RA patients showed a similar pattern of absolute neutrophil counts following TCZ administration [47].
A c c e p t e d M a n u s c r i p t

Pharmacokinetics and metabolism
The pharmacokinetics (PK) of TCZ was determined using a population PK analysis on a database composed of 3552 RA patients treated with a one-hour IV infusion of 4 or 8 mg/kg TCZ every 4 weeks for 24 weeks or with 162 mg TCZ given subcutaneously either once a week or eow for 24 weeks TCZ undergoes a biphasic removal from the circulation after its IV administration. The total clearance of TCZ was concentration-dependent and is the sum of the linear and non-linear clearances. The t1/2 of TCZ was concentration-dependent. At steady-state following a dose of 8 mg/kg every 4 weeks, the effective t1/2 decreased with decreasing concentrations within a dosing interval from 18 days to 6 days.
There are no formal studies on the effect of renal or liver impairment on the PK of TCZ.
Most patients in the population PK analysis had normal renal function or mild renal impairment. Mild renal impairment (creatinine clearance <80 mL/min and ≥50 mL/min) did not influence the PK of TCZ. Finally, population PK analyses in RA patients showed that age, gender and ethnic origin did not affect the PK of TCZ [47].
PK analyses in patients with RA did not show any effect of MTX, NSAIDs or GC on TCZ clearance. Concomitant administration of a single IV dose of 10 mg/kg TCZ with 10-25 mg MTX once weekly had no clinically significant effect on MTX exposure.
In vitro studies showed that TCZ has the potential to affect expression of multiple CYP enzymes including cytochrome P450 (CYP)1A2, CYP2B6, CYP2C9, CYP2C19,

CYP2D6 and CYP3A4 [47,48].
A c c e p t e d M a n u s c r i p t In vivo studies with omeprazole, metabolized by CYP2C19 and CYP3A4, and simvastatin, metabolized by CYP3A4, showed up to a 28% and 57% decrease in exposure one week following a single dose of TCZ, respectively [47][48][49]. The effect of TCZ on CYP enzymes may be clinically relevant for CYP450 substrates with narrow therapeutic index (e.g., warfarin, cyclosporine or theophylline). Special attention should be paid when TCZ is coadministered along with CYP3A4 substrate drugs in which a reduction in their effectiveness is undesirable, e.g., oral contraceptives, lovastatin, atorvastatin, etc. The effect of TCZ on CYP450 enzyme activity may persist for several weeks after discontinuation of the therapy [47-49].

Clinical efficacy of IL-6 pathway inhibition
Overall, the anti-inflammatory efficacy of TCZ in AOSD is good, rapid and sustained for most patients. Systemic manifestations improve more rapidly than joint

Prospective studies
A c c e p t e d M a n u s c r i p t

Ortiz-Sanjuan et al. conducted a retrospective, open-label study that included 34
Spanish patients with AOSD who underwent TCZ. Twenty-two received 8 mg/kg IV every 4 weeks, 10 were treated with 8 mg/kg IV every 2 weeks and 2 with 4 mg/kg IV A c c e p t e d M a n u s c r i p t every 4 weeks, with maintenance doses ranging from 4-8 mg/kg IV every 2 or 4 weeks [50]. All patients had experienced an inadequate response to GC and at least to one synthetic DMARD, and 50% had also failed a previous biologic agent. After 1 year of therapy, improvement from baseline was observed in joint manifestations (97.1% at baseline to 32.4%), cutaneous manifestations (58.8% to 5.9%), fever (58.8% to 5.9%), lymphadenopathy (29.4% to 0%), splenomegaly/hepatomegaly (11.8% to 0%), and pleuritis/pericarditis (8.8% to 0%). The following laboratory parameters also showed reduction at month 12 when compared with baseline results: abnormal CRP (

Case series
A c c e p t e d M a n u s c r i p t

Clinical trials
The only randomized, double-blind, placebo-controlled study with TCZ vs.

Safety profile and tolerability
The most commonly reported AEs (occurring in ≥5% of patients treated with TCZ in monotherapy or in combination with DMARDs) were upper respiratory tract infections, nasopharyngitis, headache, hypertension, neutropenia and increased hepatic alanine aminotransferase (ALT). The most serious AEs were serious infections, complications of diverticulitis, and hypersensitivity reactions. Once again, the most extensive information on AEs comes from that observed in patients with RA, where much more experience is available.

Special warnings and precautions for use
Since TCZ generally increases the risk of infections, treatment with TCZ should not be  Table 6 shows some general recommendations that we must follow in case of detecting laboratory alterations.
There are no adequate data from the use of TCZ in pregnant women. A study in animals has shown an increased risk of spontaneous abortion/embryo-fetal death at a high dose.
Thus, TCZ should not be recommended during pregnancy unless clearly necessary.
A c c e p t e d M a n u s c r i p t Furthermore, women of childbearing potential must use effective contraception during and up to 3 months after treatment [47].
Finally, live and live attenuated vaccines should not be given concurrently with TCZ as clinical safety has not been established.

Regulatory affairs
Currently, TCZ is only approved for the treatment of RA, sJIA, pJIA, GCA and chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome (CRS) in adults and pediatric patients 2 years of age and older (Table   1). However, its indication is not approved for AOSD yet, so its use in this entity must be done as off-label medication with prior information to the patient and signature of an informed consent previously to start the treatment.

Conclusions
Overall, and despite not being approved yet by the regulatory authorities, based on the data shown in the different studies mentioned in this review, we conclude that TCZ is an effective drug for the overall management of AOSD, both for systemic and joint manifestations, as well as for some severe complications of the disease.

Expert opinion
AOSD is a rare multisystem inflammatory disease of unknown origin that is included Taken together, the main limitation to the use of TCZ in AOSD is that this biologic agent has not already been approved for this indication. Therefore, its use should be off label after failure to GCs, DMARDs and IL-1 or TNF antagonists according to the clinical phenotype. In addition, there are some concerns on TCZ use in patients with

MAS.
A c c e p t e d M a n u s c r i p t In a near future, new biological agents against IL-18 or small molecules against Jak-1/Jak-2 may provide additional therapeutic options for AOSD. Other biologic agents that in inhibit IL-6 are currently under investigation. Among them, sirukumab, a human monoclonal antibody against IL-6, and sarilumab, an antagonist of IL-6R, are those that are in a more advanced phase of development, especially in patients with RA. Both molecules are administered subcutaneously every 2-4 weeks and have greater affinity for IL-6 than showed by TCZ. However, none of them have proved efficacy in AOSD.
Furthermore, since levels of sIL-6 increase significantly higher fold compared to baseline in active disease, but the fold increase of sIL-6R is much lower than sIL-6, a biologic agent blocking sIL-6R such as TCZ would require rather smaller amount of antibody to achieve our goal than others blocking sIL-6. Figure 1 shows a general therapeutic strategy for patients with active AOSD.

Five-year view
In the following years, a better definition of the AOSD phenotypes will be achieved. This fact will allow the clinicians to better identity those patients who would benefit of specific biologic agents. New biomarkers on molecules that seem to play a role in the pathogenesis of AOSD will help us to better monitor the disease allowing the clinicians

Article Highlights
• AOSD is a heterogeneous disorder at the crossroads between autoinflammatory and autoimmune diseases.
• Glucocorticoids constitute the first line of treatment for AOSD.
• Conventional DMARDs, especially MTX, are often considered in refractory cases or as GC-sparing agents.
• Biologic agents must be considered in the management of AOSD refractory to GC and conventional DMARDs, since the ultimate goal in the management of AOSD is to achieve sustained remission and reduce the risk of relapses and life-threatening complications.
• The development of composite indices based on multiple biomarkers to detect disease activity definitely could support rational decision making in the treatment of AOSD.
• TCZ, a humanized anti-IL-6 receptor antagonist, is an effective drug for the global treatment of AOSD, both for systemic and joint manifestations, as well as for some severe life-threatening manifestations of the disease.
• Overall, the benefit/risk ratio and safety profile of TCZ is favorable and similar to that described in RA and other rheumatic diseases. However, some cases of MAS have been described after the start of treatment with TCZ as well as with other biological agents.
• Besides the currently available therapeutic options, new biologic agents against IL-18 or small molecules against Jak-1/Jak-2 may be additional therapeutic options in AOSD. 1 TCZ alone or in combination with methotrexate is indicated for the treatment of severe, active and progressive RA in adults not previously treated with methotrexate or in patients intolerant or not responders to previous therapy with one or more conventional disease-modifying anti-rheumatic drugs or tumor necrosis factor-α antagonists. 2 In patients 2 years of age and older who have responded inadequately to previous therapy with non-steroidal anti-inflammatory drugs and systemic glucocorticoids. 3 Finally, subcutaneous TCZ is recently approved for the treatment of giant cell arteritis and intravenous TCZ for the treatment of chimeric antigen receptor (CAR) T cellinduced severe or life-threatening cytokine release syndrome in adults and pediatric patients 2 years of age and older.  Pharmacology description/mechanism of action: humanized anti-IL-6R antibody that binds to both the membrane-bound and soluble form of IL-6R (sIL-6R and mIL-6R), inhibiting sIL-6R and mIL-6R-mediated signaling.

Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.
Chemical structure: TCZ is a recombinant, humanized, anti-human interleukin 6 (IL-6) receptor monoclonal antibody that achieves a significant therapeutic response rate. The light chain is made up of 214 amino acids (aa). The heavy chain is made up of 448 aa. M a n u s c r i p t A c c e p t e d M a n u s c r i p t M a n u s c r i p t Table 6. Management of main laboratory abnormalities detected in adults with RA receiving treatment with TCZ in monotherapy or in combination with disease-modifying anti-rheumatic drugs (DMARDs) # . DMARDs: disease-modifying anti-rheumatic drugs; GCA: giant cell arteritis; MTX: methotrexate; RA: rheumatoid arthritis; TCZ: tocilizumab; ULN: upper limit of normality. * In patients not previously treated with TCZ, initiation is not recommended in patients with an ANC < 2 x 10 9 /L. Data of toxicity in laboratory parameters in patients with AOSD are less studied. # Modified from ref. [47] A c c e p t e d M a n u s c r i p t F Figure 1