Siltuximab (Sylvant)

Number: 0884

Policy

1. Criteria for Initial Approval

   1. Multicentric Castleman's disease or relapsed/refractory unicentric Castleman's disease

      Aetna considers siltuximab (Sylvant) medically necessary for the treatment of active multicentric Castleman’s disease with no organ failure or relapsed/refractory unicentric Castleman’s disease when both of the following criteria are met:

      1. Member is human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative; and
      2. Siltuximab (Sylvant) is used as a single agent.

   2. Cytokine release syndrome

      Aetna considers siltuximab (Sylvant) medically necessary for the treatment of chimeric antigen receptor (CAR) T-cell-induced cytokine release syndrome when either of the following criteria are met:

      1. Cytokine release syndrome is refractory to high-dose corticosteroids and anti-IL-6 therapy; or
      2. Siltuximab (Sylvant) will be used as a replacement for the second dose of tocilizumab when supplies are limited or unavailable.

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

2. Continuation of Therapy

   1. Multicentric Castleman’s disease or relapsed/refractory unicentric Castleman’s disease

      Aetna considers continuation of siltuximab (Sylvant) therapy medically necessary in members with multicentric and relapsed/refractory unicentric Castleman's disease when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

   2. Cytokine release syndrome

      Aetna consideris continuation of siltuximab (Sylvant) therapy medically necessary in all members (including new members) who meet all initial selection criteria.

See also CPB 0799 - Tocilizumab (Actemra).

Dosage and Administration

Sylvant (siltuximab) is available for injection as 100 mg and 400 mg of lyophilized powder in a single-dose vial. Sylvant is for intravenous (IV) infusion only.

The recommended dose for member's with multicentric Castlemans's disease, who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative, is 11 mg/kg given over 1 hour by intravenous infusion every 3 weeks until treatment failure.

Source: EUSA Pharma, 2019

Experimental and Investigational

Aetna considers siltuximab experimental and investigational for the treatment of the following cancers/tumors (not an all-inclusive list) because of insufficient evidence:

• Breast cancer
• Cholangiocarcinoma
• Colorectal cancer
• Coronavirus disease 2019 (COVID-19)
• Head and neck cancer
• Multiple myeloma (including smoldering multiple myeloma)
• Myelodysplastic syndrome
• Myeloma bone disease
• Non-Hodgkin lymphoma
• Non-infectious uveitis (including sarcoidosis, uveitis associated with Behcet disease, and Vogt-Koyanagi-Harada syndrome)
• Non-small cell lung cancer
• Ovarian cancer
• Pancreatic cancer
• Pancreatitis
• Plasma cell cancer
• Prostate cancer
• Renal cancer
• Rheumatoid arthritis
• Rosai-Dorfman disease
• Waldenstrom macroglobulinemia.

Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Sylvant is indicated for the treatment of patients with multicentric Castleman’s disease who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative.

Compendial Use

• Relapsed/refractory unicentric Castleman’s disease
• Chimeric antigen receptor (CAR) T-cell-related toxicities - cytokine release syndrome (CRS)

Siltuximab (Sylvant) is an interleukin-6 (IL-6) antagonist. Siltuximab binds human IL-6 and prevents the binding of IL-6 to both soluble and membrane-bound IL-6 receptors. IL-6 has been shown to be involved in diverse normal physiologic processes such as induction of immunoglobulin secretion. Overproduction of IL-6 has been linked to systemic manifestations in patients with multicentric Castleman's disease (MCD) (EUSA Pharma, 2019).

Sylvant carries the following warnings and precautions: concurrent active severe infections, precaution with vaccinations (do not administer live vaccines because IL-6 inhibition may interfere with the normal immune response to new antigens), infusion related reactions, and gastrointestinal (GI) perforation. The most common adverse reactions (>10% of patients) were rash, pruritus, upper respiratory tract infection, increased weight, and hyperuricemia (EUSA Pharma, 2019).

Castleman's Disease

Castleman's disease (CD), also known as angio-follicular lymph node hyperplasia and giant lymph node hyperplasia, is a heterogenous group of lympho-proliferative disorders associated in a subset of cases with the human immunodeficiency virus (HIV) and human herpes virus 8 (HHV-8).  There are 2 forms of CD: unicentric and multicentric; with very different prognoses.  Castleman's disease may also be associated with other malignancies, including Hodgkin lymphoma, Kaposi sarcoma, non-Hodgkin lymphoma (NHL), as well as polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome (POEMS).  Patients with multicentric CD (MCD) usually present at a median age of 50 to 65 years, although those who are HIV-infected tend to be younger; and 50 % to 65 % are male.  The incidence of HIV-associated MCD has increased in the years since the introduction of anti-retroviral therapy for the management of HIV (Astor et al, 2014).

Interleukin-6 (IL-6) has emerged as a key factor in the pathogenesis of CD.  Siltuximab, an anti-IL-6, chimeric monoclonal antibody derived from a new Chinese hamster ovary (CHO) cell line, has been demonstrated to exhibit potential therapeutic benefit in patients with CD.

van Rhee et al (2010) reported interim results from an open-label, dose-finding, phase I study in which patients with symptomatic, MCD or unresectable, unicentric CD received siltuximab at 1-, 2-, or 3-week intervals.  The main efficacy end-point of clinical benefit response (CBR) was defined as a composite of clinical and laboratory measures (e.g., anorexia, fatigue, fever/night sweats, hemoglobin, weight loss, and largest lymph node size) relevant to the management of CD.  In addition, radiologic response was independently assessed by using modified Cheson criteria.  A total of 18 (78 %) of 23 patients (95 % confidence intervals [CI]: 56 % to 93 %) achieved CBR, and 12 patients (52 %) demonstrated objective tumor response.  All 11 patients (95 % CI: 72 % to 100 %) treated with the highest dose of 12 mg/kg achieved CBR, and 8 patients (73 %) achieved objective tumor response.  Overall objective-response duration ranged from 44 to greater than or equal to 889 days, and 1 patient had complete response (CR) for greater than or equal to 318 days.  Hemoglobin increased markedly in 19 patients (median increase, 2.1 g/dL; range of 0.2 to 4.7 g/dL) in the absence of transfusion or erythropoiesis-stimulating agents.  No dose-limiting toxicity (DLT) was reported, and only 3 patients had grade 3 or higher adverse events (AEs) after a median exposure of 331 days (range of 1 to 1,148 days).  The authors concluded that these interim results strongly suggested that siltuximab is an effective treatment with favorable safety for the management of CD.  

