Sarilumab

KEVZARA ® is an interleukin-6 (IL-6) receptor antagonist indicated for treatment of: adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs). ( 1.1 ) adult patients with polymyalgia rheumatica (PMR) who have had an inadequate response to corticosteroids or who cannot tolerate corticosteroid taper. ( 1.2 ) patients who weigh 63 kg or greater with active polyarticular juvenile idiopathic arthritis (pJIA). ( 1.3 )

1.1 Rheumatoid Arthritis (RA) KEVZARA ® is indicated for treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs).

1.2 Polymyalgia Rheumatica (PMR) KEVZARA is indicated for treatment of adult patients with polymyalgia rheumatica who have had an inadequate response to corticosteroids or who cannot tolerate corticosteroid taper.

1.3 Polyarticular Juvenile Idiopathic Arthritis (pJIA) KEVZARA is indicated for treatment of active polyarticular juvenile idiopathic arthritis (pJIA) in patients who weigh 63 kg or greater.

Injection: 150 mg/1.14 mL and 200 mg/1.14 mL clear and colorless to pale-yellow solution in a single-dose pre-filled syringe. Injection: 150 mg/1.14 mL and 200 mg/1.14 mL clear and colorless to pale-yellow solution in a single-dose pre-filled pen. Injection: 150 mg/1.14 mL and 200 mg/1.14 mL solution in a single-dose pre-filled syringe ( 3 ) Injection: 150 mg/1.14 mL and 200 mg/1.14 mL solution in a single-dose pre-filled pen ( 3 )

KEVZARA is contraindicated in patients with known hypersensitivity to sarilumab or any of the inactive ingredients [see Warnings and Precautions (5.5) and Adverse Reactions (6.1) ] . KEVZARA is contraindicated in patients with known hypersensitivity to sarilumab or any of the inactive ingredients. ( 4 )

Serious Infections: Avoid KEVZARA use during an active infection. ( 5.1 ) Neutropenia, Thrombocytopenia, Elevated Liver Enzymes, Lipid Abnormalities: Monitor laboratory parameters. ( 5.2 ) Gastrointestinal (GI) Perforation: Risk may be increased with concurrent diverticulitis or concomitant use of NSAIDs or corticosteroids. Promptly evaluate acute abdominal signs or symptoms. ( 5.3 ) Hypersensitivity reactions. ( 5.5 ) Live vaccines: Avoid use with KEVZARA. ( 5.7 , 7.3 )

5.1 Serious Infections Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving immunosuppressive agents including KEVZARA. Among opportunistic infections, tuberculosis, candidiasis, and pneumocystis were reported with KEVZARA. Some patients presented with disseminated rather than localized disease and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids. The most frequently observed serious infections with KEVZARA in RA patients included pneumonia and cellulitis [see Adverse Reactions (6.1) ] . While not reported in KEVZARA clinical studies, other serious infections (e.g., histoplasmosis, cryptococcus, aspergillosis) have been reported in patients receiving other immunosuppressive agents for the treatment of RA. Avoid use of KEVZARA in patients with an active infection, including localized infections. Consider the risks and benefits of treatment prior to initiating KEVZARA in patients who have: chronic or recurrent infection; a history of serious or opportunistic infections; underlying conditions that may predispose them to infection; been exposed to tuberculosis; or lived in or traveled to areas of endemic tuberculosis or endemic mycoses. Closely monitor patients for the development of signs and symptoms of infection during treatment with KEVZARA, as signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase reactants [see Dosage and Administration (2.6) , Adverse Reactions (6.1) ] . Hold treatment with KEVZARA if a patient develops a serious infection or an opportunistic infection. Perform prompt and complete diagnostic testing appropriate for an immunocompromised patient who develops a new infection during treatment with KEVZARA; initiate appropriate antimicrobial therapy, and closely monitor the patient. Tuberculosis Evaluate patients for tuberculosis (TB) risk factors and test for latent infection prior to initiating treatment with KEVZARA. Treat patients with latent TB with standard antimycobacterial therapy before initiating KEVZARA. Consider anti-TB therapy prior to initiation of KEVZARA in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but having risk factors for TB infection. When considering anti-TB therapy, consultation with a physician with expertise in TB may be appropriate. Closely monitor patients for the development of signs and symptoms of TB including patients who tested negative for latent TB infection prior to initiating therapy. Viral Reactivation Viral reactivation has been reported with immunosuppressive biologic therapies. Cases of herpes zoster were observed in clinical studies with KEVZARA [see Adverse Reactions (6.1) ] . The risk of Hepatitis B reactivation with KEVZARA is unknown since patients who were at risk for reactivation were excluded.

