Pulm Ther

https://doi.org/10.1007/s41030-021-00160-x

REVIEW

A Comprehensive Review of Sarcoidosis Treatment

for Pulmonologists
Andrea S. Melani . Caterina Bigliazzi . Flora Anna Cimmino .
Laura Bergantini . Elena Bargagli

Received: February 28, 2021 / Accepted: May 17, 2021

Ó The Author(s) 2021

ABSTRACT self-limiting and remit spontaneously, in which

case treatment can be postponed and possibly
Due to frequent lung involvement, the pulmo- avoided without any significant impact on
nologist is often the reference physician for quality of life, organ damage or prognosis. Sys-
management of sarcoidosis, a systemic granu- temic glucocorticosteroids (GCs) are the drug of
lomatous disease with a heterogeneous course. first choice for sarcoidosis. When GCs are star-
Treatment of sarcoidosis raises some issues. The ted, there is a [ 50% chance of long-term
first challenge is to select patients who are likely treatment. Prolonged use of prednisone
to benefit from treatment, as sarcoidosis may be at [ 10 mg/day or equivalent is often associated
with severe side effects. In these and refractory
cases, steroid-sparing options are advised.
Antimetabolites, such as methotrexate, are the
second-choice therapy. Biologics, such as anti-
A. S. Melani (&)
C. Bigliazzi
F. A. Cimmino
Pneumology Unit, UOS Pneumologia/UTIP, Dip. TNF and especially infliximab, are third-choice
Scienze Mediche, Chirurgiche e Neuroscienze, drugs. The three treatments can be used con-
Policlinico Le Scotte, Azienda Ospedaliera Senese, comitantly. Regardless of whether treatment is
Viale Bracci, 53100 Siena, Italy started, the clinician needs to organize regular
e-mail: a.melani@ao-siena.toscana.it
follow-up to monitor remissions, flares, pro-
C. Bigliazzi gression, complications, toxicity and relapses in
e-mail: c.bigliazzi@ao-siena.toscana.it order to promptly adjust the drugs used.
F. A. Cimmino
e-mail: f.cimmino@ao-siena.toscana.it
Keywords: Sarcoidosis; Treatment;
L. Bergantini
UOC Malattie Respiratorie, Dip. Scienze Mediche,
Corticosteroids; Methotrexate; Azathioprine;
Chirurgiche e Neuroscienze, Università di Siena Infliximab; Adalimumab; Anti-TNF
Policlinico ‘‘Le Scotte’’, Siena, Italy
e-mail: laurabergantini@gmail.com

E. Bargagli
UOC Malattie Respiratorie, Immunology, Allergy,
Rare Respiratory Diseases and Lung Transplant
Laboratory, Dip. Scienze Mediche, Chirurgiche e
Neuroscienze, Università di Siena Policlinico ‘‘Le
Scotte’’, Siena, Italy
e-mail: bargagli2@gmail.com
 Pulm Ther

DIGITAL FEATURES
Key Summary Points
This article is published with digital features,
As sarcoidosis may be self-limiting and including a summary slide, to facilitate under-
remit spontaneously, a first challenge in standing of the article. To view digital features
its management is to decide whether for this article go to https://doi.org/10.6084/
pharmacological treatment can be m9.figshare.14602299.
postponed and possibly avoided without
any significant impact on quality of life,
organ damage or prognosis. INTRODUCTION
Systemic glucocorticosteroids are the drug Sarcoidosis is a systemic inflammatory granu-
of first choice in the treatment of lomatous disease mainly affecting the lungs and
sarcoidosis. Once started, there is a [50% thoracic lymph nodes. In a previous article in
chance of long-term treatment. Prolonged this journal, we reviewed emerging aspects of
use of prednisone at [10 mg/day or diagnosis and monitoring of the disease. This
equivalent is not advised due to frequent narrative paper aims to review and update sar-
severe side effects. coidosis management. Our search is based on
Antimetabolites and biologics are useful results from studies on sarcoidosis found in
additions to corticosteroids in refractory PubMed analysis. We searched MEDLINE elec-
sarcoidosis or as steroid-sparing options. tronic databases up to 31 December 2020 via
Methotrexate is the most commonly used PubMed, using a combination of the terms
antimetabolite. Infliximab is the biologic ‘‘sarcoidosis’’ [MeSH] OR ‘‘sarcoid’’ *[tiab] AND
most commonly used in sarcoidosis ‘‘Anti-Inflammatory Agents’’ [MeSH] AND (eng-
management. lish[la]) up to 31 December 2020. We obtained
more than 2538 hits. Abstracts were reviewed
Eye, nervous system and heart and bibliographies of relevant papers were
involvement in sarcoidosis may have searched and examined. The papers selected
major clinical consequences and require were hand-searched for additional works on the
prompt aggressive management. Other topic. The present review does not contain any
common effects of sarcoidosis, such as new studies with human participants or animals
fatigue and small fibre neuropathy, may performed by any of the authors.
not respond well to conventional
sarcoidosis treatments. Choice of Treatment
Comorbidities are common in sarcoidosis
and, except for osteoporosis, are usually Once the diagnostic work-up of sarcoidosis is
treated as in the general population. completed, the physician has to decide whether
treatment is necessary, balancing the trade-offs
Irrespective of treatment, the clinician
between pros and cons. Sarcoidosis may have a
needs to organize regular follow-ups to
self-limiting course without any negative
monitor remissions, flares, progression,
impact on quality of life or prognosis, whereas
complications, toxicity and relapses in
prolonged use of systemic glucocorticoids
order to promptly adjust treatment.
(GCs), the pharmacological treatment of first
choice, is often associated with significant tox-
icity and impaired quality of life [1]. The indi-
cations for systemic treatment in sarcoidosis are
shown in Table 1. Key criteria at the start of
treatment are the burden of symptoms and the
degree of organ damage. In a UK registry, more
Pulm Ther

