Seminars in Arthritis and Rheumatism 43 (2013) 119–124

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Seminars in Arthritis and Rheumatism

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Miscellaneous

Long term follow-up of infliximab efficacy in pulmonary andextra-pulmonary sarcoidosis refractory to conventional therapy

Eric Russell a,n, Francis Luk b, Sonia Manocha b, Tung Ho b, Carolyn O’Connor c, Humaira Hussain c

a Christiana Care Rheumatology Department,Wilmington, DEb Department of Internal Medicine, Drexel University College of Medicine, Philadelphia, PAc Department of Rheumatology, Drexel University College of Medicine, Philadelphia, PA

a r t i c l e i n f o

Keywords:

Sarcoidosis

Sarcoid

Infliximab

Remicade

Anti-TNF

Tumor necrosis factor inhibitor

72/$ - see front matter & 2012 Elsevier Inc. A

x.doi.org/10.1016/j.semarthrit.2012.10.008

viations: TNF, tumor necrosis factor; MRI, m

puterized tomography; PFT, pulmonary fun

ntral nervous system; IFX, infliximab; FEV1,

, forced vital capacity; TLC, total lung capac

g capacity; MTX, methotrexate; HCQ, hydro

HPV, human papilloma virus; PPD, purified p

esponding author. Drexel University College

tology, 245N, 15th Street, MS 426, 6th Floor,

ail address: ERussell@ChristianaCare.org (E. R

a b s t r a c t

Introduction: Infliximab, a humanized, chimeric, monoclonal antibody against tumor necrosis alpha

(TNF-a), has been shown to reduce the pulmonary and extra-pulmonary manifestations of sarcoidosis,

however, there is little information regarding sustained efficacy with long-term use of infliximab. We

retrospectively investigate whether a reduction in disease response is maintained, over a prolonged

course of therapy (up to 85 months) with infliximab, and report on adverse events associated with

its use.

Methods: Subjects with multi-organ sarcoidosis were prescribed infliximab, between January 2000 to

June 2010 due to failure of conventional therapy and were identified from the Drexel University

College of Medicine sarcoidosis clinic. Retrospective patient reported symptom and objective clinical

data analyses of pulmonary and extra-pulmonary findings were evaluated pre-infliximab and post or

concurrent infliximab therapy. Any adverse events or reasons for discontinuation during infliximab

therapy were reported.

Results: Twenty-six patients with biopsy proven sarcoidosis received anti-TNF therapy and met the

criteria for study inclusion. Clinical evidence of sustained resolution or improvement was demon-

strated in 58.5% of all organs assessed (p ¼o0.001). No clinical change in disease activity was seen in

35.8% of all organs evaluated. Despite infliximab treatment, 5.7% had progressive disease activity.

Adverse events were seen in 57.7% of patients treated with infliximab over a 46.2 month average

duration of therapy. Three (12%) patients had an adverse event that required permanent

discontinuation.

Conclusions: Infliximab is efficacious in the treatment of extra-pulmonary sarcoidosis and the efficacy is

maintained with prolonged treatment. In patients with pulmonary sarcoid, sustained improvement in

pulmonary imaging was seen after initiation of infliximab, however, post-treatment pulmonary function

testing was not conclusive. Long-term infliximab therapy was well tolerated for our study group.

& 2012 Elsevier Inc. All rights reserved.

Introduction

Sarcoidosis is a multi-organ disorder which is histologicallycharacterized by non-caseating granuloma formation. The etiol-ogy of sarcoidosis remains unclear, however, in patients withsarcoidosis, tumor necrosis factor alpha (TNF-a) is known to play

ll rights reserved.

agnetic resonance imaging;

ction test; LN, lymph node;

forced expiratory volume in

ity; DLCO, carbon monoxide

xychloroquine; AE, adverse

rotein derivative

of Medicine, Department of

Suite 6144, Philadelphia, PA

ussell).

a crucial role in the formation and maintenance of the non-caseating granuloma and production of this cytokine by alveolarmacrophages is substantially elevated [1]. In addition, TNF-aelevations have been shown to correlate with sarcoid diseaseactivity and progression [2].