In an open-label, dose-finding, phase I clinical trial, Kurzrock et al (2013) evaluated the safety and pharmacokinetics of siltuximab in patients with B-cell NHL, multiple myeloma (MM), or CD.  Patients with NHL, MM, or symptomatic CD received siltuximab 3, 6, 9, or 12 mg/kg weekly, every 2 weeks, or every 3 weeks.  Response was assessed in all disease types.  Clinical benefit response was also evaluated in CD.  A total of 67 patients received a median of 16 siltuximab doses for a median of 8.5 (maximum 60.5) months; 29 were treated 1 year or longer.  There was no DLT, antibodies to siltuximab, or apparent dose-toxicity relationship.  The most frequently reported possible drug-related AEs were thrombocytopenia (25 %), hypertriglyceridemia (19 %), neutropenia (19 %), leukopenia (18 %), hypercholesterolemia (15 %), and anemia (10 %).  None of these events led to dose delay/discontinuation except for neutropenia and thrombocytopenia (n = 1 each).  No treatment-related deaths occurred; C-reactive protein (CRP) suppression, a surrogate marker of IL-6 inhibition, was most pronounced at 12 mg/kg every 3 weeks.  Mean terminal-phase half-life of siltuximab ranged 17.73 to 20.64 days.  Thirty-two of 37 (86 %) patients with CD improved in 1 or more CBR component; 12 of 36 evaluable CD patients had radiologic response [CR, n = 1; partial response (PR), n = 11], including 8 of 19 treated with 12 mg/kg; 2 of 14 (14 %) evaluable NHL patients had PR; 2 of 13 (15 %) patients with MM had CR.  The authors concluded that no dose-related or cumulative toxicity was apparent across all disease indications.  A dose of 12 mg/kg every 3 weeks was recommended on the basis of the high response rates in CD and the sustained CRP suppression.  Moreover, they noted that randomized studies are ongoing in CD and MM.

In a phase II, randomized-controlled, double-blind, multi-center study, Wong and colleagues (2013) evaluated the safety and effectiveness of siltuximab in patients with symptomatic, measurable, HIV-negative and HHV-8-negative MCD.  Patients could be newly diagnosed/pre-treated and on stable, low-dose corticosteroids.  Patients were randomly assigned 2:1 to siltuximab 11 mg/kg or placebo given by 1-hr intravenous (IV) infusion q3w.  All patients also received best supportive care (BSC) to manage MCD symptoms.  Patients received study agent until protocol-defined treatment failure, after which patients randomized to placebo could cross-over to unblinded siltuximab.  Primary analysis occurred after the last treated patient completed assessments at 48 wks.  Primary end-point was durable tumor and symptomatic response defined as PR or CR (Cheson criteria) by independent review and improvement/stabilization in MCD-related symptoms for greater than or equal to 18 wks.  Secondary end-points included additional pre-defined efficacy measures and safety.   A total of 79 patients were randomized and treated with siltuximab (n = 53) or placebo (n = 26) from February 2010 to February 2013.  Treatment arms were well-balanced.  Median age was 48 yrs, 48 % were Asian, 39 % were white, 66 % were male, 30 % were on corticosteroids, and 58 % had prior systemic therapy.  Patients had mixed (44 %), hyaline vascular (33 %), or plasmacytic (23 %) histologic subtypes by pre-randomization central pathology review.  Baseline MCD symptoms included fatigue (86 %), malaise (61 %), night sweats (52 %), peripheral sensory neuropathy (38 %), anorexia and pruritus (37 % each).  Median treatment duration was 375 versus 152 days with siltuximab versus placebo, with 64 % versus 27 % completing 48 wks of treatment.  A higher percentage of durable tumor and symptomatic response was observed with siltuximab compared with placebo (34 % (1 CR, 17 PR) versus 0 %; p = 0.0012).  Median duration of tumor and symptomatic response in siltuximab-treated patients of 340 days indicated prolonged disease control.  Tumor response rate by central radiology review was 38 % versus 4 % (p = 0.0022).  Median time to treatment failure was not reached versus 134 days (p = 0.0084).  Median time to next treatment was not reached versus 280 days (p = 0.0013).  Durable symptomatic response rate was 57 % versus 19 % (p = 0.0018), including complete symptom resolution in 25 % versus 0 % (p = 0.0037).  Hemoglobin improvement by greater than or equal to 15 g/L at wk 13 was seen in 61 % versus 0 % anemic patients (p = 0.0002).  Sustained decreases in CRP, erythrocyte sedimentation rate, and fibrinogen, and increase in albumin were seen with siltuximab; 13 of 26 patients on placebo crossed-over to siltuximab.  The safety profile as defined by frequencies of treatment-emergent AEs was similar between siltuximab and placebo despite the greater than 2x longer treatment duration with siltuximab: Grade greater than or equal to 3 AEs 47 % versus 54 %, serious AEs 23 % versus 19 %, AEs leading to discontinuation 23 % versus 38 % (mostly due to progressive disease [PD]), AEs leading to treatment interruption 28 % versus 19 %.  Infusion reactions with siltuximab were infrequent (8 %) and low-grade, except for 1 anaphylactic reaction that led to treatment discontinuation.  Grade greater than or equal to 3 AEs frequently reported with siltuximab were fatigue (9 %); night sweats (8 %); and hyperkalemia, hyperuricemia, localized edema, hyperhidrosis, neutropenia, thrombocytopenia, hypertension, and weight gain (4 % each).  Grade greater than or equal to 3 AEs reasonably related to siltuximab reported in more than 1 patient were neutropenia and thrombocytopenia (4 % each); 3 (6 %) patients had serious AEs reasonably related to siltuximab; 2 (4 %) patients in siltuximab died due to PD after treatment discontinuation; 4 (15 %) non-crossover patients in placebo died (1 AE, 3 PD).  The authors concluded that this was the first randomized study in MCD.  The effectiveness of siltuximab in MCD patients was demonstrated by durable tumor and symptom response, and clinical benefit was confirmed by marked improvement of time to treatment failure, MCD-related symptoms, hemoglobin levels, and sustained reduction in inflammatory markers.  They stated that in conjunction with the tolerable safety profile in this population, this study provided compelling evidence that siltuximab should be considered a new treatment of choice for MCD patients.