Table 1 Indications for systemic treatment in sarcoidosis ROLE OF SYSTEMIC

Symptoms impairing quality of life GLUCOCORTICOSTEROIDS (GCS)
Persistent lung infiltrates/decline in lung function at
IN MANAGING SARCOIDOSIS
follow-up GCs are the drug of first choice when systemic
Cardiac sarcoidosis treatment is required (see Table 2 for main side
effects and suggested monitoring) [1, 7].
Neurological sarcoidosis
Although few randomized studies have shown
Ocular sarcoidosis not responding to topical therapy the benefits of GCs [8, 9], case series have doc-
umented their effectiveness since 1951 [10].
Hypercalcaemia and/or hypercalciuria resistant to
GCs do not give better outcomes than placebo
dietary vitamin D and calcium restrictions
in asymptomatic sarcoidosis without evidence
Severe skin involvement with disfiguration (e.g. lupus of lung disease, but may be useful in patients
pernio) with pulmonary infiltrates, although it is not
certain whether they can prevent fibrosis [9].
Other end organ failure
Most experts recommend oral prednisone
20–40 mg daily or equivalent in a single
administration for treatment of naı̈ve sarcoido-
than a third of patients with sarcoidosis did not sis patients [11]. A British Thoracic Society
receive any systemic pharmacological treatment Clinical Statement recommends a GC dose from
at diagnosis [2]. 10 mg of prednisolone per day in long-standing,
slowly progressive sarcoidosis [12]. Higher doses
(1 mg/kg/day or 500–1000 mg/day methylpred-
TOPICAL TREATMENT nisolone i.v. in a hospital setting for 3 days) are
IN THE MANAGEMENT sometimes attempted to obtain rapid remission
in cases of life-threatening onset of sarcoidosis
OF SARCOIDOSIS [11]. Once treatment is started, it is usually
continued for several months. Before starting
Topical therapy may be effective in managing
therapy, the patient must receive clear infor-
sarcoidosis. Topical GCs are the local treatment
mation about the details of treatment, includ-
of first choice in many cases of skin, joint and
ing possible adverse effects of the drugs. The
eye sarcoidosis. Less evidence is available about
induction dose is usually maintained for at least
the effectiveness of inhaled corticosteroids in
6–8 weeks. When there is no clinical improve-
pulmonary sarcoidosis. One study found that
ment after 12 weeks of treatment, a response to
inhaled budesonide 1.2–2 mg/day did not
longer courses is unlikely. In cases of remission,
ensure any useful result [3]. Another study
the dose of prednisone should be gradually
observed that inhaled budesonide 0.8 mg twice
reduced to as low as possible (10 mg/day), usu-
a day may help maintain improvement previ-
ally with a decrement every 4 weeks. Once a
ously achieved with GCs [4]. Two other studies
daily dose of 10 mg prednisone is reached, most
found that inhaled fluticasone 0.8–1.0 mg twice
clinicians maintain this dose for 3–6 months
a day was not effective for GC-sparing in acute
before lowering it again. GCs may sometimes be
[5] and chronic pulmonary sarcoidosis [6],
tapered to complete discontinuation. The
although it could reduce coughing. Overall,
probability of relapse after suspending GCs
these results suggest that inhaled GCs cannot be
ranges from 14 to 74% for acute disease and
routinely recommended in pulmonary sar-
about 75% for chronic forms. Approximately
coidosis, but may be useful if coughing and
half of all relapses occur 2–6 months after sus-
airway hyperreactivity are the predominant
pension and most within 12 months [11, 13].
(not severe) symptoms. In the British Thoracic
For patients who relapse while off GCs, rein-
Society sarcoidosis registry, 8% of patients were
troduction of 20 mg/day prednisone for a
receiving inhaled GCs [2].
 Pulm Ther

Table 2 Main drugs used in sarcoidosis

Drug Main adverse effects Baseline and monitoring examinations
Glucocorticoid Weight gain, fluid retention, osteoporosis, Weight, blood pressure, serum lipids and glucose
hyperglycaemia, hypertension, gastritis, muscle at baseline and every 3 months, bone mineral
weakness, opportunistic infections, psychosis, density and ophthalmologic examination
mood swings, insomnia, thrush, cataract, yearly
glaucoma, osteonecrosis of femoral head
Methotrexate Dyspepsia, mucositis, liver and bone marrow Blood, liver and renal indices at baseline and at
toxicity, fatigue, alopecia, increased risk of every 2–4 weeks for the first 3 months, every
infections including opportunists, 2–3 months thereafter; contraindicated in
hypersensitivity pneumonia patients with underlying liver disease and
chronic viral hepatitis
Azathioprine As for MTX and also jaundice, myalgia, blurred As for MTX
vision
Leflunomide* As for MTX and also diarrhoea, skin rash, As for MTX
peripheral neuropathy, alopecia, systemic
hypertension
Mycophenolate Diarrhoea, nausea, vomiting, leukopenia, As for MTX; it may cause increase in blood
anaemia, cytomegalovirus viraemia, infections, concentrations of creatinine
hyperglycaemia, hepatitis
Cyclophosphamide As for MTX and also haemorrhagic cystitis, As for MTX. Urinalysis every month
cytopenia
Hydroxychloroquine Rash, neuromyopathy, retinopathy; Eye examination at baseline and then every
cardiomyopathy, gastrointestinal intolerance, 6–12 months
skin pigmentation
Infliximab and Allergic local reactions, skin rashes, As for MTX; close monitoring during injection,
adalimumab demyelinating disease, lupus-like syndrome, dermatological evaluation at baseline.
congestive heart failure, thromboembolic Contraindicated in cases of severe congestive
disease, increased risk of reactivation of latent heart failure
infections including tuberculosis
Rituximab Reactivation of hepatitis, progressive multifocal Serum immunoglobulins every 3–6 months,
leukoencephalopathy, headache, muscle blood chemistry every 1–3 months
spasms, pancytopenia, fatigue Contraindicated in cases of severe congestive
heart failure. Overall, there is less probability of
immune response to various vaccines
MTX methotrexate
*Some authors suggest an initial dose of 80–160 mg and then 80 mg every other week

median of 3 weeks usually ensures a new treatment is substantial, and weight gain is the
remission [13]. Many patients require long-term most frequent side effect; the risk of side effects
GC treatment. The toxicity of long-term GC depends on the cumulative dose and the
Pulm Ther