Corticosteroid therapy is usually considered to be first line

therapy for patients with sarcoidosis. Often clinical remission

can be obtained without further escalation in immunosuppres-

sive therapy [3]. In patients with refractory disease, multiple

therapies have been reported including methotrexate, hydro-

xychloroquine, azathioprine, cyclophosphamide, pentoxifylline

and thalidomide [4–9]. None of these immunosuppressive

agents have been validated with randomized controlled

trials and currently there are no FDA approved agents for the

treatment of refractory, non-remitting pulmonary, or extra-

pulmonary sarcoidosis.

E. Russell et al. / Seminars in Arthritis and Rheumatism 43 (2013) 119–124120

Because of TNF-a’s known role in sarcoidosis, anti-TNF ther-apy has been an attractive therapeutic option [10]. Infliximab, ahumanized chimeric monoclonal antibody against TNF-a, iscurrently approved by the FDA for the management of rheuma-toid arthritis, Crohn’s disease, ulcerative colitis, plaque psoriasis,psoriatic arthritis, and ankylosing spondylitis [11–16]. Infliximabspecifically binds to TNF-a, rendering this cytokine biologicallyinactive thereby inhibiting its contribution to granulomaformation.

Prior studies, which evaluated infliximab efficacy in sarcoido-sis, have predominately reported data on short-term outcomes.Our retrospective study investigates infliximab efficacy inpatients with sarcoidosis refractory to conventional therapy andreports unique data on long-term outcomes of patients treatedwith this anti-TNF agent.

Table 1Demographic and Sarcoidosis Characteristics of the Study Population.

Mean Age, Years (Range) 51 (35–69)Ethnicity, N (%)

African American 21 (81)

Caucasian 4 (15)

Other 1 (4)

Gender, N (%)

Female 10 (38)

Male 16 (62)

Average age of initial sarcoidosis diagnosis (yrs.) 38.0 (22–54)

Average disease length (yrs.) 14.9 (6–50)

Ineffective immunosuppression prior to IFX, N (%)

Corticosteroids 24 (92.3)

Methotrexate 20 (76.9)

Hydroxychloroquine 23 (88.5)

Etanercept 1 (3.8)

Concurrent immunosupp-ression at IFX initiation, N (%)

Corticosteroids 16 (61.5)

Methotrexate 15 (57.7)

Hydroxychloroquine 12 (46.2)

Average duration of IFX therapy (months) 46.2

Materials and methods

Study approval was obtained through the Institutional ReviewBoard at Drexel University Office of Regulatory Research(approval number 19,544). Subjects (18–85 years of age) withdocumented single or multi-organ sarcoidosis were retrospec-tively identified from our sarcoidosis clinic using office records,dating from January 2000 to June 2010, as data sources. Inclusioncriteria included patients with sarcoidosis who were started oninfliximab due to failure or intolerance of conventional therapy,which was defined as corticosteroid and/or disease modifyinganti-rheumatic drug therapy such as methotrexate. Failure oftherapy was determined by either a pulmonologist or rheumatol-ogist and defined as either clinical or symptomatic progression ofdisease despite non-biologic therapy. All patients included in thestudy had biopsy proven sarcoidosis. Exclusion criteria includedthose patients without documentation of biopsy proven sarcoi-dosis, as well as incomplete documentation that precluded anadequate investigator analysis of disease response before or afterinfliximab initiation. Two separate investigators agreed upon apatient’s exclusion.

Data were retrospectively collected for patients who under-went serial follow-up with history and physical examinationconducted by a consistent examiner experienced with the diag-nosis and management of sarcoidosis. The duration of infliximabuse was noted for each patient, as well as the use of immuno-suppressive therapy prior to and concurrent with infliximabtherapy.