On April 23, 2014, the Food and Drug Administration (FDA) approved siltuximab (Sylvant) to treat patients with MCD.  The FDA reviewed Sylvant under its priority review program, which provides an expedited review for drugs that demonstrate the potential to be a significant improvement in safety or effectiveness in the treatment of a serious condition.  Sylvant was also granted orphan product designation because it is intended to treat a rare disease or condition.  Sylvant’s safety and effectiveness were evaluated in a clinical trial of 79 participants with MCD who were HIV and HHV-8 negative.  Participants were randomly assigned to receive a combination of Sylvant and BSC, or placebo and BSC.  Results showed 34 % of participants treated with Sylvant and BSC experienced tumor response, while no participant treated with placebo and BSC did.  Common side effects associated with the use of siltuximab include hyperuricemia, pruritis, rash, weight gain, and upper respiratory tract infection.  Siltuximab is administered as an 11 mg/kg dose given over 1 hour by intravenous infusion every 3 weeks until treatment failure.  Sylvant was not studied in patients with MCD who are HIV positive or HHV-8 positive because siltuximab did not bind to virally produced IL-6 in a non-clinical study.

An UpToDate review on "Multicentric Castleman's disease" (Astor et al, 2014) states that "Where available, immunotherapy with monoclonal antibodies directed at IL-6 (siltuximab) or the IL-6 receptor (tocilizumab) is our preferred therapy for most symptomatic, HIV/HHV-8 negative patients without evidence of organ failure.  This approach has resulted in two-year overall and relapse-free survival rates of 94 to 95 percent and 79 to 85 percent, respectively".

Siltuximab for Other Indications

Siltuximab, either as a single agent or in combination with other chemotherapeutic agents, has also been shown to have potential benefits in treating different types of cancers (e.g., colorectal cancer, head and neck cancer, multiple myeloma, non-Hodgkin lymphoma, non-small cell lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, and renal cancer).  However, its effectiveness for these indications has not been established.

In a phase I/II study, Angevin et al (2014) evaluated safety, effectiveness, and pharmacokinetics of escalating, multiple doses of siltuximab in patients with advanced/refractory solid tumors.  In the phase I dose-escalation cohorts, a total of 20 patients with advanced/refractory solid tumors received siltuximab 2.8 or 5.5 mg/kg every 2 weeks or 11 or 15 mg/kg every 3 weeks intravenously.  In the phase I expansion (n = 24) and phase II cohorts (n = 40), patients with Kirsten rat sarcoma-2 (KRAS)-mutant tumors, ovarian, pancreatic, or anti-EGF receptor refractory/resistant non-small cell lung cancer (NSCLC), colorectal, or head and neck cancer received 15 mg/kg every 3 weeks.  The phase II primary efficacy end-point was CR, PR, or SD greater than 6 weeks.  A total of 84 patients (35 colorectal, 29 ovarian, 9 pancreatic, and 11 other) received a median of 3 (range of 1 to 45) cycles.  One DLT occurred at 5.5 mg/kg.  Grade greater than or equal to 3 AEs were hepatic function abnormalities (15 %), physical health deterioration (12 %), and fatigue (11 %).  Ten percent of patients had siltuximab-related grade greater than or equal to 3 AEs.  Neutropenia (4 %) was the only possibly related AE grade greater than or equal to 3 reported in more than 1 patient.  Serious AEs were reported in 42 %; most were related to underlying disease.  The pharmacokinetic profile of CHO-derived siltuximab appeared similar to the previous cell line.  No objective responses occurred; 5 of 84 patients (6 %) had SD greater than 6 weeks.  Hemoglobin increased greater than or equal to 1.5 g/dL in 33 of 47 patients (70 %).  At 11 and 15 mg/kg, completely sustained CRP suppression was observed.  The authors concluded that siltuximab monotherapy appeared to be well-tolerated but without clinical activity in solid tumors, including ovarian and KRAS-mutant cancers.  The recommended phase II doses were 11 and 15 mg/kg every 3 weeks.

Breast Cancer

Casneuf and co-workers (2016) noted that IL-6 is an important growth factor for estrogen receptor-α (ERα)-positive breast cancer, and elevated serum IL-6 is associated with poor prognosis.  These researchers examined the role of the phosphorylated signal transducer and activator of transcription 3 pathway in ERα-positive breast cancer.  A panel of cell lines was treated with exogenous IL-6.  An IL-6 specific gene signature was generated by profiling ten ERα-positive breast cancer cell lines alone or following treatment with 10 ng/ml recombinant IL-6 or human marrow stromal cell-conditioned media, with or without siltuximab (a neutralizing anti-IL-6 antibody) and grown in 3-D tumor microenvironment-aligned cultures for 4 days, 5 days, or 6 days.  The established IL-6 signature was validated against 36 human ERα-positive breast tumor samples with matched serum.  A comparative MCF-7 xenograft murine model was utilized to determine the role of IL-6 in estrogen-supplemented ERα-positive breast cancer to assess the efficacy of anti-IL-6 therapy in-vivo.  In 8 of 9 ERα-positive breast cancer cell lines, recombinant IL-6 increased phosphorylation of tyrosine 705 of STAT3.  Differential gene expression analysis identified 17 genes that could be used to determine IL-6 pathway activation by combining their expression intensity into a pathway activation score.  The gene signature included a variety of genes involved in immune cell function and migration, cell growth and apoptosis, and the tumor microenvironment.  Validation of the IL-6 gene signature in 36 matched human serum and ERα-positive breast tumor samples showed that patients with a high IL-6 pathway activation score were also enriched for elevated serum IL-6 (greater than or equal to 10 pg/ml).  When human IL-6 was provided in-vivo, MCF-7 cells engrafted without the need for estrogen supplementation, and addition of estrogen to IL-6 did not further enhance engraftment.  Subsequently, these investigators prophylactically treated mice at MCF-7 engraftment with siltuximab, fulvestrant, or combination therapy.  Siltuximab alone was able to blunt MCF-7 engraftment.  Similarly, siltuximab alone induced regressions in 90 % (9/10) of tumors, which were established in the presence of hMSC expressing human IL-6 and estrogen.  The authors concluded that given the established role for IL-6 in ERα-positive breast cancer, these findings demonstrated the potential for anti-IL-6 therapeutics in breast cancer.