5.2 Laboratory Abnormalities Neutropenia Treatment with KEVZARA was associated with a higher incidence of decrease in absolute neutrophil count (ANC), including neutropenia [see Adverse Reactions (6.1) ] . Assess neutrophil count prior to initiation of KEVZARA and monitor neutrophil count 4 to 8 weeks after start of therapy and every 3 months thereafter [see Clinical Pharmacology (12.2) ] . For recommendations regarding initiating KEVZARA therapy and dosage modifications based on ANC results see Dosage and Administration (2.1 and 2.6) . Based on the pharmacodynamics of the changes in ANC [see Clinical Pharmacology (12.2) ] , use results obtained at the end of the dosing interval when considering dosage modification. Thrombocytopenia Treatment with KEVZARA was associated with a reduction in platelet counts in clinical studies [see Adverse Reactions (6.1) ] . Assess platelet count prior to initiation of KEVZARA and monitor platelets 4 to 8 weeks after start of therapy and every 3 months thereafter. For recommendations regarding initiating KEVZARA therapy and dosage modifications based on platelet counts see Dosage and Administration (2.1 and 2.6) . Elevated Liver Enzymes Treatment with KEVZARA was associated with a higher incidence of transaminase elevations. These elevations were transient and did not result in any clinically evident hepatic injury in clinical studies [see Adverse Reactions (6.1) ] . Increased frequency and magnitude of these elevations were observed when potentially hepatotoxic drugs (e.g., MTX) were used in combination with KEVZARA. Assess ALT/AST levels prior to initiation of KEVZARA and monitor ALT and AST levels 4 to 8 weeks after start of therapy and every 3 months thereafter. When clinically indicated, consider other liver function tests such as bilirubin. For recommendations regarding initiating KEVZARA therapy and dosage modifications based on transaminase elevations see Dosage and Administration (2.1 and 2.6) . Lipid Abnormalities Treatment with KEVZARA was associated with increases in lipid parameters such as LDL cholesterol, HDL cholesterol and/or triglycerides [see Adverse Reactions (6.1) ] . Assess lipid parameters approximately 4 to 8 weeks following initiation of treatment with KEVZARA, then at approximately 6-month intervals. Manage patients according to clinical guidelines for the management of hyperlipidemia.

5.3 Gastrointestinal Perforation Gastrointestinal perforations have been reported in clinical studies, primarily as complications of diverticulitis. GI perforation risk may be increased with concurrent diverticulitis or concomitant use of NSAIDs or corticosteroids. Promptly evaluate patients presenting with new onset abdominal symptoms [see Adverse Reactions (6.1) ] .

5.4 Immunosuppression Treatment with immunosuppressants may result in an increased risk of malignancies. The impact of treatment with KEVZARA on the development of malignancies is not known but malignancies were reported in clinical studies [see Adverse Reactions (6.1) ] .

5.5 Hypersensitivity Reactions Hypersensitivity reactions have been reported in association with KEVZARA [see Adverse Reactions (6.1) ]. Hypersensitivity reactions that required treatment discontinuation were reported in 0.3% of patients in controlled RA trials. Injection site rash, rash, and urticaria were the most frequent hypersensitivity reactions. Advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction. If anaphylaxis or other hypersensitivity reaction occurs, stop administration of KEVZARA immediately. Do not administer KEVZARA to patients with known hypersensitivity to sarilumab [see Contraindications (4) and Adverse Reactions (6.1) ] .

5.6 Active Hepatic Disease and Hepatic Impairment Treatment with KEVZARA is not recommended in patients with active hepatic disease or hepatic impairment, as treatment with KEVZARA was associated with transaminase elevations [see Adverse Reactions (6.1) , Use in Specific Populations (8.6) ] .

5.7 Live Vaccines Avoid concurrent use of live vaccines during treatment with KEVZARA due to potentially increased risk of infections; clinical safety of live vaccines during KEVZARA treatment has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving KEVZARA. […]