Unknown
neutrophils
Antigen

ustekinumab Activated T
macrophages cells

TNF-α Naive T cells IL-12

Apremilast Th1 cells Mesenchimal stromal
Pentoxyfilline cells
Roflumilast IFN-γ
Antigen
Etarnecept Atorvastatin
presenting Th17 cells
Golimumab
cells
IL1-β
IL-6
anakinra

canakinumab T17.1 cells

IL-10 IL-6
T reg cells
TGF-β cyclosporine

Vasoactive Tocilizumab
intestinal
peptide Transdermal
Nicotine

Sarcoid
Granuloma

Fig. 1 Schematic depicting mechanisms of sarcoidosis pathegenesis and treatment. Drugs against specific pathogenic steps are
displayed in blue boxes and arrows

duration of treatment [1, 7, 14]. Patients who do breast-feeding women, as they cross the pla-
not respond to GCs, those who cannot be con- centa. Live vaccinations are not advised during
trolled over the long term with \ 10 mg/day immunosuppressant treatment. A yearly influ-
prednisone, or those who develop intolerance enza vaccination is recommended along with
to GC are candidates for treatment with alter- pneumonia vaccine at baseline and every
native drugs (Fig. 1) [15]. 5 years [19]. Baseline serology for HIV, hepatitis
B and C, and the interferon-gamma release
assay (IGRA) test for tuberculosis is recom-
ROLE OF ANTIMETABOLITES mended, and positive cases should be referred
IN MANAGING SARCOIDOSIS to a specialist.
Methotrexate (MTX) is the additional (or
Antimetabolite immunosuppressants are the alternative) drug of first choice with respect to
first addition (or alternative) to GC treatment. GCs [15–18, 20, 21]. When MTX is added to
Some characteristics of these drugs are shown in GCs in cases of refractory sarcoidosis, at least
Table 2 [7, 15–19]. Note that tapering the dose one third of all patients may still not respond.
of GCs is not recommended for at least 2–- MTX mainly inhibits adenosine deaminase,
3 months after the addition of an antimetabo- increasing adenosine levels, with several inter-
lite, as the latter takes several weeks to reach actions and consequences for the immune sys-
maximum therapeutic effect. Some clinics start tem. It may be administered orally with variable
the antimetabolite and GCs together in patients uptake. Doses are usually given weekly to limit
with severe forms of sarcoidosis, such as cardiac toxicity. The starting dose of MTX is often
sarcoidosis, neurological sarcoidosis and poste- 5 mg/week s.c. or i.m., with gradual 2.5 mg
rior uveitis. Antimetabolites are contraindicated increments every 2 weeks up to a dose of 15 mg/
during active infections, pregnancy and in week or higher, if tolerated and necessary [20].
 Pulm Ther

Rheumatology guidelines permit the use of Nudix hydrolase 15 (NUDT15) mutations are
MTX up to 25 mg/week [18]. Combination with reported to be responsible for poor metaboliza-
oral folic acid at 1–2 mg/day reduces the toxic- tion of AZA. TPMT and NUDT15 genotyping
ity but not anti-inflammatory effects, and is and phenotyping are recommended for AZA
recommended [20]. As MTX is excreted by the users. Life-threatening bone marrow toxicity is
kidneys, it is contraindicated in patients with mostly observed in carriers of homozygous
advanced chronic kidney disease (glomerular TPMT mutations, while heterozygous muta-
filtration rate \ 30–50 ml/min). Penicillin, pro- tions (occurring in 11% of the population) are
benecid, proton-pump inhibitors and valproate often associated with intermediate enzyme
can increase plasma concentrations of MTX, levels and require a lower than standard dosage
while trimethoprim may predispose to additive [24]. Co-administration of drugs that influence
hepatotoxicity and blood toxicity. By contrast, TPMT or xanthine oxidase activity, such as
concomitant use of neomycin and paro- allopurinol and febuxostat, can increase AZA
momycin have been found to reduce gastroin- toxicity. In a retrospective unblinded uncon-
testinal absorption of MTX. Side effects lead to trolled cohort study, AZA and MTX showed
discontinuation of MTX in approximately 20% similar outcomes but AZA use was associated
of users. The most common adverse events are with twice the risk of infections [25]; however,
gastrointestinal (more frequent in younger the definition of infection was not identical
patients) and may sometimes be attenuated by between treatment groups. Unlike MTX and
splitting the dose, taking tablets during a meal leflunomide, which are excreted by the kidneys,
or switching to parenteral administration. At AZA may be relatively safe in patients with renal
periodic checks, approximately 25% of patients failure (excluding stage 3 or higher chronic
on MTX showed serum transaminase levels kidney failure). AZA is a particularly useful
more than three times the upper limit of normal alternative to MTX in patients who have
during the first year; liver toxicity may respond chronic liver toxicity at baseline. An increased
to dose reduction [21] and warrants referral to a risk of lymphoma has been reported in patients
liver specialist. Avoidance of alcohol intake is using a combination of anti-TNF-a and AZA
suggested during MTX treatment. About 4% of [18]. AZA is probably the safest second-line drug
users discontinue MTX due to excessive liver for couples planning a pregnancy [17].
toxicity. Approximately 10% of patients with Leflunomide (LEF) inhibits mitochondrial
rheumatological diseases on MTX monotherapy dihydroorotate dehydrogenase, blocking
experience neutropenia, severe in 0.4% of cases expansion of activated T lymphocytes. The
[22]. Another serious though uncommon com- typical oral starting dose is 10 mg/day or every
plication is hypersensitivity pneumonia; the other day, which can be increased after a few
risk is dose-dependent and usually occurs after weeks to 20–30 mg/day if well tolerated. Two
months to years of MTX treatment. MTX retrospective cohort studies on 108 patients
should be discontinued at least 2–3 months supported the use of LEF, alone but usually in
prior to any planned pregnancy; otherwise combination with MTX, in sarcoidosis patients
women of reproductive age should practise [26]. The action of LEF is similar to that of MTX,
effective birth control [17]. The effect of MTX but their toxicity profiles are different. LEF is
on male fertility is unclear [23]. usually associated with less nausea than MTX,
Azathioprine (AZA) is the prodrug of 6-mer- but a proportion of patients interrupt treatment
captopurine that halts the purine pathway and due to diarrhoea and/or liver damage. Silent
proliferating cells. The oral starting dose of AZA liver fibrosis has been reported in patients on
is usually 50 mg/day, with 25 mg increments MTX and LEF. Although uncommon, LEF can
every 2 weeks to a maximum of 150–- cause peripheral neuropathy, and some authors
200 mg/day. About 20% of users report gas- therefore suggest caution in prescribing it for
trointestinal side effects; AZA may also cause patients with diabetes or the elderly. As LEF has
pancreatitis, often not dose-related [14, 18]. a prolonged half-life of more than 30 days, in
Thiopurine S-methyltransferase (TPMT) and patients who develop severe toxicity,
Pulm Ther