Castration-resistant Prostate Cancer (CRPC)

In an open-label, 2-part, phase II trial, Fizazi et al (2012) assessed mitoxantrone/prednisone (M/P) with and without siltuximab for patients with metastatic castration-resistant prostate cancer (CRPC) who received prior docetaxel-based chemotherapy.  Part 1 assessed the safety of bi-weekly siltuximab 6 mg/kg plus M 12 mg/m(2) every 3 weeks and P.  Part 2 assessed safety and effectiveness of siltuximab plus M/P versus M/P alone.  The primary end-point was progression-free survival (PFS).  Progression was defined as progressive disease per Response Evaluation Criteria in Solid Tumors (RECIST), or greater than or equal to 3 new skeletal lesions with clinical deterioration or without deterioration confirmed by repeated bone scan.  Rising prostate-specific antigen (PSA) was not considered progression.  Siltuximab plus M/P was well-tolerated in Part 1 (n = 9).  In Part 2, 48 and 49 patients received siltuximab plus M/P or M/P alone, respectively.  Enrolment was prematurely terminated by the Independent Data Monitoring Committee since an apparent imbalance in patient baseline characteristics (favoring the M/P only arm) made it unlikely that the study could achieve its primary efficacy end-point.  Median PFS was 97 days with siltuximab combination and 228 days with M/P alone (hazard ratio [HR], 1.72; p = 0.043).  Use of a novel non-validated PFS definition may have contributed to this result.  Abnormal laboratory assessments were more frequent with the combination.  Infection and febrile neutropenia rates were similar between groups.  Greater CRP suppression was achieved during siltuximab combination treatment compared with M/P alone (p = 0.0003).  The authors concluded that while siltuximab plus M/P appeared well-tolerated, improvement in outcomes was not demonstrated.

In an open-label, dose-escalation, multi-center, phase 1 study, Hudes et al (2013) evaluated the safety and tolerability of siltuximab in combination with docetaxel, the pharmacokinetics of docetaxel alone and with siltuximab, and the effectiveness and pharmacodynamics of siltuximab plus docetaxel for the treatment of CRPC.  Patients with metastatic, progressive CRPC received docetaxel 75 mg/m(2) q3w plus siltuximab 6 mg/kg q2w (n = 12), 9 mg/kg q3w (n = 12), or 12 mg/kg q3w (n = 15).  Dose-limiting toxicity, PSA, and radiologic response according to WHO criteria were evaluated.  Dose-limiting toxicity was reported in 1 of 11 patients receiving 6 mg/kg, 1 of 12 receiving 9 mg/kg, and in 1 of 14 receiving 12 mg/kg.  Grade greater than or equal to 3 AEs were neutropenia (73 %), leukopenia (60 %), lymphopenia (30 %), dyspnea (19 %), and fatigue (14 %).  Toxicities were not dose-dependent.  Siltuximab did not affect docetaxel pharmacokinetics.  The pharmacokinetic profile for siltuximab in combination was similar to single-agent siltuximab pharmacokinetics.  Twenty-three (62 %; 95 % CI: 45 % to 78 %) of 37 combination-treated patients achieved a confirmed greater than or equal to 50 % PSA decline.  Of 17 patients with measurable disease at baseline, 2 confirmed and 2 unconfirmed radiologic PRs ranging 190 to 193 days were achieved with 9- and 12-mg/kg siltuximab.  C-reactive protein concentrations were suppressed throughout treatment in all patients.  The authors concluded that these results suggested that siltuximab in combination with docetaxel was safe and showed preliminary efficacy in patients with CRPC, although alternative siltuximab schedules may be better tolerated for future studies.

Cholangiocarcinoma

Nguyen and colleagues (2021) stated that cholangiocarcinoma has an unimproved prognosis; and IL-6 has an oncogenic potential in some cancer diseases. However, the role of IL-6 in cholangiocarcinoma carcinogenesis is not well understood. These investigators examined the role of IL-6 signaling in cholangiocarcinoma carcinogenesis and the effectiveness of siltuximab on cholangiocarcinoma in-vitro and in-vivo. The expression of IL-6 was analyzed on human cholangiocarcinoma cell lines and murine and human cholangiocarcinoma tissues, using reverse transcription real-time polymerase chain reaction (RT-PCR) and immunohistochemistry. Furthermore, the effect of anti-IL-6 chimeric monoclonal antibody, siltuximab, was examined in-vitro by proliferation, migration, and two-dimensional and three-dimensional (2D and #D) invasion assays and in-vivo by xenograft mouse model. Western blot was used to study the molecular alteration. Result showed high expression of IL-6 in human cholangiocarcinoma cells, and IL-6 stimulants enhanced cholangiocarcinoma cell proliferation. In addition, murine and human cholangiocarcinoma tissues expressed significantly higher levels of IL-6, compared with adjacent non-tumor tissues. On the cholangiocarcinoma engineered mouse model, IL-6 level was associated with tumor volume. Taken together, these findings indicated an oncogenic potential of IL-6 in cholangiocarcinoma carcinogenesis. Siltuximab sufficiently abrogated IL-6 signaling and inhibited cholangiocarcinoma progression in-vitro and in-vivo. The results additionally indicated a relative alteration of IL-6 signaling and its molecular targets, such as STAT3, Wnt/β-catenin, and mesenchymal markers. The authors concluded that IL-6 played an essential role in cholangiocarcinoma carcinogenesis, and siltuximab has the potential to be considered as a new therapeutic option for patients with cholangiocarcinoma.

Coronavirus Disease 2019 (COVID-19)

Del Pozo et al (2020) noted that the pandemic caused by the new SARS-CoV2 coronavirus has led to an effort to find treatments that are effective against this disease that the World Health Organization (WHO) calls coronavirus disease 2019 (COVID-19). In severe cases of COVID-19, there is an increase in cytokines, among which IL-6 appeared to play an important role. These investigators carried out a search for studies using IL-6 blocking drugs (tocilizumab, siltuximab, and sarilumab) in PubMed, Web of Science, and Scopus. Furthermore, they conducted a search of ongoing trials registered at clinicaltrials.gov. the authors found very little published clinical experience with these drugs, consisting mainly of case reports or case series with few patients. These researchers stated that the results of clinical trials are needed to clarify the role of these drugs in patients with COVID-19.