The following serious adverse reactions are described elsewhere in labeling: Serious infections [see Warnings and Precautions (5.1) ] Neutropenia, thrombocytopenia, elevated liver enzymes, lipid abnormalities [see Warnings and Precautions (5.2) ] Gastrointestinal perforation [see Warnings and Precautions (5.3) ] Immunosuppression [see Warnings and Precautions (5.4) ] Hypersensitivity reactions [see Warnings and Precautions (5.5) ] Most common adverse reactions are: Rheumatoid Arthritis (incidence ≥3 %): neutropenia, increased ALT, injection site erythema, upper respiratory infections and urinary tract infections. ( 6.1 ) Polymyalgia Rheumatica (incidence ≥ 5%): neutropenia, leukopenia and injection site pruritus. ( 6.1 ) Polyarticular Juvenile Idiopathic Arthritis: nasopharyngitis, neutropenia, upper respiratory tract infection and injection site erythema. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Rheumatoid Arthritis All patients in the safety data described below had moderately to severely active rheumatoid arthritis. The safety of KEVZARA in combination with conventional DMARDs was evaluated based on data from seven studies, of which two were placebo-controlled, consisting of 2887 patients (long-term safety population). Of these, 2170 patients received KEVZARA for at least 24 weeks, 1546 for at least 48 weeks, 1020 for at least 96 weeks, and 624 for at least 144 weeks. The pre-rescue placebo-controlled population includes patients from the two Phase 3 efficacy studies (Studies 1 and 2) from weeks 0 to 16 for Study 1 and weeks 0 to 12 for Study 2, and was used to assess common adverse reactions and laboratory abnormalities prior to patients being permitted to switch from placebo to KEVZARA. In this population, 582 patients, 579 patients, and 579 patients received KEVZARA 200 mg, KEVZARA 150 mg, or placebo once every two weeks, respectively, in combination with conventional DMARDs. The 52-week placebo-controlled population includes patients from one Phase 2 study of 12-week duration and two Phase 3 efficacy studies (one of 24-week duration and the other of 52-week duration). This placebo-controlled population includes all subjects from the double-blind, placebo-controlled periods from each study and was analyzed under their original randomization assignment. In this population, 661 patients, 660 patients, and 661 patients received KEVZARA 200 mg, KEVZARA 150 mg, or placebo once every two weeks, respectively, in combination with conventional DMARDs. Most safety data are described for the pre-rescue population. For rarer events, the 52-week placebo-controlled population is used. The most common serious adverse reactions were infections . The most frequent adverse reactions (occurring in at least 3% of patients treated with KEVZARA in combination with DMARDs) observed with KEVZARA in the clinical studies were neutropenia, increased ALT, injection site erythema, upper respiratory infections, and urinary tract infections. In the pre-rescue placebo-controlled population, premature discontinuation due to adverse reactions occurred in 8%, 6% and 3% of patients treated with KEVZARA 200 mg, KEVZARA 150 mg, and placebo, respectively. The most common adverse reaction (greater than 1%) that resulted in discontinuation of therapy with KEVZARA was neutropenia. The use of KEVZARA as monotherapy was assessed in 132 patients, of which 67 received KEVZARA 200 mg and 65 patients received KEVZARA 150 mg without concomitant DMARDs. The safety profile was generally consistent with that in the population receiving concomitant DMARDs. Overall Infections In the pre-rescue placebo-controlled population, the rate of infections in the 200 mg and 150 mg KEVZARA + DMARD group was 110 and 105 events per 100 patient-years, respectively, compared to 81 events per 100 patient-years in the placebo + DMARD group. The most commonly reported infections (2% to 4% of patients) were upper respiratory tract infections, urinary tract infections, and nasopharyngitis. In the 52-week placebo-controlled population, 0.8% of patients (5 patients) treated with KEVZARA 200 mg + DMARD, 0.6% (4 patients) treated with KEVZARA 150 mg + DMARD and 0.5% (3 patients) treated with placebo + DMARD had an event of herpes zoster [see Warnings and Precautions (5.1) ] . The overall rate of infections with KEVZARA + DMARD in the long-term safety population was consistent with rates in the controlled periods of the studies. Serious Infections In the pre-rescue population, the rate of serious infections in the 200 mg and 150 mg KEVZARA + DMARD group was 3.8 and 4.4 events per 100 patient-years, respectively, compared to 2.5 events per 100 patient-years in the placebo + DMARD group. In the 52-week placebo-controlled population, the rate of serious infections in the 200 mg and 150 mg KEVZARA + DMARD group was 4.3 and 3.0 events per 100 patient-years, respectively, compared to 3.1 events per 100 patient-years in the placebo + DMARD group. In the long-term safety population, the overall rate of serious infections was consistent with rates in the controlled periods of the studies. The most frequently observed serious infections included pneumonia and cellulitis. Cases of opportunistic infection have been reported [see Warnings and Precautions (5.1) ] . Gastrointestinal Perforation In the 52-week placebo-controlled population, one patient on KEVZARA therapy experienced a gastrointestinal (GI) perforation (0.11 events per 100 patient-years). In the long-term safety population, the overall rate of GI perforation was consistent with rates in the controlled periods of the studies. Reports of GI perforation were primarily reported as complications of diverticulitis including lower GI perforation and abscess. Most patients who developed GI perforations were taking concomitant nonsteroidal anti-inflammatory medications (NSAIDs) or corticosteroids. The contribution of these concomitant medications relative to KEVZARA in the development of GI perforations is not known [see Warnings and Precautions (5.3) ] . Hypersensitivity Reactions In the pre-rescue placebo-controlled population, the proportion of patients who discontinued treatment due to hypersensitivity reactions was higher among those treated with KEVZARA (0.3% in 200 mg, 0.2% in 150 mg) than placebo (0%). The rate of discontinuations due to hypersensitivity in the long-term safety population was consistent with the placebo-controlled period. Injection Site Reactions In the pre-rescue placebo-controlled population, injection site reactions were reported in 7% of patients receiving KEVZARA 200 mg, 6% receiving KEVZARA 150 mg, and 1% receiving placebo. These injection site reactions (including erythema and pruritus) were mild in severity for the majority of patients and necessitated drug discontinuation in 2 (0.2%) patients receiving KEVZARA. Laboratory Abnormalities Decreased neutrophil count In the pre-rescue placebo-controlled population, decreases in neutrophil counts less than 1000 per mm 3 occurred in 6% and 4% of patients in the 200 mg KEVZARA + DMARD and 150 mg KEVZARA + DMARD group, respectively, compared to no patients in the placebo + DMARD groups. Decreases in neutrophil counts less than 500 per mm 3 occurred in 0.7% of patients in both the 200 mg KEVZARA + DMARD and 150 mg KEVZARA + DMARD groups. Decrease in ANC was not associated with the occurrence of infections, including seriou s infections. […]