cholestyramine treatment should be considered [30], although the drugs themselves can sustain
to enhance withdrawal of the drug and earlier muscular pain as a side effect. Fewer results are
remission of adverse events [15]. available for cases of lung sarcoidosis. A ran-
Mycophenolate mofetil (MMF) is the pro- domized placebo-controlled study of 18 pul-
drug of the mycophenolic acid it is well absor- monary sarcoidosis patients, initially treated for
bed when administered orally and is activated 6 months with CQ 750 mg/day, tapering every
by plasma esterases. MPA blocks guanine 2 months to 250 mg, reported a significant
nucleotide production, inhibiting lymphocyte improvement in symptoms and lung function,
proliferation, and is without significant myelo- but relapses were observed after the drug was
toxicity. As it is eliminated by the kidneys, the discontinued [31]. Unlike immunosuppressant
dose should be adjusted in patients with renal drugs, CQ and HCQ are not associated with
failure (\ 30 ml/min) [27]. The usual oral start- increased risk of infectious complications. The
ing dose is 500 mg twice a day, which can be most common adverse effects are gastrointesti-
increased by 250 mg every few weeks to a nal, but the main concern is the risk of irre-
maximum dose of 1500 mg twice daily. The versible retinopathy, which increases with
most common side effects are gastrointestinal; cumulative dose and is a contraindication for
dividing the daily dose into more than two long-term treatment [29]. The risk of retinal
doses may help to control mild symptoms [15]. toxicity increases with doses over 5 mg/kg body
A retrospective single-centre study of 37 sar- weight/day, cumulative doses greater than
coidosis patients did not find any significant 600–1000 g, stage 3–5 chronic kidney diseases
improvement in lung function tests associated and co-medication with tamoxifen for more
with MMF, whereas a good response was than 6 months [32]. CQ and HCQ are consid-
reported in ocular and neurosarcoidosis patients ered safe for use in pregnant and breast-feeding
[28]. MMF is therefore used mainly to treat women [17].
extrapulmonary sarcoidosis.
Cyclophosphamide is cytotoxic to resting
and dividing lymphocytes and is therefore ROLE OF ANTIMETABOLITES
usually administered intravenously at IN THE MANAGEMENT
500–1000 mg/week or every other week as a OF SARCOIDOSIS
short-term rescue option in very severe acute
forms of sarcoidosis, not controlled by MTX or Biologics have gained a place as third-line
AZA [15]. therapy in sarcoidosis patients who do not
Chloroquine (CQ) and the relatively less benefit fully from GCs and antimetabolites, or if
toxic derivative hydroxychloroquine (HCQ), these drugs prove too toxic. This patient subset
known antimalarial drugs, prevent the acidifi- is about 5–15% of those seen in tertiary sar-
cation of lysosomal enzymes necessary for coidosis centres [33]. Anti-TNF-a agents are the
antigen presentation and toll-like receptor 2 biologic of first choice. The main indications for
activation. They may also inhibit the conver- anti-TNF-a treatment in sarcoidosis are reported
sion of 25-(OH)vitamin D to 1,25-(OH)vitamin in Table 3 [33]. Anti-TNF-a agents are usually
D, suppressing sarcoidosis-associated hypercal- effective, and no more than 10% of drug dis-
caemia and hypercalciuria. CQ and HCQ have continuations are due to lack of effectiveness
large-volume tissue distribution, long half-life [33–35]. The risk of intolerance and infections,
and renal excretion. Concurrent use may including reactivation of latent tuberculosis, is
increase levels of digoxin and metoprolol, as relatively high, mainly with regard to inflix-
they are substrates for cytochrome P450. HCQ imab (IFX), the most effective biologic for sar-
may reduce absorption of MTX, while con- coidosis. Paradoxically, reports of sarcoid-like
comitant use of proton-pump inhibitors may reactions may occur in patients treated with
reduce absorption of HCQ [29]. These orally anti-TNF-a agents for diseases other than sar-
administered drugs are used for patients with coidosis [33].
skin sarcoidosis, hypercalcaemia [11] or myalgia
 Pulm Ther

Among anti-TNF-a agents, intravenous IFX is from France suggests that anti-TNF treatment
the drug of first choice in sarcoidosis. In a may give more benefits in extrapulmonary (28
24-week randomized double-blind controlled cardiac, 44 skin and 63 neuro) sarcoidosis than
trial with 138 chronic pulmonary sarcoidosis in pulmonary forms. Adverse events were
patients (almost all already on GCs and observed in about half of users and led to dis-
antimetabolites), IFX obtained a significant continuation of treatment in almost a quarter of
increase in predicted forced vital capacity the population [34]. One study showed that
(FVC)% over placebo (?2.4%, primary out- TNF-a Gly308Ala polymorphisms were predic-
come), but not in St. George’s Respiratory tive of response to IFX therapy [38]. As discon-
Questionnaire (SGRQ), 6-minute walking dis- tinuation of treatment is associated with at least
tance (6MWD) or post-exertional Borg dyspnea a 50% chance of relapse, many patients are
score; discontinuation due to side effects was treated for years. A gradual withdrawal of the
about 5% [36]. In this seminal study, there was drug by extending the interval between doses
no difference in the response rate to IFX for 3 has been suggested [33].
versus 5 mg/kg of ideal body weight [36], but As IFX is a chimeric monoclonal antibody
5 mg/kg is usually preferred as induction regi- comprising mouse proteins, chronic use may
men. Loading doses are typically given at weeks induce autoantibodies that reduce drug efficacy.
0, 2 and 6; then the frequency of maintenance Allergic reactions are possible (usually \ 5% of
infusions is every 4–8 weeks, increasing to every total), although they are seldom severe. Stop-
week if the patient fails to respond. It is thought ping and restarting IFX treatment is thought to
that patients with more severe disease obtain predispose to autoantibody production and
greater benefits [12]. In the only other ran- allergic reactions. Concurrent use of other
domized trial of IFX to date, there was no sig- immunosuppressants is believed to reduce the
nificant difference in response between those risk of autoantibody generation and does not
receiving IFX or placebo, but treatment was seem to increase the risk of adverse effects or
only studied for 6 weeks, possibly too short a infections. Likewise, concomitant use of IFX
period to observe results, and the study popu- and a higher daily dose of prednisone 15 mg or
lation numbered only 13, possibly too small a equivalent is contraindicated, as it may block
sample size [37]. A large retrospective study anti-TNF therapies.
Biosimilars are biologics that do not signifi-
cantly differ in safety and efficacy from the
Table 3 Main indications for anti-TNF-a therapy in reference product, but are cheaper. Clinicians
sarcoidosis are advised against switching patients currently
treated with the IFX reference product to
Active disease for more than 1 year refractory to first- biosimilars [33]. However, an IFX biosimilar has
and second-choice treatments been shown to be effective in sarcoidosis
Forced vital capacity \ 55% patients [39], so it is thought that treatment of
naı̈ve patients can start with IFX generics.
Moderate to severe dyspnea Adalimumab (ADA) is a fully human anti-
Diffuse reticular-nodular lung infiltrates TNF-a monoclonal antibody, usually used in
patients intolerant to IFX [40] and in cases of
High baseline lung inflammation measured by positron
ocular sarcoidosis (see Ocular sarcoidosis sec-
emission tomography tion). Although the composition of ADA is fully
Elevated serum levels of C-reactive protein human, almost 20% of a large European series
treated with ADA developed autoantibodies
Chronic uveitis
[41]. The risk of allergic reactions to ADA is not
Lupus pernio insignificant [33]. Another advantage over IFX
is that subcutaneous administration makes self-
Severe neurological involvement
administration possible. ADA is usually admin-
istered subcutaneously at a dose of 40 mg every
Pulm Ther

2 weeks, prolonging the scheduled timing when Beyond antimicrobial function, many
response is good and increasing to once a week antibiotics have immunomodulatory effects.
in the absence of response. ADA does not elicit Monotherapy with antimicrobials is not effec-
as robust a response as IFX, usually takes longer tive for sarcoidosis. However, an 8-week open-
to show its benefits and is associated with a label trial has shown that concomitant use of
lower remission rate when discontinued [33]. levofloxacin, ethambutol, azithromycin and
Rituximab is a chimeric monoclonal anti- rifampin, also known as CLEAR therapy, may
body against CD20? cells. It leads to B-cell improve quality of life and FVC in some pul-
depletion lasting up to 6 months after admin- monary sarcoidosis patients [45], although
istration. In a prospective observational study, CLEAR was generally not well tolerated. A ran-
rituximab did not have any statistically signifi- domized, placebo-controlled, single-masked
cant effect, but it improved FVC in 5 out of 10 trial of 30 subjects with chronic symptomatic
patients [42]. Rituximab has been used effec- skin sarcoidosis found an improvement in skin
tively in extrapulmonary sarcoidosis. The dose lesions at 180-day follow-up of the group
and administration schedule are not fully receiving CLEAR for 8 weeks [46]. Another
defined, but 1000 mg is often given intra- ongoing study is evaluating the efficacy of
venously (independent of body weight), CLEAR in patients with chronic lung sarcoidosis
repeating 2 weeks later [33]. Rituximab is rela- (NCT02024555). A Japanese study of cardiac
tively well tolerated, but infusion-related reac- sarcoidosis showed good outcomes and safety
tions are common (30% with the first infusion), using the macrolide clarithromycin 200–-
and premedication with paracetamol and cor- 400 mg/day with tetracycline doxycycline
ticosteroids (usually 100 mg hydrocortisone) are hydrochloride 100–200 mg/day [47]. Other
usually advocated. It has a lower response rate drugs that are or could be used in the manage-
and a longer response time than anti-TNF-a and ment of sarcoidosis are reported in Table 4
is unlikely to be associated with autoantibody [48–70].
production. Because it suppresses
immunoglobulin production, there is an overall
increased risk of (mainly viral) infections. MANAGEMENT OF EYE,
Rituximab has been shown to reactivate herpes NEUROLOGICAL AND CARDIAC
simplex virus and herpes zoster virus, while SARCOIDOSIS
immunoglobulin replacement therapy can be
effective in reducing risk of infections in Eye, neurological and cardiac involvement are
patients on prolonged rituximab therapy, but relatively common in sarcoidosis and have
there are currently no guidelines regarding important implications for prognosis. They are
timing and indications [33]. therefore considered in a separate section.
The beneficial effects of adrenocorticotropic The course of ocular sarcoidosis is usually
hormone (ACTH) in sarcoidosis have been unrelated to that of extra-ocular sarcoidosis.
known for many years, as it was initially Topical GCs are often effective for anterior
approved by the Food Drug Administration uveitis, with an administration frequency
(FDA) for the treatment of sarcoidosis in 1952. ranging from once a day to hourly, based on the
In a single-blind prospective study, ACTHAR degree of inflammation. Cycloplegic eye drops
gel, a repository corticotropin injection therapy are used concomitantly to relieve pain. Perioc-
consisting of a mixture of pituitary extracts ular or intravitreal GC-depot injections and
enriched with ACTH, at a subcutaneous dose of implants are used to treat panuveitis, posterior
80 or 40 IU twice a week offered benefits and uveitis and when frequent use of drops is
GC-sparing effects in 16 patients with chronic impracticable. Unfortunately, regional GC
pulmonary sarcoidosis who completed 24 weeks treatments are often associated with local
of treatment [43]. A Delphi panel recommended adverse effects, such as glaucoma and/or catar-
that lack of efficacy for ACTHAR gel should be act [71]. A few alternatives to topical GCs have
evaluated after 3–6 months of therapy [44]. been tested: intravitreal MTX and ADA are
 Pulm Ther