Ghosn and associates (2021) stated that IL-6 blocking agents have been used for treating severe COVID-19. Their immunosuppressive effect might be valuable in patients with COVID-19 characterized by substantial immune system dysfunction by controlling inflammation and promoting disease tolerance. In a Cochrane review, these investigators examined the effect of IL-6 blocking agents compared to standard of care (SOC) alone or with placebo on their safety and effectiveness outcomes in COVID-19. They searched the WHO International Clinical Trials Registry Platform (up to February 11, 2021) and the L-OVE platform, and Cochrane COVID-19 Study Register to identify trials up to February 26, 2021. These researchers included randomized controlled trials (RCTs) evaluating IL-6 blocking agents compared with SOC alone or with placebo in patients with COVID-19, regardless of disease severity. They followed standard Cochrane methodology. The protocol was amended to reduce the number of outcomes considered. Two review authors independently collected data and assessed the risk of bias with the Cochrane Risk of Bias 2 tool. They rated the certainty of evidence with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach for the critical outcomes such as clinical improvement (defined as hospital discharge or improvement on the scale used by trialists to evaluate clinical progression or recovery) (day (D) 28 / greater than or equal to D60); WHO Clinical Progression Score of level 7 or above (i.e., the proportion of subjects with mechanical ventilation +/- additional organ support OR death) (D28 / greater than or equal to D60); all-cause mortality (D28 / greater than or equal to D60); incidence of any AEs; and incidence of serious AEs (SAEs). These researchers identified 10 RCTs with available data including 1 platform trial comparing tocilizumab and sarilumab with SOC. These trials evaluated tocilizumab (9 RCTs including 2 platform trials; 7 were reported as peer-reviewed articles, 2 as pre-prints; 6,428 randomized participants); and 2 sarilumab (1 platform trial reported as peer reviewed article, 1 reported as pre-print, 880 randomized participants). All trials included were multi-center trials. They were carried out in Brazil, China, France, Italy, U.K., U.S., and 4 were multi-country trials. The mean age range of participants ranged from 56 to 65 years; 4,572 (66.3 %) of trial participants were men. Disease severity ranged from mild to critical disease. The reported proportion of participants on oxygen at baseline but not intubated varied from 56 % to 100 % where reported; 5 trials reported the inclusion of intubated patients at baseline. These investigators identified a further 20 registered RCTs of tocilizumab compared to placebo/SOC (5 completed without available results, 5 terminated without available results, 8 ongoing, 2 not recruiting); 11 RCTs of sarilumab (2 completed without results, 3 terminated without available results, 6 ongoing); 6 RCTs of clazakisumab (5 ongoing, 1 not recruiting); 2 RCTs of olokizumab (1 completed, 1 not recruiting); 1 of siltuximab (ongoing) and 1 RCT of levilimab (completed without available results). Of note, 3 were cancelled (2 tocilizumab, 1 clazakisumab); 1 multiple-arm RCT evaluated both tocilizumab and sarilumab compared to SOC, 1 3-arm RCT evaluated tocilizumab and siltuximab compared to SOC and consequently they appeared in each respective comparison. The authors concluded that on average, tocilizumab reduced all-cause mortality at D28 compared to SOC alone or placebo and probably resulted in slightly fewer SAEs than SOC alone or placebo. Nevertheless, tocilizumab probably resulted in little or no increase in the outcome clinical improvement (defined as hospital discharge or improvement measured by trialist-defined scales) at D28. The impact of tocilizumab on other outcomes is uncertain or very uncertain. With the data available, these investigators were unable to examine heterogeneity. Individual patient data meta-analyses are needed to identify which patients are more likely to benefit from this treatment. Evidence for an effect of sarilumab is uncertain and evidence for other anti-IL6 agents is unavailable. A total of 39 RCTs of IL-6 blocking agents with no results are currently registered, of which 9 are completed and 7 trials were terminated with no results available.

Khan et al (2021) noted that there is accumulating evidence for an overly activated immune response in severe COVID-19, with several studies exploring the therapeutic role of immunomodulation. In a systematic review and meta-analysis, these investigators examined the effectiveness of specific IL inhibitors for the treatment of COVID-19. They carried out electronic databases on January 7, 2021 to identify studies of immunomodulatory agents (anakinra, sarilumab, siltuximab and tocilizumab) for the treatment of COVID-19. The primary outcomes were severity on an Ordinal Scale measured at day 15 from intervention and days to hospital discharge; and secondary endpoints included overall mortality. A total of 71 studies (2,058 patients) were included; 6 were randomized trials. Most studies examined outcomes in patients who received tocilizumab (60/71). In prospective studies, tocilizumab was associated with improved unadjusted survival (RR 0.83, 95 % CI: 0.72 to 0.96, I2 = 0.0 %), but conclusive benefit was not demonstrated for other outcomes . In retrospective studies, tocilizumab was associated with less severe outcomes on an Ordinal Scale (generalized OR 1.34, 95 % CI: 1.10 to 1.64, I2 = 98 %) and adjusted mortality risk (HR 0.52, 95 % CI: 0.41 to 0.66, I2 = 76.6 %). The mean difference in duration of hospitalization was 0.36 days (95 % CI: -0.07 to 0.80, I2 = 93.8 %). There was substantial heterogeneity in retrospective studies, and estimates should be interpreted cautiously. Other immunomodulatory agents showed similar effects to tocilizumab, but insufficient data precluded meta-analysis by agent. The authors concluded that tocilizumab was associated with a lower relative risk of mortality in prospective studies, but effects were inconclusive for other outcomes. Moreover, these investigators stated that current evidence for the effectiveness of anakinra, siltuximab or sarilumab in COVID-19 is insufficient, with further studies urgently needed for conclusive findings.