Pulmonary and extra-pulmonary (ocular, cutaneous, lympha-tic, musculoskeletal, cardiac, neurologic, sinus, liver and renal)data were collected. Prior magnetic resonance imaging (MRI) orcomputerized tomography (CT) scans were reviewed to assessorgan disease burden prior to and after initiation of infliximab. Inaddition, available chest radiographs were evaluated to assesslymphadenopathy attributed to sarcoidosis. Documented physi-cian evaluation was reviewed to establish sarcoid burden incutaneous and ocular sarcoidosis. Based on this documentedobjective data, a patient’s clinical response was interpreted asresolved, improved, unchanged, or progressed after startinginfliximab therapy. Each organ with documented sarcoid involve-ment was graded in this manner. Those organs defined as‘‘resolved’’ demonstrated complete resolution of clinical diseaseactivity. ‘‘Improved’’ disease was used to describe the organs thathad reduced sarcoid burden or reduced frequency in diseaseactivity but still had evidence of disease. Organs labeled as‘‘unchanged’’ demonstrated disease activity that was clinicallyno different than prior to infliximab initiation. Patients withorgans interpreted as ‘‘progressed’’ displayed clinical features ofprogressive disease despite starting infliximab. The same grading

scale was used to assess patient reported symptom response toinfliximab. Patient reported, organ-specific, symptomatic res-ponse to infliximab was designated as either resolved, improved,changed or progressive, as documented by the examining physi-cian. Pulmonary function testing (PFT) was collected in patientswith documented pulmonary sarcoid. PFT data were collectedretrospectively, both pre-infliximab and post-infliximab therapy.

Adverse events during infliximab therapy and any reasons fordiscontinuation of infliximab therapy were reported. All datacollection was completed by physician investigators and verifiedby the principal investigator.

Statistical analysis

Wilcoxon Signed Ranks Test (nonparametric) analysis wasutilized to compare improved and resolved versus worseneddisease outcome by organ system affected. This comparison wascalculated for data pertaining to objective clinical and subjectivesymptom outcomes. The same statistical tool was utilized tocompare PFT data prior to and after infliximab therapy in patientswith pulmonary sarcoidosis.

Results

Forty-two patients with sarcoidosis received infliximab infu-sions. Sixteen patients were excluded due to incomplete data(N ¼ 10), absence of confirmatory biopsy (N ¼ 5), or incompleteinfliximab dosing (N ¼ 1). Poor patient follow-up was the causeof incomplete data collection and thereby prevented consistentdocumentation to retrospectively review. Twenty-six patientsmet the criteria for study inclusion. African Americans and maleswere the prominent groups represented in the study cohort (81%and 62%, respectively). The average duration of disease activitywas 14.9 years (Table 1).

Objective disease activity, measured by imaging of theinvolved organ or physician assessment (for cutaneous and ocularsarcoid analysis), was most represented in the lung, skin, lymphnode and central nervous system (57.7%, 42.3%, 42.3%, 30.8%,respectively; Table 2). Clinical improvement was most pro-nounced in patients with cutaneous sarcoidosis, demonstratingsustained clinical resolution (36.4%) or improvement (63.6%) inall of the patients with sarcoid lesions treated with infliximab(Table 2, p ¼ 0.005). Patients with documented neurosarcoid

Table 2Clinical and Symptomatic Outcomes of Infliximab Therapy by Organ Documented With Evidence of Sarcoidosis.

Sarcoid Organ Disease Activity Resolved Sustained Improvement Disease Activity

Unchanged

Disease Activity

Progressed

p-Value

Clinical N

(%)a

Symptom N

(%)b

Clinical N

(%)

Symptom N

(%)

Clinical N

(%)

Symptom N

(%)

Clinical N

(%)

Symptom N

(%)

Clinical N

(%)

Symptom N

(%)

Clinical Symptom

Lung 15 (57.7) 15 (57.7) 4 (26.7) 0 (0.0) 4 (26.7) 9 (60.0) 5 (33.3) 4 (26.7) 2 (13.3) 2 (13.3) 0.055 0.03

Skin 11 (42.3) 11 (42.3) 4 (36.4) 4 (36.4) 7 (63.6) 7 (63.6) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0.005 0.005

LN 11 (42.3) NA 2 (18.2) NA 1 (9.1) NA 7 (63.6) NA 1 (9.1) NA 0.31 –

CNS 8 (30.8) 8 (30.8) 3 (37.5) 2 (25.0) 2 (25.0) 4 (50.0) 3 (37.5) 2 (25.0) 0 (0.0) 0 (0.0) 0.03 0.01

Eye 3 (11.5) 3 (11.5) 1 (33.3) 1 (33.3) 0 (0.0) 0 (0.0) 2 (66.7) 2 (66.7) 0 (0.0) 0 (0.0) 0.005 0.5