7.1 Use with Other Drugs Population pharmacokinetic analyses did not detect any effect of methotrexate (MTX) on sarilumab clearance. KEVZARA has not been investigated in combination with JAK inhibitors or biological DMARDs such as TNF antagonists [see Dosage and Administration (2.2) ] .

7.2 Interactions with CYP450 Substrates Various in vitro and limited in vivo human studies have shown that cytokines and cytokine modulators can influence the expression and activity of specific cytochrome P450 (CYP) enzymes and therefore have the potential to alter the pharmacokinetics of concomitantly administered drugs that are substrates of these enzymes. Elevated interleukin-6 (IL-6) concentration may down-regulate CYP activity such as in patients with RA and hence increase drug levels compared to subjects without RA. Blockade of IL-6 signaling by IL-6Rα antagonists such as KEVZARA might reverse the inhibitory effect of IL-6 and restore CYP activity, leading to altered drug concentrations. The modulation of IL-6 effect on CYP enzymes by KEVZARA may be clinically relevant for CYP substrates with a narrow therapeutic index, where the dose is individually adjusted. Upon initiation or discontinuation of KEVZARA, in patients being treated with CYP substrate medicinal products, perform therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., theophylline) and adjust the individual dose of the medicinal product as needed. Exercise caution when co-administering KEVZARA with CYP3A4 substrate drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives, lovastatin, atorvastatin, etc. The effect of KEVZARA on CYP450 enzyme activity may persist for several weeks after stopping therapy [see Clinical Pharmacology (12.3) ].

7.3 Live Vaccines Avoid concurrent use of live vaccines during treatment with KEVZARA [see Warnings and Precautions (5.7) ] .

Lactation: Discontinue drug or nursing taking into consideration importance of drug to mother. ( 8.2 )