Wang and colleagues (2022) noted that sepsis is a syndrome with high mortality, which seriously threatens human health. During the pandemic of COVID-19, some severe and critically ill COVID-19 patients with multiple organ dysfunction developed characteristics typical of sepsis and met the diagnostic criteria for sepsis. Timely detection of cytokine storm and appropriate regulation of inflammatory response may be significant in the prevention and treatment of sepsis. In a systematic review and meta-analysis, these researchers examined the safety and effectiveness of specific IL-1 inhibitors, specific IL-6 inhibitors, and GM-CSF blockades in the treatment of COVID-19 (at the edge of sepsis) patients. They carried out a literature search on PubMed, Embase, Clinical Key, Cochrane Library, CNKI, and Wanfang Database using proper keywords such as "SARS-CoV-2", "Corona Virus Disease 2019", "COVID-19", "anakinra", "tocilizumab", "siltuximab", "sarilumab", "mavrilimumab", "lenzilumab" and related words for publications released until August 22, 2021. Other available resources were also used to identify relevant articles. The present systematic review was performed based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol. Based on the inclusion and exclusion criteria, a total of 43 articles were included in the final review. The meta-analysis results showed that tocilizumab could reduce the mortality of patients with COVID-19 (at the edge of sepsis) (RCTs: odds ratio (OR) 0.71, 95 % CI: 0.52 to 0.97, low-certainty evidence; non-RCTs: risk ratio (RR) 0.68, 95 % CI: 0.55 to 0.84, very low-certainty evidence) as was anakinra (non-RCTs: RR 0.47, 95 % CI: 0.34 to 0.66, very low-certainty evidence). Sarilumab might reduce the mortality of patients with COVID-19 (at the edge of sepsis), but there was no statistical significance (OR 0.65, 95 % CI: 0.36 to 1.2, low-certainty evidence). For safety outcomes, whether tocilizumab had an impact on SAEs was very uncertain (RCTs: OR 0.87, 95 % CI: 0.38 to 2.0, low-certainty evidence; non-RCTs 1.18, 95 % CI: 0.83 to 1.68, very low-certainty evidence) as was on secondary infections (RCTs: OR 0.71, 95 % CI: 0.06 to 8.75, low-certainty evidence; non-RCTs: RR 1.15, 95 % CI: 0.89 to 1.49, very low-certainty evidence). The authors concluded that this systematic review showed that tocilizumab, sarilumab, and anakinra could reduce the mortality of patients with COVID-19 (at the edge of sepsis), and tocilizumab did not significantly affect SAEs and secondary infections. The current evidence of the studies on patients treated with siltuximab, mavrilimumab, and lenzilumab is insufficient. In order to establish evidence with stronger quality, high-quality studies are needed.

The authors stated that this review had several drawbacks. First, the lack of RCTs limited the analyses. Some included studies were case reports or case series and had no proper control groups. Meanwhile, some articles of which the full texts or data were not accessible and those in languages other than Chinese and English were excluded from the analysis. This might have led to over-looking some critical findings or observations. Furthermore, in this study, the Sequential (Sepsis-Related) Organ Failure Assessment (SOFA) score or related indicators of some patients included in the study were median or mean, so not all patients were septic patients, but the results of this population also reflected a trend problem because some patients might be or would be in a state of sepsis. Third, these investigators found that most patients used anti-viral drugs, glucocorticoids, immunoglobulins, plasma, broad-spectrum antibiotics, and other drugs at the same time; therefore, they could not rule out the impact of these drugs on the disease.

Villaescusa and co-workers (2022) stated that since the beginning of the pandemic, numerous national and international clinical trials have been carried out with a large number of drugs. Many of them are intended for the treatment of other pathologies; however, despite the great effort made, no specific drug is available for the treatment of the symptoms of respiratory disease caused by SARS-CoV-2 infection. These investigators provided data to justify the use of drugs to tackle the effects produced by IL-6 as the main inflammatory mediator in patients with COVID-19 with severe respiratory complications, considering all clinical evidence linking the poor prognosis of these patients with increased IL-6 levels in the context of cytokine release syndrome (CRS). Furthermore, data were provided to justify the proposal of a rational dosing of siltuximab based on reactive C protein (RCP) levels, considering the limited results published so far on the use of this drug in COVID-19. These researchers carried out a literature search on the clinical trials of siltuximab published to-date as well as on the different IL-6 signaling pathways and the effects of its over-expression. Knowledge of the mechanisms of action on these pathways may provide important information for the design of drugs useful in the treatment of these patients. The authors concluded that all data suggested that siltuximab is an excellent candidate for improving the inflammatory phase of COVID-19; thus, a priori it has a good chance of improving the incidence of mortality in this serious disease, although validated and properly designed clinical trials are needed to confirm the clinical use of siltuximab compared to other IL-6 pathway blocking drugs.

Multiple Myeloma

In a phase II, multi-center study, Voorhees et al (2013) evaluated the safety and effectiveness of siltuximab for patients with relapsed or refractory MM who had greater than or equal to 2 prior lines of therapy, one of which had to be bortezomib-based.  A total of 14 initial patients received siltuximab alone, 10 of whom had dexamethasone added for suboptimal response; 39 subsequent patients were treated with concurrent siltuximab and dexamethasone.  Patients received a median of 4 prior lines of therapy, 83 % were relapsed and refractory, and 70 % refractory to their last dexamethasone-containing regimen.  Suppression of serum CRP levels was demonstrated.  There were no responses to siltuximab but combination therapy yielded a partial (17 %) + minimal (6 %) response rate of 23 %, with responses seen in dexamethasone-refractory disease.  The median time to progression, PFS and overall survival for combination therapy was 4.4, 3.7 and 20.4 months, respectively.  Hematological toxicity was common but manageable.  Infections occurred in 57 % of combination-treated patients, including greater than or equal to grade 3 infections in 18 %.  The authors concluded that further study of siltuximab in modern corticosteroid-containing myeloma regimens is needed, with special attention to infection-related toxicity.