Liver 1 (3.8) NA 0 (0.0) NA 0 (0.0) NA 1 (100) NA 0 (0.0) NA 0.5 –

Kidney 1 (3.8) NA 1 (100) NA 0 (0.0) NA 0 (0.0) NA 0 (0.0) NA 0.5 –

Sinus 1 (3.8) 1 (3.8) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (100) 1 (100) 0 (0.0) 0 (0.0) 0.5 0.5

Bone 1 (3.8) 1 (3.8) 1 (100) 1 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0.5 0.5

Muscle 1 (3.8) 1 (3.8) 1 (100) 0 (0.0) 0 (0.0) 1 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0.5 0.5

Total 53 40 17 (32.1) 8 (20) 14 (26.4) 21 (52.5) 19 (35.8) 9 (22.5) 3 (5.7) 2(5.0) –

NA ¼ not assessed, no documentation of a symptomatic response.a Clinical ¼ objective clinical outcome assessed using imaging data (MRI, CT scan, CXR), laboratory (for renal sarcoid) and physician evaluation (in cases of cutaneous

sarcoid).b Symptom ¼ patient reported organ-specific, symptomatic response to infliximab as either resolved, improved, changed or progressive, as documented by the

examining physician.

E. Russell et al. / Seminars in Arthritis and Rheumatism 43 (2013) 119–124 121

demonstrated either sustained resolution or improvement inclinical disease activity in 62.5% of these patients (p ¼ 0.03).Lymph node disease was unchanged in the majority of patientstreated with infliximab (63.6%) and resolved or improved in 27%.Single instances of kidney, bone and muscle sarcoidosis demon-strated resolution of disease with infliximab therapy. Two distinctcases of liver and sinus disease demonstrated unchanged diseaseactivity with initiation of infliximab (Table 2).

Clinical evidence of sustained resolution or improvement wasdemonstrated in 58.5% of all organs assessed (p ¼o0.001). Noclinical change in disease activity was seen in 35.8% of all organsevaluated. Of all organs assessed, 5.7% had progressive diseaseactivity that included two patients with sarcoid of the lung andone patient with progressive lymph node disease. Overall, symp-tom resolution or improvement was documented in 73% of allorgans involved (Fig. 1).

Two patients achieved complete physician documented remis-sion after initiation of infliximab, which was subsequently dis-continued (one patient had liver, lung and lymph node disease

32.1

26.4

20

52.5

0

10

20

30

40

50

60

Resolved Improvement

% o

f tot

al o

rgan

s w

ith s

arco

idos

is

Fig. 1. Summary of total organ re

the other had renal disease). Corticosteroid therapy was discon-tinued in 73.3% of patients after the initiation of infliximab(Table 3).

There was a small average improvement in the forced expira-tory volume at 1 second (FEV1), forced vital capacity (FVC) andtotal lung capacity (TLC) in patients with pulmonary sarcoidosis(2%, 4%, and 11% improvement, respectively). These results didnot reach statistical significance. There was no appreciabledifference in carbon monoxide diffusing capacity (DLCO) eitherbefore or after initiation of infliximab in this group (Fig. 2A). Twopatients had significant, progressive deterioration of PFTS of theFEV1, FVC and/or DLCO despite initiation of infliximab (data notshown).

In a subgroup analysis of the pulmonary sarcoid patients withabnormal PFTs prior to infliximab therapy, there was a mildimprovement in the average FEV1 (3% increase), FVC (5%increase) and DLCO (5% increase). There was a statisticallysignificant improvement in the TLC of 17% after initiation ofinfliximab in this subgroup analysis (Fig. 2B).

35.8

5.7

22.5

5

Unchanged Worsened

Clinical disease activity

Symptomatic disease activity

sponse to infliximab therapy.

Table 3Immunosuppression Outcomes With Infliximab Therapy.

Diagnosed in remission and IFX discontinued, N (%) 2 (7.6)

Other immunosuppressants stopped while on IFX, N (%)

Corticosteroid 11 (73.3)

MTX 1 (6.3)

HCQa 2 (16.7)

a For one patient, HCQ stopped during IFX treatment due to a persistent rash

attributed to HCQ.