Table 4 Other drugs which are or can be used in the management of sarcoidosis
Drug Main activity Outcome References
Abatacept Anti-CTLA-4 Under investigation for sarcoidosis [48]
Anakinra IL-1 receptor antagonist Under investigation for cardiac sarcoidosis NCT04017936
Apremilast Phosphodiesterase-4 inhibitor blocking Encouraging results in skin sarcoidosis [49]
TNF-a release from macrophages
Atorvastatin Inhibition of IFN-c production by T No GC-sparing effect in lung sarcoidosis, but [50]
lymphocytes reduction of mild-to-moderate flares
Canakinumab Anti-IL-1b, interfering with innate Under investigation for lung sarcoidosis NCT02888080
immunity
Cyclosporine Calcineurin antagonist, inhibiting No advantage [51, 52]
T-lymphocyte function
Daclizumab Blocking CD25, part of the IL-2 Encouraging results but reports (although rare) [53]
receptor of cancer
Etanercept Anti-TNF No benefits for pulmonary and eye sarcoidosis [54, 55]
Golimumab Anti-TNF No advantage [56]
Lenalidomide Inhibition of NF-jB, a major Better tolerated than thalidomide [57]
inflammatory signalling family
Maraviroc Inhibitor of the chemokine CCR5-r Under investigation NCT0213471
Mesenchymal Inhibition of T lymphocytes by GC-sparing effect in patients with advanced [58]
stromal cells decreasing IFN-c activity lung sarcoidosis, but with increase in mean
pulmonary artery pressure
Transdermal Attenuation of M1 polarization and Promising results [59]
nicotine NF-jB activation; activation of Tregs
Pentoxifylline Phosphodiesterase-4 inhibitor blocking Promising results in lung sarcoidosis but [60]
TNF-a release from macrophages common gastrointestinal intolerance
Roflumilast Phosphodiesterase-4 Inhibitor blocking Promising reduction of flares in chronic [61]
TNF-a release from macrophages fibrotic lung sarcoidosis
Thalidomide Inhibition of NF-jB, a major Contrasting results in patients with refractory [62–64]
inflammatory signalling family lung and skin sarcoidosis but common side
effects
Tocilizumab, Anti-IL-6r antibody, involved in Improvement in case series [65]
sarilumab differentiation of Th17 and Th17.1
cells
Tofacitinib, Inhibitor of Janus kinase, a major Improvement in case series, especially for skin [66–69]
ruxolitinib inflammatory signalling family sarcoidosis
Ustekinumab Blocker of the minor subunit of IL-12, No advantage [56]
involved in differentiation of naı̈ve T
cells into Th1 cells
Pulm Ther

Table 4 continued
Drug Main activity Outcome References

Vasoactive Improvement of Treg function Promising results [70]

intestinal
peptide

promising for non-infectious uveitis [71]. A and permanent lesions are frequent. There have
randomized controlled trial comparing regional been no randomized controlled trials on sarcoid
versus systemic GCs on long-term vision in involvement of the central nervous system.
patients with uveitis (not only of sarcoid origin) Treatment is usually based on expert opinions
found that the latter treatment achieved better and case series. GCs at a starting dose of 1 mg/
outcomes [72]. GC therapy at standard dosage kg/day are the first-line therapy. Except for
and schedule is usually effective in ocular sar- facial nerve palsy, which may benefit from only
coidosis [72]. Among GC-sparing drugs, MTX a few weeks of therapy, long-term treatment is
and MMF have been used in ocular sarcoidosis the rule, and most patients also receive second-
with good results; many ophthalmologists pre- and third-line therapy. MTX is traditionally the
fer MMF [73, 74]. Anti-TNFs are also effective in first second-line choice, with a response rate of
patients with refractory uveitis, rituximab being about 60%, as seen in pulmonary sarcoidosis
another alternative [71]. In a multicentre [78]. In comparative studies, MTX has been
French study of patients treated with anti-TNF found to be more rapidly effective and associ-
drugs for refractory uveitis, IFX proved as ated with less risk of relapse (but more adverse
effective as ADA, but with a non-significantly effects) than MMF [79]. Short-term pulses of
higher incidence of severe adverse events, cyclophosphamide may be attempted in severe
mainly skin rashes and fatigue [75]. Two con- cases to accelerate early response. Case series
trolled studies with 446 subjects showed effi- have reported good results with IFX, which
cacy of ADA in adults (about 10% of whom had seems to be more effective than cyclophos-
sarcoidosis) with active (VISUAL I) and inactive phamide [80] and is increasingly used
(VISUAL II) non-infectious intermediate or [34, 35, 81]; however, infective complications
posterior uveitis or panuveitis [76, 77]. ADA has and toxicity are common, and withdrawal of
received FDA approval for non-infectious uvei- treatment is associated with high rates of
tis. Approximately one fifth of patients with relapse [33–35]. Note that the longer the history
ocular sarcoidosis undergo eye surgery, includ- of neurosarcoidosis before starting IFX, the
ing cataract extraction (17%), trabeculectomy lower the odds of a favourable treatment
(4%), retinal detachment repair (1%) and response [33]. Many questions remain unsolved
epiretinal membrane peel (1%). To avoid a regarding maintenance treatment, such as the
severe postoperative inflammatory reaction, duration of therapy and the best strategy for
surgery should ideally be considered when qui- tapering. Radiation therapy with 20–25 Gy may
escence of intraocular inflammation has been be considered a last therapeutic option in
achieved for at least 3 months. The main causes patients who do not respond to drugs [78].
of irreversible vision loss are glaucoma (usually Some patients may require neurosurgery at
a complication of ocular sarcoidosis) and some point during the disease. Small fibre neu-
chronic maculopathy related to posterior uvei- ropathy (SFN) is increasingly recognized in sar-
tis. When macular oedema persists without coidosis. There are no specific approved
active inflammation, intravitreal injections of therapies to treat pain and/or paraesthesia
bevacizumab may be effective [71]. associated with SFN. GCs and conventional
Neurosarcoidosis usually requires treatment immunosuppressants often have little effect. In
because spontaneous remission is uncommon a retrospective analysis of 115 severe cases with
 Pulm Ther