In a randomized, double-blind, placebo-controlled, multi-center study, Brighton and colleagues (2019) examined blocking IL-6 with siltuximab to delay the transition from high-risk smoldering MM (SMM) MM.  A total of 85 patients with high-risk SMM were randomized to 15 mg/kg siltuximab (43 patients) or placebo (42 patients).  The primary end-point was 1-year PFS rate, based on IMWG CRAB criteria.  Secondary end-points included progressive disease indicator rate, PFS, and safety.  Median age was 62 years (range of 21 to 84); 57 % were men and 87 % had a baseline Eastern Cooperative Oncology Group (ECOG) score of 0.  The 1-year PFS rate was 84.5 % (siltuximab) and 74.4 % (placebo).  After a median follow-up of 29.2 months, 32.6 % of PFS events occurred with siltuximab and 42.9 % with placebo.  Median PFS was not reached with siltuximab but was 23.5 months with placebo [HR 0.50 (95 % CI: 0.24 to 1.04); p = 0.0597].  The safety profile of siltuximab was comparable with placebo.  Most AEs observed in the siltuximab group were grade 2/3; the most common serious AEs were infections/infestations, and renal/urinary disorders.  Mortality was low in both groups (3 deaths in the siltuximab group and 4 in the placebo group).  The authors concluded that although this study did not meet the pre-specified protocol hypothesis criteria, these findings suggested that siltuximab may delay the progression of high-risk SMM.

Myelodysplastic Syndrome

In a phase II, randomized, double-blind, multi-center study, Garcia-Manero et al (2014) evaluated the safety and effectiveness of siltuximab in patients with low- and intermediate-1-risk myelodysplastic syndrome (MDS) who require transfusions for MDS anemia.  Patients were randomized in a 2:1 ratio to siltuximab 15 mg kg (-1) every 4 weeks + best supportive care (BSC) or placebo + BSC for 12 weeks.  The primary end-point was reduction in red blood cell (RBC) transfusions to treat MDS anemia, defined as greater than or equal to 50 % relative decrease and greater than or equal to 2-unit absolute decrease in RBC transfusions; 50 and 26 patients were randomized to the siltuximab and placebo groups, respectively.  The study did not meet its pre-specified hypothesis, with 6 (12 %) patients in the siltuximab group and 1 (3.8 %) in the placebo group having reductions in RBC transfusions (p = 0.271).  At the time of the planned futility analysis, the pre-specified cut-off criteria were not met, and the study was terminated early due to lack of efficacy.  No unexpected safety findings were observed.  The authors concluded that compared to placebo, treatment with siltuximab did not reduce RBC transfusions in transfusion-dependent patients with low- and intermediate-1-risk MDS.  They stated that future studies might explore siltuximab in patients with less iron overload and with elevated IL-6 levels and/or using higher doses for MDS.

Myeloma Bone Disease

Bolzoni and colleagues (2018) noted that bone destruction is the hallmark of MM.  About 80 % of MM patients at diagnosis presents myeloma bone disease (MBD) leading to bone pain and pathological fractures, significantly affecting patients' quality of life (QOL).  Bisphosphonates are the treatment of choice for MBD, but osteolytic lesions remain a critical issue in the current management of MM patients.  Several studies clarified the mechanisms involved in MM-induced osteoclast formation and activation, leading to the identification of new possible targets and the development of better bone-directed therapies.  These investigators summarized the latest advances in the knowledge of the pathophysiology of the osteoclast formation and activation induced by MM cells, and the new therapeutic targets identified.  Recently, neutralizing antibodies (i.e., denosumab, siltuximab, daratumumab), as well as recombinant fusion proteins, and receptor molecular inhibitors, have been developed to block these targets.  Clinical trials testing their anti-MBD potential are ongoing.  The authors concluded that although further studies are needed to arrive at a clinical approving, the basis for the development of better bone-directed therapies has been established.

Non-Infectious Uveitis

Lin and colleagues (2015) noted that IL-6 is a pleiotropic cytokine implicated in the pathogenesis of many immune-mediated disorders including several types of non-infectious uveitis.  These uveitic conditions include Vogt-Koyanagi-Harada syndrome, uveitis associated with Behcet disease, and sarcoidosis.  These investigators summarized the role of IL-6 in immunity, highlighting its effect on Th17, Th1, and plasmablast differentiation.  They reviewed the down-stream mediators activated in the process of IL-6 binding to its receptor complex.  These researchers also summarized the biologics targeting either IL-6 or the IL-6 receptor, including tocilizumab, sarilumab, sirukumab, olokizumab, clazakizumab, and siltuximab.  The target, dosage, potential side effects, and potential uses of these biologics were summarized based on the existing literature.  The authors concluded that anti-IL-6 therapy for non-infectious uveitis shows promise in terms of efficacy and side effect profile.

Pancreatitis

Hao and associates (2017) stated that chronic pancreatitis (CP) is a progressive inflammatory disease of the pancreas, leading to its fibrotic destruction.  There are currently no drugs that can stop or slow the progression of the disease.  The etiology of the disease is multi-factorial, whereas recurrent attacks of acute pancreatitis are thought to precede the development of CP.  A better understanding of the pathology of CP is needed to facilitate improved diagnosis and treatment strategies for this disease.  These researchers developed a mathematical model of CP based on a dynamic network that includes macrophages, pancreatic stellate cells, and prominent cytokines that are present at high levels in the CP microenvironment.  The model was represented by a system of partial differential equations.  The model was used to explore in silico potential drugs that could slow the progression of the disease (e.g., infliximab, tocilizumab and siltuximab).

Plasma Cell Cancers

Rossi and associates (2015) stated that human IL-6 is a cytokine produced by many cell types that has pleiotropic effects.  Inhibitors of IL-6 reduce inflammation, hepatic acute phase proteins, and anemia and have anti-angiogenic effects.  Blocking IL-6 has demonstrated therapeutic efficacy in Castleman's disease without major toxicity.  Interestingly, the inhibition of CRP production is a trustworthy surrogate marker of anti-IL-6 therapy efficacy.  Clinically registered IL-6 inhibitors include siltuximab and tocilizumab.  In various cancers, in particular plasma cell cancers, large randomized trials showed no efficacy of IL-6 inhibitors, despite a full inhibition of CRP production in treated patients, the numerous data showing an involvement of IL-6 in these diseases, and initial short-term treatments demonstrating a dramatic inhibition of cancer cell proliferation in-vivo.  A likely explanation is the plasticity of cancer cells, with the presence of various subclones, making the outgrowth of cancer subclones possible using growth factors other than IL-6.

