Abstract
Sarcoidosis may cause severe ventilatory impairment requiring corticosteroid treatment. Chloroquine (CQ) can be an effective treatment for lung sarcoidosis with few side effects, but has not been accepted as standard therapy. We investigated the benefits of prolonged CQ therapy in 23 symptomatic patients with biopsy-proven pulmonary sarcoidosis (duration, ⩾ 2 yr). Patients were initially treated for 6 mo with CQ, 750 mg/d, tapering every 2 mo to 250 mg/d. Eighteen patients were then randomized to either a Maintenance group (CQ, 250 mg/d) or to an Observation group (no CQ). After the initial treatment, significant improvement was observed in symptoms, pulmonary function, angiotensin-converting enzyme, and lung gallium scan. Patients randomized to the Maintenance group showed a slower decline in pulmonary function (FEV1, 51.4 ± 28.2 ml/yr [Maintenance] versus 196.3 ± 33.4 ml/yr [Observation], p < 0.02) and had fewer relapses: 2 of 10 patients in the Maintenance group at 29.5 ± 4.9 mo versus 6 of 8 patients in the Observation group at 15.5 ± 2.9 mo. Adverse effects were seen mainly during high-CQ dosage. We conclude that CQ should be an important consideration for the treatment and maintenance of chronic pulmonary sarcoidosis.
Sarcoidosis is a disease of unknown etiology characterized by granulomatous inflammation most commonly involving the lungs, lymph nodes, eyes, and skin, although any organ system may be affected. More than 90% of patients will manifest pulmonary involvement during the course of their disease, self-limited in approximately half of the patients. There is an important subset of patients, however, in whom disease progresses on to symptomatic, at times disabling, chronic pulmonary fibrosis (1, 2).
Although the indications for medical therapy in sarcoidosis are controversial, standard therapy for serious, progressive, or life-threatening disease consists of systemic corticosteroids (2– 4). Systemic corticosteroids given for periods of 6 mo or longer have limited effectiveness in advanced or chronic pulmonary sarcoidosis and do not appear to alter the natural history of the disease (1, 2, 4). One trial demonstrated a small effect in preserving pulmonary function (5). The side effects with high-dose and long-term steroids are numerous, disabling, and well documented in this population (6).
Many other agents have been tried with varying success in pulmonary sarcoidosis, mostly in small, uncontrolled trials and anecdotal reports. These include colchicine, phenylbutazone, and immunosuppressive agents such as methotrexate, cyclosporin, chlorambucil, and azathioprine (2). The lysosomotropic amines chloroquine (CQ) and hydroxychloroquine have been shown to be of possible benefit in lung disease but they are not frequently used. They are currently the treatment of choice for the dermatologic manifestations of sarcoidosis (7). We hypothesize that if antimalarial agents are effective in sarcoidosis of the skin they ought to be effective in pulmonary sarcoidosis because the pathologic abnormalities are similar. Studies performed in the 1960s suggested that CQ could be of benefit in the treatment of pulmonary sarcoidosis (8-11). The first randomized trial with 30 patients in a cross-over design demonstrated that patients treated with CQ had more radiographic improvement that did patients with no treatment (12). This trial included subjects with sarcoidosis of varying duration and stages, and a high rate of spontaneous remission was observed (9 of 30). A subsequent randomized, placebo-controlled trial of 57 patients with stage 2 or 3 sarcoidosis of at least 6 mo duration demonstrated significant improvements in dyspnea, FEV1, FVC, and radiographic appearance during 4 mo of treatment with CQ (13). However, a significant rate of spontaneous resolution was observed in controls, FEV1 and FVC declined after cessation of treatment, and at 12 mo of follow-up no difference between treated and untreated patients was found. Possibly because of this lack of difference after 12 mo of treatment, CQ has never been maintained as a mainstay in the treatment of sarcoidosis.
After successfully treating some patients with chronic symptomatic sarcoidosis with CQ, we decided to investigate the response to CQ treatment of a group of patients in which spontaneous resolution would have been unlikely. We also investigated the possible benefit of CQ maintenance therapy in controlling the functional progression of pulmonary sarcoidosis.
The study was carried out in the Pulmonary Clinic of the Royal Victoria Hospital (Montreal, PQ, Canada) and was approved by the institutional Clinical Research Ethics Committee. Informed written consent was obtained from all subjects.
Twenty-three subjects entered the study. The inclusion criteria consisted of (1) the presence of pathologically documented sarcoidosis; (2) evidence of symptomatic pulmonary disease for at least 2 yr; (3) radiographic disease of stage 2 or 3 (11), and (4) evidence of physiologic abnormalities on pulmonary function testing, defined as a value of less than 80% predicted (14) in any one of the following: forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), or the single-breath carbon monoxide diffusing capacity of the lung (Dl CO-SB). Although preferred, a previous trial of corticosteroids was not an absolute requirement for consideration of chloroquine therapy. Subjects with homozygous glucose-6-phosphatase deficiency were excluded. All subjects entered were clinically deemed by their treating physicians to require treatment for their disease.
During the initial 6 mo, chloroquine phosphate (CQ) was administered at 750 mg/d for 2 mo, 500 mg/d for 2 mo, and 250 mg/d for 2 mo. Time 0 was defined as the date of the first prescription. Subjects were clinically assessed every month with monitoring of the incidence and severity of side effects to CQ, as well as scoring of disease symptoms. Pulmonary function studies were done at the time of entry in the study and at the completion of the run-in phase.
Subjects completing the run-in phase were subsequently randomized to either an Observation group or to a Maintenance group (low-dose chloroquine, 250 mg/d) and followed at 3-mo intervals with clinical assessments and pulmonary function measurements. If symptoms or physiologic signs worsened, a subsequent visit was scheduled within 6 wk and pulmonary function tests were repeated. A relapse was defined as a decline in lung function from time 0 (the beginning of run-in) in any value of FEV1, FVC, or Dl CO-SB of 15% or more for two consecutive measurements. This was considered a failure of therapy due to recurrent sarcoidosis. Radiography alone was not used to define relapse. Serial symptom measures were not used as outcomes because of the unblinded nature of the study. Compliance was assessed by pill count.
Complete lung function studies were performed according to American Thoracic Society (ATS) guidelines (15, 16) and included the measurement of FEV1, FVC, Dl CO-SB, and (during the run-in phase) the plethysmographic measurement of total lung capacity (TLC). Values were standardized to percent predicted values by published regression equations (14).
All subjects had posteroanterior and lateral chest roentgenograms, computed tomography, and gallium scanning, which were performed at entry and the end of the 6-mo run-in phase. Roentgenograms and computed tomography were assessed for change through the run-in period by a staff radiologist unaware of the protocol. Gallium scanning was executed with 300 MBq of 67Ga intravenously, scanned for total body uptake 48 h later on a General Electric (Milwaukee, WI) Camstar scanner. These were graded for total pulmonary uptake on serial tests by nuclear radiologists blinded to treatment status according to the following scale: 0, no abnormal uptake; 1, minimal uptake; 2, mild uptake; 3, moderate uptake; 4, severe uptake.
Serum calcium and angiotensin I-converting enzyme (ACE) levels were monitored at time 0 and 6 mo into the run-in phase.
All subjects enrolled were examined every 6 mo by one of us, who conducted both a corneal and retinal examination, and measured visual acuity and color discrimination on Ishihara color plates (7).
Dyspnea was scored according to the ATS five-point scale (17). Cough and hoarseness were scored on a modified version of this five-point scale: 0, none; 1, mild or less than daily and not disruptive; 2, moderately severe or daily but not disruptive; 3, severe or daily and occasionally disruptive of leisure/occupational activities; 4, severe or constant and necessitating a change in usual activities. Symptoms were reported during the run-in phase only.
All subjects at the closure of the trial were surveyed anonymously for preferences regarding chloroquine or previous experience with corticosteroids. Qualitative comments were invited, including comments on satisfaction with therapy and side effects.
Data are expressed as mean values with standard deviation (SD) unless indicated as standard error (SE). Significant differences between the time points 0 and 6 mo were evaluated within individuals with a paired Student t test (18). All physiologic measurements of FEV1, FVC, and Dl CO-SB made through the randomized trial to either relapse or closure of the trial were summarized as slopes in a two-stage mixed model that has been proposed for unbalanced longitudinal data (19) and compared for significance with a F test. Effectiveness of CQ maintenance therapy after randomization was assessed by comparing groups by a product-limit analysis and the Wilcoxon statistic (20). Statistical significance was declared at a two-tailed p value < 0.05.
Twenty-four subjects (average age, 42.5 yr [range, 29–67 yr]; 4 black and 17 white; 10 female) with chronic pulmonary sarcoidosis were referred for consideration of chloroquine therapy, and all but 1 (who had homozygous glucose-6-phosphatase deficiency) were entered into the trial. Of the 23 remaining subjects, pulmonary sarcoidosis had been present for an average of 6.2 yr (range, 2–18 yr). Two were current smokers and one was an ex-smoker. All subjects had either stage 2 (n = 8) or stage 3 (n = 15) radiographic disease with a disease duration of 2–6 and 2–18 yr, respectively. Sixteen of 23 subjects had evidence of extra pulmonary sarcoidosis either at enrollment or historically, including hoarseness of voice (n = 4), ocular disease (n = 5), dermatologic manifestations (n = 7), systemic lymphadenopathy (n = 5), liver function abnormalities in the absence of focal abnormalities, or biliary disease on ultrasonography (n = 4) and splenomegaly (n = 2).
Sixteen of the 23 subjects had previously been treated with high-dose oral corticosteroids (a minimum of 40 mg of prednisone per day for at least 6 mo), 7 of them having required more than one course. None of the subjects previously treated with corticosteroids had sustained symptomatic or physiologic improvement, and all were being considered for further prolonged corticosteroid therapy. Of the eight subjects never treated with corticosteroids, seven had refused treatment and it was contraindicated in one subject with complicated diabetes mellitus.
Of the 23 subjects enrolled in the trial, 4 did not complete the 6-mo course of acute therapy: 1 subject suffered an unrelated traumatic death, and 3 had intolerable side effects (abdominal pain with vomiting in 2 subjects, destabilization of a preexisting anxiety disorder in 1 subject), manifested within 10 d of starting the medication. These four subjects were not significantly different from members of the group completing the run-in phase, and are excluded from further analysis. One patient withdrew for personal reasons after the 6 mo of initial treatment and did not return for follow-up; this patient's results are included only in the results of the run-in phase.
Baseline laboratory parameters of the 19 patients are shown in Table 1. The majority of subjects manifested a mixed picture of restrictive and obstructive lung dysfunction with mild impairment of diffusing capacity. Serial physiologic data over the preceding 6 mo to 8 yr were available for 14 of 19 subjects completing the run-in phase. These preenrollment measurements showed a mean decline in FEV1 of −265 ± 140 ml/yr, which is greater than the 35 ml/yr described in normal, nonsmoking subjects (21).
| Parameter | Baseline (mean ± SD) | Month 6 (mean ± SD) | p Value | |||
|---|---|---|---|---|---|---|
| FEV1, L | 2.01 (0.58) | 2.36 (0.64) | 0.001 | |||
| Percent predicted | 66 (15) | 74 (16) | 0.002 | |||
| FVC, L | 2.97 (0.78) | 3.36 (0.90) | 0.003 | |||
| Percent predicted | 71 (13) | 80 (13) | 0.005 | |||
| TLC, L | 5.07 (1.31) | 5.36 (1.18) | 0.07 | |||
| Percent predicted | 85 (13) | 92 (13) | 0.08 | |||
| Dl CO-SB, mm Hg/min | 18.8 (5.2) | 20.2 (5.6) | 0.02 | |||
| Percent predicted | 68 (13) | 73 (13) | 0.02 | |||
| ACE, nmol/L | 1,750 (1,336) | 977 (886) | 0.01 | |||
| Calcium, mmol/L | 2.42 (0.15) | 2.32 (0.12) | 0.01 | |||
| Gallium, score 0 to 4 | 1.9 (1.3) | 0.8 (0.8) | 0.004 |
Laboratory evaluation revealed increased pulmonary uptake of gallium in 17 of 19 subjects, with a mean score of 1.9 ± 1.3 (five-point scale). The serum ACE level was increased in 16 of 19 subjects, with a mean value of 1,750 ± 1,336 nmol/L (normal range for laboratory, 140–530 nmol/L). The serum calcium was normal in all but one subject, in whom it was 2.78 mmol/L (normal, 2.12–2.62). Table 1 also shows that the FEV1 group mean increased from 2.01 ± .058 to 2.36 ± 0.64 L (p = 0.001) and the FVC group mean increased from 2.97 ± 0.78 to 3.36 ± 0.90 L (p = 0.003). Diffusing capacity of the lung improved from 18.8 ± 5.2 to 20.2 ± 5.6 mm Hg/min (p = 0.02). The TLC did not change significantly, from 5.07 ± 1.31 to 5.36 ± 1.18 L (p = 0.07). No correlation was found between radiographic stage and degree of physiologic improvement.
The physiologic improvement was associated with significant clinical improvement at 6 mo as manifested by reduced symptom scores for dyspnea (1.75 to 0.50, p < 0.001) and cough (1.80 to 0.33, p < 0.001) (Figure 1). Hoarseness resolved in three of five subjects with the symptom at baseline and improved in the remaining two (p = 0.02).
Fig. 1. Symptom scores for dyspnea, cough, and hoarseness of voice through the run-in phase of chloroquine. There was a significant improvement in dyspnea (p < 0.001) and cough (p < 0.001). Hoarseness resolved in three of five patients and improved in the remaining two (p < 0.02).
[More] [Minimize]Marked improvement in pulmonary radiographic abnormalities of 5 of 19 subjects was reported by the radiologist, mild improvement was noted in 7 subjects, and no significant change was observed in 7 subjects. Chest computerized tomography (CT) scanning confirmed these observations, revealing significant improvement primarily in airspace opacities, with little change in linear or bandlike opacities. Significant improvement was also noted during the 6-mo run-in phase in the lung gallium scan, whose mean scores decreased from 1.9 ± 1.3 to 0.8 ± 0.8 (p = 0.004) and in the serum ACE level, which fell from 1,750 ± 1,336 to 977 ± 886 nmol/L (p = 0.01). Mean serum calcium values at months 0 and 6 were, respectively, 2.42 ± 0.15 and 2.32 ± 0.12 mmol/L (p = 0.01); the serum calcium returned to normal in the one subject with an elevated baseline level and has since remained normal on maintenance therapy. Other organs actively involved at baseline generally improved. Skin manifestations regressed in five patients and improved in two. Lymphadenopathy either remained stable (two patients) or improved (three patients). Two patients with splenomegaly had reductions in spleen size as determined by physical examination and CT scan. No ocular lesions were considered active at baseline, and none relapsed while CQ was taken.
Eighteen of 19 subjects completing the run-in phase were randomized. Ten received 250 mg of CQ per day (Maintenance group) and 8 formed the Observation group (control). All but one subject randomized to treatment took more than 80% of the prescribed doses. Subjects were monitored for a mean of 19.7 ± 11.2 mo (range, 6 to 48 mo).
There were no significant differences (p values > 0.10) in clinical, physiologic, or laboratory parameters in the two groups at randomization (Table 2). One subject in each group continued to smoke, and one ex-smoker was randomized to chloroquine. Subjects in both groups also had similar declines in FEV1 (−170 ± 183 ml/yr in the control group versus −120 ± 129 ml/yr in the CQ group, p = 0.58), FVC (−83 ± 367 ml/yr in the control group versus −138 ± 272 ml/yr in the CQ group, p = 0.62), and Dl CO-SB (−1.0 ± 2.2 mm Hg/min/yr in the control group versus −3.2 ± 5.8 mm Hg/min/yr in the CQ group, p = 0.37) before study entry, and improved comparably with the induction therapy.
| Chloroquine (mean ± SD) | Control (mean ± SD) | p Value | ||||
|---|---|---|---|---|---|---|
| Number | 10 | 8 | ||||
| Age, yr | 43.3 (8.5) | 41.1 (7.9) | 0.69 | |||
| Female, % | 50 | 50 | 1.00 | |||
| Duration of disease, yr | 5.0 (5.5) | 4.5 (3.2) | 0.83 | |||
| Stage (2/3) | 3/7 | 2/6 | 0.98 | |||
| Radiologic fibrosis | 3 | 3 | 0.98 | |||
| Smoking, pack-years | 3.8 (6.6) | 3.4 (6.5) | 0.97 | |||
| FEV1, L | 2.20 (0.60) | 2.48 (0.70) | 0.48 | |||
| Percent predicted | 66 (17) | 72 (16) | 0.68 | |||
| FVC, L | 3.52 (0.96) | 3.32 (0.81) | 0.57 | |||
| Percent predicted | 89 (7.7) | 84 (15.0) | 0.59 | |||
| Dl CO-SB, mm Hg/min | 19.9 (5.0) | 20.9 (6.6) | 0.61 | |||
| Percent predicted | 70 (15) | 76 (18) | 0.69 |
Control subjects showed a significantly faster decline in FEV1 (−196.3 ± 33.4 versus −51.4 ± 28.2 ml/yr, p = 0.02) and Dl CO-SB (−2.08 ± 0.37 versus −0.59 ± 0.37 mm Hg/min/yr, p = 0.03) than did subjects receiving maintenance therapy. The differences in FVC decline (−144.1 ± 48.0 ml/yr [control] versus −32.9 ± 40.8 ml/yr [maintenance]; p = 0.10) did not reach significance (Table 3). Two subjects on maintenance therapy failed because of declining Dl CO-SB after a mean 29.5 ± 4.9 mo of follow-up; six of eight control subjects failed, three with falling FEV1 and 3 with falling Dl CO-SB at 15.5 ± 2.9 mo (product-limit Wilcoxon, p = 0.06). All subjects who failed were progressively symptomatic, and clinical reevaluation was consistent with relapse of sarcoidosis.
| Chloroquine (mean ± SD) | Control (mean ± SD) | p Value | ||||
|---|---|---|---|---|---|---|
| FEV1 slope, ml/yr | −51.4 (28.2) | −196.3 (33.4) | 0.02 | |||
| FVC slope, ml/yr | −32.9 (40.8) | −144.1 (48.0) | 0.10 | |||
| Dl CO-SB slope, mm Hg/min/yr | −0.59 (0.37) | −2.08 (0.37) | 0.03 | |||
| Mean follow-up, mo | 20.7 | 18.6 | ||||
| Total follow-up, patient-months | 207 | 149 | ||||
| Patients failing, number/total | 2/10 | 6/8 | ||||
| Time to failure, mo | 29.5 (4.9) | 15.5 (2.9) | 0.06 |
Three of 23 subjects (13%) initially enrolled experienced intolerable side effects and could not continue CQ treatment (1 subject died of an unrelated traumatic death). Fifteen of the 19 remaining subjects (65% of the original 23) reported transient, tolerable side effects, almost exclusively during the first 2 mo of high-dose therapy at 750 mg/d; these had fully resolved in 11 and were minimal in 4 subjects at the 500-mg/d dose (Table 4). Two subjects required early dose reductions from 750 to 500 mg/d to manage abdominal pain. The predominant side effect of CQ observed in patients receiving 250 mg/ d and monitored for up to 48 mo was visual haloes without change in visual acuity (3 of 10 subjects). Ophthalmologic examination demonstrated stable corneal deposits in 7 of 10 (70%) subjects. Evidence of retinopathy was suspected in one patient after administration of ∼ 420 g of chloroquine; this patient's ability to read Ishihara color plates declined without symptoms or decline in visual acuity. Chloroquine was stopped in this individual, who developed pulmonary relapse.
| Side Effect | Chloroquine Dosage | Total % | ||||||
|---|---|---|---|---|---|---|---|---|
| 750 mg/d | 500 mg/d | 250 mg/d | ||||||
| Blurred vision | 10 | 0 | 0 | 10 (43) | ||||
| Dizziness | 6 | 0 | 0 | 6 (26) | ||||
| Nausea | 6 | 1 | 0 | 6 (26) | ||||
| Abdominal cramps | 4 | 1 | 0 | 4 (17) | ||||
| Rash | 4 | 0 | 0 | 4 (17) | ||||
| Insomnia | 3 | 0 | 0 | 3 (13) | ||||
| Anorexia | 2 | 1 | 0 | 3 (13) | ||||
| Gray hair | 2 | 0 | 1 | 3 (13) | ||||
| Tinnitus | 2 | 0 | 0 | 2 (9) | ||||
| Visual haloes | 0 | 2 | 3 | 3 (13) | ||||
| Libido loss | 1 | 0 | 1 | 2 (9) | ||||
| Anxiety | 1 | 0 | 0 | 1 (4) | ||||
| Pruritus | 1 | 0 | 0 | 1 (4) | ||||
| Loss of color vision | 0 | 0 | 1 | 1 (4) | ||||
| None | 4 | 14 | 14 | |||||
| Number of patients | 23 | 19 | 19 | |||||
Eleven of the 18 subjects surveyed anonymously at the closure of the trial preferred chloroquine to corticosteroids, whereas 2 preferred corticosteroids. Qualitative comments included the lack of weight gain and an increased sense of well-being despite the initial side effects.
This study demonstrates that in chronic pulmonary sarcoidosis the administration of high-dose chloroquine improves multiple parameters of disease activity, that subsequent low-dose chloroquine continued beyond 6 mo significantly attenuates the decline in pulmonary function, and that these can be accomplished in most patients with acceptable side effects.
The natural history of sarcoidosis is characterized by spontaneous remissions but also by worsening or relapse even after apparent recovery. Remissions during a lifetime can be expected in 53–91% of patients with stage 1 disease and in 31– 74% of patients with stage 2 disease, whereas patients with stage 3 disease will remit less than 30% of the time (1, 2, 22– 24). After 2 yr of disease duration, the yearly chance of remission greatly declines and spontaneous remissions may be seen in 10 to 16% of patients with stage 2 disease, and in 6% of patients with stage 3 disease (24). Although the overall prognosis of sarcoidosis is good, approximately half of the patients will have at least a mild degree of permanent organ dysfunction (23). The heterogeneity in the natural history of sarcoidosis, its uncertain clinical course, and the serious side effects of corticosteroid treatment (6) compound the challenge of clinical management.
Corticosteroids remain the mainstay of therapy despite the paucity of controlled clinical trials in well-defined populations showing that such treatment improves long-term outcome. The most convincing evidence has come from a trial in which at least 18 mo of oral corticosteroid therapy directed at improving pulmonary radiologic appearance was more efficacious in preserving vital capacity than expectant management with symptom-or function-directed therapy (5). Even in patients who respond to corticosteroids, up to two-thirds with stage 2 or 3 disease will relapse when therapy is discontinued (25) and as a result regular follow-up of these patients has been advocated (2, 4, 6, 25).
Because of the relative long-term poor efficacy of corticosteroids in the treatment of sarcoidosis, their severe side effects with long-term therapy, and the frequent relapses after treatment, we decided to explore the efficacy of chloroquine in the treatment and maintenance of advanced pulmonary sarcoidosis. The efficacy of chloroquine is well established for dermatologic manifestations (7) and has been demonstrated to have acute benefits in the treatment of various stages of pulmonary sarcoidosis (12, 13) and neurologic sarcoidosis (26). Our study was designed to assess the initial effects of chloroquine on chronic advanced and symptomatic pulmonary sarcoidosis, as well as to evaluate the possible benefit of prolonged low-dose maintenance therapy.
The initial 6 mo of treatment was uncontrolled. Nevertheless, all patients satisfied accepted criteria indicating a need for treatment, i.e., symptomatic and progressive stage 2 and stage 3 disease (with abnormal pulmonary function), and all had disease of at least 2 yr duration. A large number of patients (16 of 23) had been treated with corticosteroids and had experienced relapses. The chances of having spontaneous remission after 2 yr of active disease is low (24), suggesting that the improvement seen in our patients after 6 mo of chloroquine was due to the effects of CQ rather than to spontaneous remission.
Significant clinical, physiologic, and imaging (X-ray and gallium) improvement was evident after 6 mo of CQ. Furthermore, treatment was able to reverse the steady decrease in function documented over months to years in most patients for whom such data were available. The improvement seen by CT scan in the airspace abnormalities in many of our patients suggests that an active pulmonary inflammatory process responsive to therapy is often present in these cases. This was accompanied by a fall in 67Ga uptake and a decrease in ACE levels. The rapid decline in pulmonary function was significantly attenuated when CQ therapy was maintained after the initial 6 mo of treatment (Table 3). We conclude from these results that chloroquine maintenance therapy is useful in diminishing disease activity, delaying and perhaps preventing relapse in these patients.
The exact mechanism by which aminoquinolines attenuate or abolish the inflammatory activity of sarcoidosis remains unclear. At our current level of understanding the development of sarcoidosis requires first the exposure to an antigenic stimulus and the consequent development of cellular immunity directed against the antigen. This is mediated through antigen-presenting cells and antigen-specific T lymphocytes. Alveolar macrophages in patients with sarcoidosis produce higher than normal concentrations of tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and interleukin 6 (IL-6), among others (27-29). Chloroquine probably acts on the macrophage by inhibiting antigen presentation and the production of TNF-α and IL-6, thus decreasing or abolishing the first steps in the pathogenesis of the disease (30, 31). The function of the lung T lymphocytes in sarcoidosis may be twofold: antigen recognition and implication of the local immune response (25) linked to secretion of interleukin 2 (IL-2), interferon γ, and other mediators of granulomatous inflammation (32, 33). These functions are probably inhibited by chloroquine via reduction in both production and response to IL-2 (34) as well as decreased induction of nuclear factor κB (35).
The potential toxicity of chloroquine to the retina and frequent side effects remain the principal reasons for not using this drug as long-term treatment. Prevention of retinal toxicity is now successfully managed with regular ophthalmologic surveillance (7). Despite the high incidence of side effects (Table 4) with CQ at 750 mg/d, most subjects were able to continue the medication, as the side effects were tolerable and did not interfere with personal or occupational function, and the great majority of the side effects disappeared with the lower dose schedules. Furthermore, most subjects surveyed preferred the side effects of chloroquine to those of corticosteroids. Since the end of this study, we have been using a treatment regimen of 250 mg of chloroquine twice daily for 6 mo. This regimen is much better tolerated and seems to be as effective as the regimen described above.
In summary, chloroquine appears to have a substantial antiinflammatory effect in pulmonary sarcoidosis, more likely suppressive than curative given the risk of relapse after the withdrawal of therapy. This antiinflammatory effect is at least analogous if not better than the therapeutic effect of systemic corticosteroids with much better tolerated short- and long-term side effects. In view of our findings, we suggest that chloroquine should be an important consideration as a first-line drug for the treatment and maintenance therapy of pulmonary sarcoidosis. However, a long-term controlled trial comparing systemic corticosteroid with chloroquine is needed to confirm the utility of CQ versus corticosteroids in the treatment of sarcoidosis.
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Dr. Baltzan is a fellow of the Medical Research Council of Canada.