E. Russell et al. / Seminars in Arthritis and Rheumatism 43 (2013) 119–124122

Adverse events were seen in 57.7% of patients treated withinfliximab over a combined average duration of therapy of 46.2months (Tables 1 and 4). Three (12%) patients had an adverseevent that required permanent discontinuation of infliximab.Reasons for permanent discontinuation included severe pneumo-nia, positive purified protein derivative (PPD) tuberculosis skintest, and recurrent sinusitis attributed to infliximab use. Minorinfection, rash, and pneumonia were the most documentedadverse events (19.1%, 19.1% and 14.3%, respectively; Table 4).

Discussion

Our study demonstrates the therapeutic efficacy of infliximab forthe treatment of pulmonary and extra-pulmonary sarcoidosis. Ourdata suggest that this efficacy is maintained over a prolonged courseof therapy. While randomized controlled trials evaluating anti-TNFtherapy have been few, several case reports and other case serieshave been published reporting efficacy of Infliximab in treating bothrefractory pulmonary and extra-pulmonary sarcoidosis [17–23]. Aprior small case series demonstrated objective evidence ofimproved extra-pulmonary and pulmonary sarcoid outcomes inthe majority of patients treated with infliximab [24]. Despitenumerous reports of infliximab efficacy in treatment of persistentsarcoidosis, etanercept, another TNF inhibitor, has not demonstratedthe same positive outcomes. A small randomized trial of stage II andIII pulmonary sarcoidosis treatment with etanercept monotherapy,utilizing rheumatoid arthritis dosing parameters, was terminatedearly due to a trend toward treatment failure [25]. This study had apredominately Caucasian population and only reported on pulmon-ary sarcoid outcomes. A potential explanation for this treatmentclass discrepancy may have been an inadequate etanercept dosingrequired for a therapeutic response. Our study demonstrated thatescalation in infliximab dosing was required for the majority ofpatients with an average maximum infliximab dose of 511 mg

8181

75

65

83 85 86

50

60

70

80

90

100

pre-IFX

post-IFX

FEV1p = 0.72

FVCp = 0.06

TLCp = 0.07

DLCOp = 1.

% p

redi

cted

val

ue

Fig. 2. (A) Average pulmonary functions values in all patients diagnosed with lung sa

values). (B) Pulmonary function values in patients with abnormal PFT prior to initiation

in 1 s; FVC ¼ forced vital capacity; TLC ¼ total lung capacity; DLCO ¼ carbon monox

(range 300–1000 mg) and an average dosing frequency of every5.5 weeks [range every 4–6 weeks, (data not shown)].

Our patient cohort received infliximab therapy for an averageduration of 46.2 months in a patient population with an averagesustained disease activity of 14.9 years (Table 1). The studypopulation was unique from prior studies in that the ethnicbreakdown was predominately African American (Table 1). Sar-coidosis has been shown to be more chronic and fatal in thisethnicity and may suggest why this ethnic subgroup failed torespond to conventional treatments, such as corticosteroids ormethotrexate, and subsequently required addition of alternativetreatment with infliximab [26]. In addition, African Americansoften demonstrate a later peak incidence of disease presentation,often within the 4th decade of life [27]. This observation mayaccount for the older age of onset seen in our patient cohort(average age 38 years old, Table 1). Because our study demon-strated sustained disease control in a predominately AfricanAmerican study cohort, future investigational opportunities existto determine whether there is a treatment response predilection,with TNF inhibition, for African Americans with sarcoidosis.

A previously conducted randomized, double blind, placebocontrolled, trial of 138 patients demonstrated that infliximabwas effective in reducing the extra-pulmonary, multi-organ man-ifestations of sarcoidosis [28]. The study demonstrated a positivetreatment response in 12 of 13 organ systems with sarcoidinvolvement as measured by a study-specific grading tool forassessing sarcoid disease burden. The results of their 24-weektrial are consistent with our long-term outcomes of extra-pulmonary disease. Our patient cohort had a large proportion ofCNS sarcoid (30.8%), which demonstrated sustained disease con-trol, as objectively evaluated by MRI, in the majority of theneurosarcoid patients treated with infliximab (75%, Table 2). Inaddition, infliximab therapy demonstrated an excellent therapeu-tic response in those with cutaneous sarcoid. All cutaneoussarcoid patients (N ¼ 11) had either complete resolution orimprovement in skin lesions as assessed objectively by physicianexam. Single cases of bone, muscle, and kidney sarcoid demon-strated complete resolution of clinical disease activity in our studycohort (Table 2), however, due to the limited representation ofthese organ systems, future prospective studies are needed tofurther investigate whether a causal relationship exists in extra-pulmonary sarcoid improvement treated with infliximab therapy.