Renal Cell Carcinoma

In a 3-part, phase I/II study, Rossi et al (2010) evaluated the effectiveness of siltuximab in patients with progressive metastatic renal cell carcinoma (RCC).  In part 1, 11 patients received 1, 3, 6, or 12 mg/kg at weeks 1, 4 and q2w × 2 thereafter; in part 2, 37 patients randomly received 3 or 6 mg/kg q3w × 4; and in part 3, 20 low-risk patients received 6 mg/kg q2w × 6.  Modified World Health Organization (WHO) response criteria were assessed at weeks 7, 11, the 6-week follow-up, and when clinically indicated.  Siltuximab was well-tolerated overall, with no maximum tolerated dose or immune response observed.  In all, 5 out of 11, 17 out of 37, and 9 out of 20 patients in parts 1, 2, and 3, respectively, received extended treatment beyond 4 to 6 initial infusions.  In part 2, stable disease (SD) (greater than or equal to 11 weeks) or better was achieved by 11 out of 17 (65 %) 3 mg/kg treated patients (1 PR at approximately 8 months, 10 SD) and 10 out of 20 (50 %) 6 mg/kg treated patients (10 SD).  In part 3, documented CR or PR was not observed, but 13 out of 20 (65 %) patients achieved SD.  The authors concluded that siltuximab stabilized disease in more than 50 % of progressive metastatic RCC patients; 1 PR was observed.  The authors concluded that given the favorable safety profile of siltuximab and poor correlation of tumor shrinkage with clinical benefit demonstrated for other non-cytotoxic therapies, further evaluation of dose-escalation strategies and/or combination therapy may be considered for patients with RCC.

Rheumatoid Arthritis

Kim et al (2015) stated that rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by polyarthritis.  Numerous agents with varying mechanisms are used in the treatment of RA, including non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs), and some biological agents.  Studies to uncover the cause of RA have recently ended up scrutinizing the importance of pro-inflammatory cytokine such as tumor necrosis factor-alpha (TNF-α) and IL-6 in the pathogenesis of RA.  Inhibitors of TNF-α are increasingly used to treat RA patients who are non-responsive to conventional anti-arthritis drugs.  Despite its effectiveness in a large patient population, up to 2/3 of RA patients are found to be partially responsive to anti-TNF therapy.  Therefore, agents targeting IL-6 such as tocilizumab (TCZ) attracted significant attention as a promising agent in RA treatment.  The authors reviewed the mechanism of anti-IL-6 in the treatment of RA, provided the key safety and effectiveness data from clinical trials of approved anti-IL-6, TCZ, as well as 6 candidate IL-6 blockers and their future perspectives in the treatment of RA.

Rosai-Dorfman Disease

Lee and colleagues (2018) noted that Rosai-Dorfman disease (RDD) is a rare, macrophage-related disorder of unknown cause that presents as a localized or systemic disorder involving lymph nodes and other organs.  RDD is often self-limiting, however, sometimes permanent or even fatal.  The rarity and unpredictability of RDD renders optimal timing and modality of treatment difficult.  Bone involvement is especially rare, and predicts a chronic course with decreased likelihood of spontaneous remission.  These researchers presented a case of refractory, disseminated RDD that achieved a CR with siltuximab indicating a major role for IL-6 in this disease.  The treatment schedule of quarterly infusion appeared to have long-term benefit with minimal adverse effects.  The authors stated that the drawback of this single-case study was the lack of measurement of IL-6; however, the clinical response suggested cytokine dysregulation as part of the pathophysiology and should be answered in future studies.  They stated that based on the excellent response in this case, larger clinical trials with siltuximab should be considered.

Waldenstrom Macroglobulinemia

Ferrario and associates (2017) noted that the role of IL-6 in tumorigenesis and in particular in hematological malignancies is crucial.  On the basis of the favorable results obtained in the subset of MCD, siltuximab has been evaluated in hematological malignancies such as MM, MDS and NHL.  These investigators discussed available data related to the role of IL-6 as a therapeutic target, the characteristics of siltuximab in term of pharmacokinetics and pharmacodynamics properties and a detailed analysis of the studies involving hematological malignancies with a peculiar focus on NHL.  The authors stated that the results obtained with siltuximab in hematological malignancies and in particular with NHL are inferior to those obtained in MCD.  The complex interaction between malignant clones, inflammatory background and host response could justify this difference.  These researchers stated that new interesting areas of study are the role of siltuximab in early phase of MM (smoldering MM) and if there may be a possible future application in the treatment of Waldenstrom macroglobulinemia.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
Other CPT codes related to the CPB:
96365	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour
96413	Chemotherapy administration, intravenous infusion technique; up to 1 hour, single or initial substance/drug
HCPCS codes covered if selection criteria are met:
J2860	Injection, siltuximab, 10 mg
ICD-10 codes covered if selection criteria are met:
D47.Z2	Castleman's disease [Multicentric or relapsed/refractory unicentric]
D89.831 – D89.839	Cytokine release syndrome
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
B10.89	Other human herpesvirus infection
B20	Human immunodeficiency virus [HIV] disease
B97.35	Human immunodeficiency virus, type 2 [HIV 2] as the cause of diseases classified elsewhere
C00.0 - C14	Malignant neoplasm of lip, oral cavity, and pharynx
C18.0 - C20	Malignant neoplasm of colon, rectosigmoid junction or rectum
C22.1	Intrahepatic bile duct carcinoma
C25.0 - C25.9	Malignant neoplasm of pancreas
C34.00 - C34.92	Malignant neoplasm of bronchus and lung [non-small cell lung cancer]
C50.011 - C50.929	Malignant neoplasm of breast
C56.1 - C56.9	Malignant neoplasm of ovary
C61	Malignant neoplasm of prostate
C64.1 - C64.9	Malignant neoplasm of kidney, except pelvis
C76.0	Malignant neoplasm of head, face, and neck
C85.80 - C85.99	Non-hodgkin lymphoma
C88.0	Waldenstrom macroglobulinemia.
C90.00 - C90.32	Multiple myeloma
D46.0 - D46.9	Myelodysplastic syndromes
D76.3	Other histiocytosis syndromes [Rosai-Dorfman disease]
H20.00 - H20.29, H20.041 - H20.9	Iridocyclitis other than secondary infectious [non-infectious uveitis]
J12.82	Pneumonia due to coronavirus disease 2019
K85.0 - K85.9	Acute pancreatitis
K86.1	Other chronic pancreatitis
M05.00 - M06.9	Rheumatoid arthritis
U07.1	COVID-19

The above policy is based on the following references: