DECEMBER 1974

The American Journal of Mediclne

VOLUME 57

NUMBER 6

EDITORIAL

Course and Prognosis of Sarcoidosis

Around the World

L. E. SILTZBACH, M.D. This is a retrospective comparison of large intensively investigated

New York, New York series of sarcoidosis in five large cities-London, New York, Paris,
Los Angeles and Tokyo-of three different continents. The patients
D. GERAINT JAMES, M.D.
E. NEVILLE. M.B.. B.S.
studied have both clinical and histologic evidenc:e of sar-
coidosis. The same rigid diagnostic criteria in all series provide
London, England
some measure of conformity and homogeneity in vastly different
J. TURIAF, M.D. populations suffering from the same disease.
J. P. BATTESTI. M.D.
It is hoped that this retrospective analysis will lead to a more am-
Paris. Franc,5 bitious worldwide computerized analysis of sarcoidosis so that an
OM. P. SHARMA, M.D. assault may be made on the final unknown bridgehead, namely, its
Los Angeles, California
etiology.

YUTAKA HOSODA. M.D. SEX, AGE AND ETHNIC BACKGROUND

R MIKAMI, M.D.
There is no particular sex predilection in any of the series. and
M. ODAKA, M.D
women account for 891 of the 1,609 (55 per cent) patients over-all
Tokyo, Japan
(Table I). The Tokyo series is entirely Japanese. In the London and
Paris series the majority are white, whereas in the Los Angeles and
New York series the majority are black. London sees sarcoidosis
in its West Indian migrants, Paris observes it commonly in its Marti-
nique population in France, New York in its Puerto Ricalns and Los
From the Mount Sinai Hospital, New York, New
Angeles notes it in its Mexican migrants. Thus far Jap,an only ob-
York; the Royal Northern Hospital, London, En-
gland: the Hopital Bichat, Paris, France; the Los serves sarcoidosis in its own nationals, but it will be interesting to
Angeles County Hospital, University of Southern observe whether in the future it will be found to affect other island-
California. Los Angeles, California; and the ers migrating to live in Tokyo, much in the same way as this phe-
Japan Sarcoidosrs Committee, Tokyo, Japan.
nomenon has been observed in London, Paris and New York.
Requests for reprints should be addressed to
The majority of patients in all series were under 40 years of age
Dr. D. Geraint James, Royal Northern Hospital.
London, N7 6 LD England. Manuscript accepted at the time of first presentation; over-all 1,128 of the 1,609 (70 per
March 12. -1974. cent) patients were under 40 years of age (Table I).

a47
SARCOIDOSIS AROUND THE WORLD-SILTZBACH ET AL.

TABLE I Features of Sarcoidosis in London, New York, Paris, Los Angeles and Tokyo

London New York Paris Los Angeles Tokyo Over-All

No. % No. % No. % No. % No. % No. %

Sex
Women 302 56 211 68 146 45 100 67 132 47 891 55
Ethnic group
Japanese 282 100 282 18
White 474 89 111 36 277 84 16 11 ... 878 54
Negro 35 6 146 47 42 13 123 82 ... .. 346 22
Puerto Rican 0 0 54 17 0 0 0 0 ... ..I 54 3
Mexican 0 0 0 0 0 0 11 7 .. 11 1
Others 28 5 0 0 10 3 0 0 .. ... 38 2
Age at presentation
Under 40 yr 358 67 221 71 238 72 103 69 208 74 1,128 70
Over 40 yr 179 33 90 29 91 28 47 31 74 26 481 30
Onset
Routine chest film 119 22 124 40 156 47.5 30 20 126 45 555 34
Respiratory symptoms 49 9 5Y 19 53 16 73 49 234” 18*
Erythema nodosum 150 28 33 11 22 7 14 9 219” 16*
12 156 55
Other skin lesions 37 7 19 6 14 4 18 88* 71
Ocular symptoms 53 10 22 7 29 8.5 15 10 119* ,9*
____.
Totals 537 100 311 100 329 100 150 100 282 100 1,609 100
-
* Excluding the Japanese figures.