A small majority of patients with pulmonary sarcoid demon-strated either resolution or improvement in parenchymal lungdisease as analyzed by CT scan (53.4%, Table 2). While pulmonaryimaging did show improvement, pulmonary function test results,

69.972.6

63.1

54.1

73.477.7

80.1

58.6

0FEV1

p = 0.53FVC

p = 0.17TLC

p = 0.042DLCO

p = 0.50

rcoidosis (N ¼ 13, 2 patients with lung sarcoid excluded due to incomplete PFT

of infliximab therapy (N ¼ 7). IFX ¼ infliximab; FEV1 ¼ forced expiratory volume

ide diffusing capacity; PFT ¼ pulmonary function test.

Table 4Adverse Events Reported During Infliximab

Therapy.

Adverse Events N (%)

None 11 (42.3)Patients with AE 15 (57.7)# of distinct AE 21

Minor infection 4 (19.1)

Rash 4 (19.1)

Pneumonia 3 (14.3)

Sepsis 1 (4.7)

Anaphylaxisa 1 (4.7)

Pustular psoriasis 1 (4.7)

Leukopenia 1 (4.7)

Psoriatic lesions 1 (4.7)

Positive PPD 1 (4.7)

Arthralgias 1 (4.7)

HPV reactivation 1 (4.7)

IFX stopped permanentlyb 3 (12)

a Anaphylaxis with first infliximab treatment.

Subsequent infusions pretreated with intravenous

corticosteroids without further complications.b Reason IFX stopped: recurrent sinusitis,

positive PPD and severe PNA.

E. Russell et al. / Seminars in Arthritis and Rheumatism 43 (2013) 119–124 123

after initiation of infliximab, were more equivocal. Our studydemonstrated a slight improvement in FEV1 FVC, and TLC but notin the DLCO after initiation of infliximab, although this data didnot reach statistical significance. However, when a subgroupanalysis of patients with abnormal pulmonary function testsprior to initiation of infliximab was done, a statistically significantimprovement in TLC was seen (p ¼ 0.04). The modest improve-ments seen in the FEV1, FVC and DLCO in this subgroup analysiscould be considered within the normal pulmonary function dailyvariance. Despite equivocal pulmonary function analysis, a major-ity of patients with pulmonary sarcoidosis reported a subjectiveimprovement in pulmonary symptoms such as reduced dyspneaon exertion, shortness of breath, and cough (60%, Table 2). Theseresults differed from a phase II, randomized, placebo controlledtrial of 138 patients, who demonstrated a statistically significantimprovement in predicted FVC, the primary endpoint of thestudy, in patients with chronic pulmonary sarcoidosis treatedwith anti-TNF therapy [29]. However, despite their findings, aclinical correlation could not be garnered from this study, as theywere unable to demonstrate symptomatic improvement as mea-sured by Saint George’s Respiratory Questionnaire (SGRQ) totalscore and Borg’s CR10 dyspnea score.

Infliximab therapy was maintained in the majority of thosewho had resolution of disease activity (32.1% of involved organsystems in the study cohort, Fig. 1). Two patients in the studywere diagnosed in remission and infliximab was successfullydiscontinued. Because of the off label use of infliximab, therecurrently is no consensus regarding duration of infliximab oropinion on whether to stop therapy in order to assess for asustained remission. A small study did attempt to answer thisquestion through a retrospective analysis of a small patientsample and described an 86% relapse rate in patients withrecalcitrant sarcoidosis who discontinued infliximab [30].