8.1 Pregnancy Risk Summary The limited human data with KEVZARA in pregnant women are not sufficient to inform drug-associated risk for major birth defects and miscarriage. Monoclonal antibodies, such as sarilumab, are actively transported across the placenta during the third trimester of pregnancy and may affect immune response in the in utero exposed infant (see Clinical Considerations ) . From animal data, and consistent with the mechanism of action, levels of IgG, in response to antigen challenge, may be reduced in the fetus/infant of treated mothers (see Clinical Considerations and Data ) . In an animal reproduction study, consisting of a combined embryo-fetal and pre- and postnatal development study with monkeys that received intravenous administration of sarilumab, there was no evidence of embryotoxicity or fetal malformations with exposures up to approximately 84 times the maximum recommended human dose (MRHD) (see Data ) . The literature suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. KEVZARA should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations Fetal/Neonatal Adverse Reactions Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to KEVZARA in utero [see Warnings and Precautions (5.7) ]. From the animal data, and consistent with the mechanism of action, levels of IgG, in response to antigen challenge, may be reduced in the fetus/infant of treated mothers (see Data ) . Data Animal Data In a combined embryo-fetal and pre- and postnatal development study, pregnant cynomolgus monkeys received sarilumab at intravenous doses of 0, 5, 15, or 50 mg/kg/week from confirmation of pregnancy at gestation day (GD) 20, throughout the period of organogenesis (up to approximately GD 50), and continuing to natural birth of infants at around GD 165. Maintenance of pregnancy was not affected at any doses. Sarilumab was not embryotoxic or teratogenic with exposures up to approximately 84 times the MRHD (based on AUC with maternal intravenous doses up to 50 mg/kg/week). Sarilumab had no effect on neonatal growth and development evaluated up to one month after birth. Sarilumab was detected in the serum of neonates up to one month after birth, suggesting that the antibody had crossed the placenta. Following antigen challenge, decreased IgG titers attributed to the immunosuppressive action of sarilumab were evident in studies with older monkeys, with exposures up to approximately 80 times the MRHD (based on AUC with intravenous doses up to 50 mg/kg/week) and juvenile mice treated with an analogous antibody, which binds to murine IL-6Rα to inhibit IL-6 mediated signaling, at subcutaneous doses up to 200 mg/kg/week. These findings suggest the potential for decreased IgG titers, following antigen challenge, in infants of mothers treated with KEVZARA. Parturition is associated with significant increases of IL-6 in the cervix and myometrium. The literature suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition. For mice deficient in IL-6 (ll6 -/- null mice), parturition was delayed relative to wild-type (ll6 +/+ ) mice. Administration of recombinant IL-6 to ll6-/- null mice restored the normal timing of delivery.

8.2 Lactation Risk Summary No information is available on the presence of sarilumab in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Maternal IgG is present in human milk. If sarilumab is transferred into human milk, the effects of local exposure in the gastrointestinal tract and potential limited systemic exposure in the infant to sarilumab are unknown. The lack of clinical data during lactation precludes clear determination of the risk of KEVZARA to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for KEVZARA and the potential adverse effects on the breastfed child from KEVZARA or from the underlying maternal condition.

8.4 Pediatric Use KEVZARA is approved for active polyarticular juvenile idiopathic arthritis (pJIA) in pediatric patients who weigh 63 kg or greater. Use of KEVZARA in this patient population is supported by evidence from adequate and well-controlled studies of KEVZARA in adults with RA, pharmacokinetic data from adult patients with RA, and a pharmacokinetic, pharmacodynamic, dose-finding, and safety study in pediatric patients with pJIA 2 years of age and older. KEVZARA is not approved in pediatric patients weighing less than 63 kg because of the lack of an appropriate dosage form [see Adverse Reactions (6.1) , Pharmacokinetics (12.3) , and Clinical Studies (14.1 , 14.3) ] . The safety and effectiveness of KEVZARA have not been established in pediatric patients with pJIA below the age of 2 years.

8.5 Geriatric Use Of the total number of patients with RA exposed to KEVZARA in clinical studies [see Clinical Studies (14.1 )] , 450 patients (15%) were 65 years of age and over, while 48 patients (1.6%) were 75 years and over. In clinical studies, no overall differences in safety and efficacy were observed between older and younger patients. The frequency of serious infections among KEVZARA and placebo-treated patients 65 years of age and older was higher than those under the age of 65. Of the total number of patients with PMR exposed to KEVZARA in the clinical study (Study 3) [see Clinical Studies (14.2) ] , 16 patients (27.1%) were under 65 years of age, 33 patients (55.9%) were 65 to 75 years of age, and 10 patients (17.0%) were 75 years and over. The median age in the PMR study was 69.0 years and all patients were on baseline corticosteroid. There were no differences in the incidence of serious infections between the KEVZARA group and placebo group. In Study 3, no overall differences in safety were observed between older and younger patients. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.

8.6 Hepatic Impairment The safety and efficacy of KEVZARA have not been studied in patients with hepatic impairment, including patients with positive HBV or HCV serology [see Warnings and Precautions (5.6) ] .

8.7 Renal Impairment No dose adjustment is required in patients with mild to moderate renal impairment. KEVZARA has not been studied in patients with severe renal impairment [see Clinical Pharmacology (12.3) ] .

Sarilumab binds to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R), and has been shown to inhibit IL-6-mediated signaling through these receptors. IL-6 is a pleiotropic pro-inflammatory cytokine produced by a variety of cell types including T- and B-cells, lymphocytes, monocytes, and fibroblasts. IL-6 has been shown to be involved in diverse physiological processes such as T-cell activation, induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, and stimulation of hematopoietic precursor cell proliferation and differentiation. IL-6 is also produced by synovial and endothelial cells leading to local production of IL-6 in joints affected by inflammatory processes such as rheumatoid arthritis.