SFN, an improvement in symptoms was seen in despite optimal medical therapy [88, 89]. Due to
75% of patients treated with intravenous the risk of infection, immunosuppression
immunogammaglobulin (2 mg/kg ideal body should ideally be started after the wound for
weight distributed over 2–5 days) and in 67% of device implantation has healed or at least
those treated with IFX infusions versus less than reduced to the lowest possible maintenance
15% in those who did not receive any therapy dose [88]. Standard-dose GCs are the pharma-
[82]. Most patients with SFN receive symp- cological treatment of first choice for CS.
tomatic treatment with drugs such as gaba- Available data suggest that early introduction of
pentin, pregabalin or antidepressants [82]. GCs can maintain left ventricular ejection
Preliminary data show a promising effect of fraction in patients with normal function and
cibinetide (ARA290), an 11-amino-acid peptide improve it in those with mild to moderate
erythropoietin receptor derivative that stimu- dysfunction at diagnosis, while contrasting
lates fibre repair and is administered subcuta- results are reported in cases of severe failure
neously [83, 84]. Fatigue is another common [90]. A Japanese study failed to find any differ-
symptom of sarcoidosis. The relationship ence between an initial high dose
between SFN and fatigue is not clear. The of [ 40 mg/day and a lower dose of \ 30 mg
treatment of sarcoidosis-associated fatigue is [91]. GC-sparing (or adjunctive) treatments
challenging [85]. GCs may offer benefits in include MTX [92], AZA [93], MMF [89] and
newly diagnosed, symptomatic, untreated cyclophosphamide [94]. Anti-TNFs may be
patients, but in those already treated and clini- effective in cardiomyopathy of sarcoidosis [95],
cally stabilized, an increase in daily dose of GCs although caution is required as they can lower
and/or addition of other drugs may often not be cardiac output. Relapses are common after
useful. Some small trials with stimulants have reducing or discontinuing GCs [91, 96]. Many
found them well tolerated and effective [85]. experts start treatment of CS patients with a
Apart from these pharmacological approaches, combination of GC and other immunosup-
respiratory rehabilitation programmes, even in pressants, as this may be associated with a
patients with stage 3 and 4 pulmonary sar- reduced risk of relapse and disease progression,
coidosis, have improved exercise capacity and compared to GC alone [96]. An ongoing ran-
quality-of-life scores and have been proven safe domized controlled trial, known as CHASM, is
[86, 87]. comparing treatment of cardiac sarcoidosis with
The treatment of cardiac sarcoidosis requires prednisone 0.5 mg/kg/day (max 30 mg) for
particular attention, as it may manifest in very 6 months versus prednisolone 20 mg/day for 1
severe forms or even as sudden death. However, month, then 10 mg/day for 1 month and then
the fact that mortality due to cardiac sarcoidosis 5 mg/day for another month plus MTX
is mainly observed in untreated patients sug- 15–20 mg once weekly for 6 months; the first
gests that treatment may be successful [88]. endpoint was the effect on the cardiac positron
Beyond pharmacological treatment, a perma- emission tomography (PET)/computed tomog-
nent pacemaker is promptly recommended in raphy (CT) summed perfusion rest score [97].
cases of bradycardia, symptomatic second- or Antiarrhythmic therapies have not been studied
third-degree atrioventricular block, heart failure systematically, but amiodarone or sotalol can be
or ventricular arrhythmia. An implantable car- useful in patients with ventricular arrhythmia
dioverter defibrillator is added in cases of left refractory to immunosuppressants [88]. Cathe-
ventricular ejection fraction less than 35% or ter ablation can be useful in patients with ven-
from 36 to 49% with late gadolinium tricular arrhythmia refractory to
enhancement cardiac magnetic resonance evi- immunosuppression and anti-arrhythmic
dence of myocardial scars, complete atrioven- agents, and those who do not tolerate these
tricular block, sustained ventricular tachycardia drugs, even if relapses are common [98]. The
or ventricular fibrillation during electrophysio- Heart Rhythm Society (HRS) consensus recom-
logical testing and/or unexplained syncope or mends management of atrial fibrillation with
near-syncope felt to be arrhythmic in aetiology anticoagulants due to an increased risk of
Pulm Ther

thromboembolism [88]. Heart transplant, Prophylaxis for Pneumocystis jirovecii pneumonia