Adverse events were observed in our study. Over half of thepatients (57.7%) experienced an adverse event during the dura-tion of their treatment course. However, infliximab discontinua-tion rates of only 12% were observed despite an average durationof infliximab therapy of 46.2 months (Table 4). The longestdocumented treatment course was 85 months. Serious adverseevents like sepsis, anaphylaxis, and pustular psoriasis were observedconcurrent to infliximab therapy. However, anti-TNF therapy was

not permanently discontinued due to the therapeutic response thoseparticular patients experienced. One case of pneumonia was seriousenough to warrant discontinuation of infliximab permanently.Recurrent sinusitis and a positive PPD were other reasons forpermanent treatment discontinuation. This study was not designedto directly correlate adverse reaction with infliximab therapy, there-fore, reported adverse events can only be interpreted as incidental toconcurrent infliximab therapy.

There are limitations to our study. This was a small, retro-spective study and the lack of a corresponding control group is aweakness inherent to the study design. Unlike our patientcohort, the natural course of sarcoidosis is that of resolution inthe majority of patients and therefore employing a matchedcontrol is problematic for this type of study. A number ofpatients had to be excluded from the study due to incompletedocumentation (N ¼ 10). This was due to poor patient follow-up,over the study period, and prevented consistent documentationfor our analysis. These exclusions could be interpreted as biased,however, the investigators felt that interpreting incomplete datacould potentially present false outcome data. Pulmonary func-tion test and CT scan data were used for objective analysis ofpulmonary response to infliximab therapy. Other pulmonaryassessment tools, such as a 6-minute walk test, were rarelyperformed for the patient population studied and would likelyhave added to the validity of the data. In addition, due to theretrospective nature of our study, validated tools used to assesspatient reported symptomatic pulmonary response, such as SaintGeorge’s Respiratory Questionnaire or Borg’s CR10 dyspnea scorewere not utilized [31,32]. Currently there are no validated globalpulmonary or extra-pulmonary sarcoid assessment tools toaccurately assess patient response to a particular therapy.Finally, this study did not report pulmonary staging. Our studydemonstrated that pulmonary imaging did improve with inflix-imab, however, future prospective studies will need to furtherclarify whether this treatment effect is seen at all stages ofpulmonary sarcoid.

In conclusion, our study provides objective clinical andpatient reported symptomatic improvement with long-terminfliximab treatment for pulmonary and extra-pulmonary sar-coidosis. This study demonstrated that infliximab had a morerobust treatment efficacy in extra-pulmonary symptoms. Pul-monary imaging did show improvement with infliximab therapy,however, pulmonary function testing outcomes were less con-clusive. Our study supports previous reports that infliximab isefficacious in treatment of sarcoidosis and also illustrates thatthis efficacy is maintained with continued treatment. In addition,we demonstrate that long-term infliximab therapy was welltolerated for this study group over an extended treatmentcourse. Controlled trials are needed to assess infliximab’s rolein treatment of recalcitrant sarcoidosis. In addition, sarcoidspecific assessment tools that demonstrate disease response totreatment are needed.

COI disclosure

Eric Russell reports no personal or financial support or authorinvolvement with organizations with financial interest inthis study.

Sonia Manocha reports no personal or financial support orauthor involvement with organizations with financial interest inthis study.

Francis Luk reports no personal or financial support or authorinvolvement with organizations with financial interest inthis study.

E. Russell et al. / Seminars in Arthritis and Rheumatism 43 (2013) 119–124124

Tung Ho reports no personal or financial support or authorinvolvement with organizations with financial interest inthis study.

Carolyn O’Connor reports no personal or financial support orauthor involvement with organizations with financial interest inthis study.

Humaira Hussain reports no personal or financial support orauthor involvement with organizations with financial interest inthis study.

Acknowledgments

The authors would like to thank Dr. Edward Gracely with theDepartment of Epidemiology and Biostatistics at Drexel Univer-sity College of Medicine who provided statistical analysis for thisstudy. We also would like to thank Dr. Herbert Patrick whohelped initiate this project.

Drs. Eric Russell and Humaira Hussain contributed to thestudy design, interpretation of data and preparation of thismanuscript. They take full responsibility for the integrity andaccuracy of its data.

Drs. Manocha, Luk and Ho contributed to the data collectionand critical analysis of the manuscript content.

Dr. O’Connor contributed to the critical analysis of the manu-script content.

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