apparently without extra complications, may be with trimethoprim/sulfamethoxazole 160/800
considered when all other therapies have failed. three times a week is usually advised for patients
with sarcoidosis on more than 10 mg/day
prednisone (or its equivalent), or C 0.4 mg/kg/
MANAGEMENT week MTX, or C 3 mg/kg/day AZA or biologics
OF COMPLICATIONS for at least several weeks [15, 16, 18, 19].
AND COMORBIDITIES RELATED GCs and immunosuppressants are often not
TO SARCOIDOSIS effective for treating sarcoidosis-associated pul-
monary hypertension (SAPH), a severe compli-
Some forms of lung sarcoidosis progress towards cation of sarcoidosis. Several drugs are currently
diffuse fibrosis. Pirfenidone and nintedanib are used for treatment of pulmonary hypertension;
anti-fibrotic drugs currently used in idiopathic some of these drugs have also been used in
pulmonary fibrosis (IPF). Although the patho- SAPH. In an open-label study of 21 SAPH
genesis and the clinical course of fibrosis in patients, ambrisentan did not lead to improve-
pulmonary sarcoidosis seem to differ from that ment [103]. In another 12-month randomized,
of IPF, these drugs could be promising to blunt double-blind study of 17 sarcoidosis patients
the progression of fibrosing forms. However, refractory to standard treatment, bosentan did
nintedanib is currently the only approved not provide any useful result [104]. In a
treatment for pulmonary fibrosis associated 16-week, double-blind, placebo-controlled trial,
with interstitial lung disease other than IPF. The treatment of 35 SAPH patients with bosentan
INBUILD study showed that nintedanib is did not increase 6MWD, but improved pul-
effective in reducing FVC decline even in monary haemodynamics [105]. In a 24-week
patients with lung fibrosis due to sarcoidosis open-label trial, subjects with SAPH received
[99]. Lung transplant remains an option in 20 mg/day tadalafil for the first 4 weeks and
patients with end-stage pulmonary sarcoidosis then 40 mg/day for the subsequent 20 weeks,
not helped by medical therapy. Lung transplant without any improvement in 6MWD or quality
candidates necessarily undergo assessment of of life [106] (138). Another study found that
other organ involvement. Patients with myce- treatment with sildenafil was associated with
toma and bronchiectasis usually require bilat- improved haemodynamics but not 6MWD
eral lung transplant with aggressive [107]. In a 16-week open-label trial, patients on
antimicrobial therapy in the perioperative per- inhaled iloprost showed haemodynamic
iod. Long-term outcomes after lung transplant improvements [108]. Data from the French
are similar to those of other indications, Registry indicate that 97 out of 126 patients
although short-term results may be slightly with severe SAPH on pulmonary arterial hyper-
worse [100]. Increased risk of infections, some- tension-targeted therapy (40 also receiving
times with opportunistic microorganisms, has background immunosuppressants) showed
been observed in sarcoidosis, although severe improvement in pulmonary haemodynamics
forms are relatively uncommon [101]. This but little or no improvement in exercise capac-
could be related to immunosuppressant therapy ity [109]. Overall, these results suggest that
and the disease itself. Fibrocystic forms with specific treatment of pulmonary artery hyper-
bronchiectasis may be the most predisposed to tension (endothelin receptor antagonists,
infections [101]. The treatment of sarcoidosis- phosphodiesterase-5 inhibitors, prostanoids
related bronchiectasis is similar to that of other and riociguat) may be applicable to SAPH,
forms of bronchiectasis. Haemoptysis is rela- improving haemodynamics, but whether this
tively frequent, often associated with mycetoma translates into sustained advantages for life
and usually treated with embolization. Pul- expectancy and patient-related outcomes is
monary aspergillosis is a severe complication unclear.
and a marker of advanced lung disease [102]. Overall, many comorbidities, such as car-
diovascular, thromboembolic and autoimmune
 Pulm Ther

disorders, sleep-related respiratory disease, dia- When GCs are started, there is a [ 50% chance
betes, osteoporosis and malignancy, are more of requiring long-term therapy. Nevertheless, a
prevalent in sarcoidosis patients than in the long-term maintenance dose of more than
healthy population [110]. When required, the 10 mg/day prednisone is not advised and sug-
same therapies as in the general population are gests introduction of GC-sparing drugs. The
recommended for comorbidities, except osteo- need for second- or third-choice drugs usually
porosis. Conventional administration of cal- suggests referral to a specialist centre with
cium supplements and vitamin D is not experience in their use. MTX is the preferred
recommended for sarcoidosis patients, as it second-choice drug in sarcoidosis treatment. It
increases the risk of hypercalcaemia. Up to a is a GC-sparing agent or is used when GCs alone
third of sarcoidosis patients have elevated levels are not effective; AZA is the first alternative in
of 1,25-dihydroxyvitamin D, produced by sar- patients with liver disease, a previous history of
coid granuloma cells. This excess leads to liver toxicity or advanced kidney disease. Full
increased gut absorption of calcium, hypercal- benefit from the second-choice drug takes up to
ciuria ([ 300 mg/day in 20–50% of cases) and 6 months. If patient condition worsens in this
hypercalcaemia (5–10% of cases). When hyper- period or toxic effects develop, the clinician
calciuria overwhelms kidney capacity of reab- should introduce a third-choice therapeutic
sorption, it may lead to nephrolithiasis and option. IFX is the main preferred third-line
renal failure. Calcium and vitamin D should option, perhaps except in cases of eye sar-
therefore be withheld in sarcoidosis patients, coidosis. Of the second- and third-choice drugs
who should also avoid excessive sun exposure for management of sarcoidosis, only MTX and
and dairy intake, unless low levels of calcitriol IFX have been investigated in double-blind
are demonstrated. Dietary calcium and vitamin placebo-controlled randomized trials. Failure of
D restrictions and increased fluid intake are these treatments should raise concerns about
often sufficient to normalize calcium home- the possibility of non-adherence, superimposed
ostasis. If necessary, hypercalcaemia and complications or incorrect diagnosis. Note that
hypercalciuria usually respond to GCs and treatment of the most severe lung complica-
sodium phytate. Failing GCs, ketoconazole or tions involves therapies other than GCs, i.e.
hydroxychloroquine are effective alternatives. vasodilators for SAPH, anti-fibrotics for fibrosis,
Sarcoidosis patients with evidence of osteopenia antibiotics for infective complications. The
and/or osteoporosis should also be treated with treatment of sarcoidosis-associated fatigue and
bisphosphonates [111]. SFN are often challenging, and traditional
treatments do not always offer benefits; their
effective management is sometimes an unmet
CONCLUSION need.
The one-size-fits-all approach is not ideal for
Pulmonologists often play a key role in the sarcoidosis. As knowledge increases, personal-
management of sarcoidosis, because the lungs ization of therapy (and hopefully more effective
are by far the most commonly affected organ. and safer treatment) will be an aim. One
However, a multidisciplinary approach is sug- example of personalization is the case of AZA,
gested to achieve the best outcome, as extra- where individual genetics (pharmacogenomics)
pulmonary organs are often involved. are used to guide the treatment prescribed.
When systemic treatment is recommended
for sarcoidosis, oral GCs are the option of first
choice. GCs are usually effective in treating
granulomatous inflammation. The dose and
ACKNOWLEDGEMENTS
duration of GC treatment should be chosen on
We would like to acknowledge Helen Hampt,
a case-by-case basis, bearing in mind the high
who contributed to language editing, and other
risk of relapses during tapering and the fact that
collaborators who helped to collect studies.
long-term treatment periods are often required.
Pulm Ther

Funding. No funding or sponsorship was REFERENCES

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