MODE OF ONSET Stage 0: This indicates a clear chest roentgeno-

The mode of onset of sarcoidosis is pinpointed most gram which was noted in 16 per cent of the London
accurately by an attack of erythema nodosum or series, 8 per cent of the New York series, 6 per cent
acute uveitis or by the development of hilar adenopa- of the Paris series, 7 per cent of the Los Angeles and
thy. When it is first recognized as a result of routine 5 per cent of the Tokyo series (Table II).
mass roentgenography, it is more difficult to identify
the onset unless serial roentgenograms indicate a
Stage 1: Bilateral hilar lymphadenopathy is the
change from normal to abnormal findings. In these
earliest change, noted in nearly one half of the Lon-
series, sarcoidosis was most frequently recognized
don, New York and Tokyo series, one third of the
initially on chest roentgenograms, obtained either
Paris series and one quarter of the Los Angeles se-
routinely or as a result of respiratory symptoms (in
ries. It is a feature of acute, early reversible sar-
over one third of all patients). Alternative presenta-
coidosis, being associated with other reversible le-
tions comprised erythema nodosum or other skin le-
sions such as erythema nodosum and acute iritis.
sions or ocular symptoms. Erythema nodosum was
Resolution of bilateral hilar lymphadenopathy was
more commonly the onset in the London series than
observed in the majority of patients in all cities ex-
elsewhere, with a frequency of 28 per cent of all pre-
cept Tokyo (Table Ill).
sentations compared with about 10 per cent else-
where.
Stage 2: Bilateral hilar lymphadenopathy is associ-
INTRATHORACIC SARCOIDOSIS
ated with pulmonary infiltration which may be fine or
By international convention, the chest roentgeno- coarse miliary nodulation or a fluffy cotton-wool ap-
graphic appearances are staged as follows: pearance. This is a transition stage between stages

TABLE II Stage at Presentation Based on Chest Roentgenogram

~ .~~. ~~
London New York Paris Los Angeles Tokyo
Stage No. % No. % No. % No. % No. %
0 85 16 26 8 20 6 10 7 14 5
1 243 45 133 43 123 37.5 38 25 144 51
2 129 24 108 35 162 49 52 35 84 30
3 80 15 44 14 24 7.5 50 33 18 6
Unknown 22 8
--- ~___ ___~.

848 December 1974 The American Journal of Medicine Volume 57

 SARCOIDOSIS AROUND THE WORLD-SILTZBACH ET AL.

TABLE III Resolution of Changes on Chest Roentgenogram in Sarcoidosis

London New York Pans Los Angeles Tokyo*

~.. -__
No. of x No. of % No. of % No. of % No. elf %
Patrents Clearing Patrents Clearing Patients Clearing Patients Clearing Patients Clearing

85 ... 26 . 20 ... 10 ... 14. ..

243 75 133 54 123 87 38 53 144 35
129 54 108 31 162 74 52 49 84 24
80 26 44 10 24 .. 50 27 18 0
Unknown 221

Totals 537 62 311 38 329 69 150 43 282 27

.-____ ~~~__ ~~~
* Thirty-five per cent of these subjects were recently discovered not exceeding 1 year after the onset and 25 per cent of them had
shown persisting involvement before 1968. This mav be the reason why the resolution rates were considerably low, although the
average observation period was 2.5 years.

1 and 3, for, as the hilar lymph nodes shrink, the pul- so of patients with bilateral hilar lymphadenopathy;
monary slhadowing becomes more obvious. The inci- we do not advocate steroid therapy for this stage 1
dence of clearing lies somewhere between the good involvement.
prognosis of stage 1 and the poor outlook of stage 3 The course of stage 2 involvement is less favor-
sarcoidosis (Table Ill). In less than one half of the pa- able with a resolution rate of about 46 per cent and
tients presenting at this stage does resolution of the that of stage 3 involvement is poor with an expected
chest radliogram occur. incidence of resolution of only about 1.2 per cent.
Systemic therapy is indicated to prevent progression
Stage :3: This is a late stage of pulmonary infiltra- and fibrosis and hopefully to achieve resolution in at
tion without hilar lymphadenopathy. The prognosis is least some of these patients. It is also widely used for
poor at this stage for there may be dense fibrosis, relief of breathlessness and other respiratory symp-
bulla formation, right ventricular hypertrophy and pul- toms.
monary hypertension, with corresponding physiologic
evidence of pulmonary insufficiency. EXTRATHORACIC SARCOIDOSIS

Resolution of changes on the chest radiogram var- There are striking similarities in the patterns of ex-
ied from none to 26 per cent in the various series trathoracic involvement in all five cities (Table IV).
(Table Ill). Peripheral lymphadenopathy, ocular and skin involve-
Over-All Course and Prognosis. When bilateral hilar ment are noted in about one-fifth, the spleen is in-
lymphadenopathy is associated with erythema no- volved in about one-tenth, and the bones, parotid and
dosum, the outcome is uniformly favorable. Eventual nervous system in about one-twentieth of all series.
resolution may be anticipated in about 60 per cent or The incidence of erythema nodosum is variable: it

TABLE IV Frequency of Involvement of Various Tissues in Sarcoidosis in London, New York, Paris,
Los Angeles and Tokyo

Tokyo
London New York Pans Los Angeles --~ Over-All
~_ No. of
No. of No. of No. of No. of Pa- No. of
Tissue Involved Patients % Patients % Patients % Patients % tients % Patients %
_~_
~~~_ ..____
~___
lntrathoracic 452 84 285 92 300 90 140 93 246 87 1,423 88
Hilar nodes 372 70 241 77 227 70 90 60 228 81 1,158 72
Lung parenchyma 209 40 152 49 186 56.5 102 68 102 36 751 46
Lymph inodes 153 29 116 37 75 23 47 31 66 23 457 28
Eyes 147 27 62 20 37 11 17 11 91 32 354 22
Skin 135 25 59 19 39 12 31 27 33 12 297 18
Erythema nodosum 167 31 33 11 22 6.5 14 9 10 4 246 15
Spleen 62 12 57 18 20 6 20 15 4 1 163 10
Bones 191475 4 13/139 9 6/165 3.5 3/60 4 5 2 46 4
Parotid 33 6 25 8 21 6 10 6 15 5 104 6
Central nervous system 38 7 13 4 14 4 3 2 11 4 79 5
_ ~_. ~_ _ _~~_~~_~. .~
Totals 537 311 329 150 282 1,609 100
_ ~.~.

December 1974 The American Journal of Medicine Volulme 57 849

SARCOIDOSIS AROUND THE WORLD-SILTZBACH ET AL.

TABLE V Histologic Confirmation of Sarcoidosis

No. of Patients

Tissue London New York Paris Los Angeles Tokyo Totals

Bronchial biopsy ... ... 142 2 ... 144

Lymph node 100 89 46 53 118 406
Skin 82 31 14 19 19 165
Liver biopsy 76 12 11 38 9 146
Others 42 33 31 32 10 148
Totals 300 165 244 144 156 1,009
Positive Kveim- 384 285 187 36 76 968
Siltzbach test - = 82% - = 92% - = 77% - = 72% - = 54% ~ = 79%
466 311 243 50 141 1,211

appears to be top-heavy in London, and has a more transient maculopapular eruptions; they were ob-
accurate over-all frequency in the other cities occur- served in 18 per cent of the patients in these series
ring in about 10 per cent of the patients. (Table IV).
Lymphadenopathy. Hilar and peripheral lymphade- Erythema nodosum due to sarcoidosis is associ-
nopathy and splenomegaly occur sufficiently often to ated with bilateral hilar lymphadenopathy, polyarthral-
demarcate sarcoidosis as a lymphoproliferative dis- gia and occasionally acute iriiis. It predominates in
order, a fact which should be taken into account in women of the child-bearing age, and is often associ-
any understanding of its pathogenesis. Peripheral ated with pregnancy or lactation, suggesting a hor-
lymphadenopathy occurred in about 28 per cent and monal factor in its genesis. It has a predilection for
splenomegaly in about 10 per cent over-all in these Irish women in London and Puerto Ricans in New
series (Table IV). York City.
Ocular Lesions. These include acute and chronic iri- Bone Involvement. Bone involvement occurred in
docyclitis, choroidoretinitis, papilledema, keratocon- about 4 per cent of the patients in the various series.
junctivitis, conjunctival follicles, and the late compli- It is found in patients with chronic skin lesions, so the
cations of cataract and secondary glaucoma. There dermatologist is more likely than the chest physician
are certain well defined clinical syndromes of sar- to detect bone cysts. Bone involvement reflects
coidosis with eye involvement. Acute iritis, erythema chronic persistent irreversible sarcoidosis in all sys-
nodosum and bilateral hilar lymphadenopathy have a tems.
benign self-limiting course, whereas chronic iridocy- Parotid Glands. Enlarged parotid glands were found
clitis, associated with lupus pernio or skin plaques, in about 6 per cent of the patients in all series.
bone cysts and pulmonary fibrosis, is persistent and Central Nervous System. Nervous system involve-
troublesome. Keratoconjunctivitis sicca with or with- ment occurred in about 5 per cent of the patients in
out parotid and lacrimal gland enlargement mimics the various series. Facial palsy is a frequent neuro-
Sjbgren’s syndrome. Parotid gland enlargement, an- logic presentation, occurring either alone or with
terior uveitis and facial nerve palsy constitute Heer- other cranial palsies or with papilledema. Other pre-
fordt’s syndrome. sentations include peripheral neuritis, myopathy,
Ocular involvement may be anticipated in about meningitis and space-occupying brain lesions.
one fifth of all patients with sarcoidosis if slit-lamp
examination of the eyes is routinely undertaken. HISTOLOGY
Skin Lesions. Lesions other than erythema nodo- Whenever possible the clinical diagnosis of sar-
sum include lupus pernio, plaques, scars, keloids and coidosis should be histologically confirmed. The di-

TABLE VI Skin Tests

London New York Paris Los Angeles Tokyo Totals

Test No. % No. -& No. % No. % No. % No. %

Positive Kveim- 3841466 82 285/311 92 1871243 77 36150 72 761141 54 968/1,211 79

Siltzbach
Negative tuberculin 2461448 55 191 63 266 81 128 85 1511242 62 982/l, 480 66
test

850 December 1974 The American Journal of Medicine Volume 57

 SARCOIOOSIS AROUND THE WORLD-SILTZEACH ET AL.

TABLE VII Blood Tests

~____~_~
London New York Parls Los Angles Toyko

No. % No. % No. % No. % NCI. %

Hyperglobulinemia 851250 34 158/260 61 481212 22.5 129 86 25!:LO2 25

Hypercalcemia 571238 24 33 ./236 14 171249 7 16 11 9.1102 5
.-___- _

versity of tissues involved is matched only by the di- may be expected in about 13 per cent of patients
versity of technics used for obtaining tissue samples with sarcoidosis.
(Table V). Irrespective of the technic used, the earlier
histologic confirmation is sought, the more likely is a TREATMENT
positive biopsy obtained. At the late stage of hyaline
The sheet-anchor of treatment is corticosteroid ther-
fibrosis, it may be difficult to find the characteristic
apy which is given to about one half of the patients
epithelioid granulomas which characterize the earlier
with sarcoidosis. It was prescribed for about one third
stage of sarcoidosis.
of the patients in London and New York and two
The Kveim-Siltzbach skin test, using differing ma-
thirds of the patients in Paris, Los Angeles and Tokyo
terials and lots, was also positive in about four fifths
(Table VIII). The absolute indications for corticoste-
of the patients (Table V). We have found it to be a re-
roid therapy are ocular involvement, persistent hy-
liable, specific, safe and simple outpatient technic in-
percalciuria, hypersplenism, hypoxemia and progres-
valuable in delineating multisystem sarcoidosis from
sive pulmonary lesions, involvement of the central
the numerous other causes of systemic and nonspe-
nervous system and myocardium, disfiguring cuta-
cific local sarcoid-tissue reactions.
neous lesions, salivary and lacrimal gland lesions, fa-
OTHER INVESTIGATIONS cial palsy and troublesome polyarthralgia.

Tuberculin Reaction. The tuberculin skin test reac-

MORTALITY
tion was negative in 66 per cent of the patients
(Table VI). Patients who exhibited some degree of tu- The chance of survival seems to be the same wheth-
berculin hypersensitivity had only weakly positive er the patient lives in London, New York., Paris, Los
tests. Insensitivity to tuberculin, and to other antigens Angeles or Tokyo (Table VIII). The over-all mortality is
like dinitrochlorobenzene, is only a relative and not about 6 per cent; in some (5 per cent) of these pa-
an absolute characteristic, nor does the insensitivity tients, death is a direct result of sarcoidosis and in
appear to be as profound as it is in malignant lym- the remainder (1 per cent) death is due to unrelated
phoproliferative disorders. diseases. These are necessarily generalizations for
the patients in these series have been under continu-
BIOCHEMICAL ABNORMALITIES ous observation for different. durations. The New
York, Paris and London sarcoidosis clinics have been
Abnormal Globulin Levels. Globulin levels above 3.5
functioning for two decades or so whereas the others
g/100 ml were noted in a significant percentage of
were formed more recently. Nonetheless the trends
the patients, ranging from 22.5 to 61 per cent in the
are surprisingly similar.
various series (Table VII), being highest in black pa-
tients in New York and Los Angeles.
CONCLUSION
Serum Calcium Levels. Calcium levels above 11
mg/ 100 ml were noted in from 7 to 24 per cent of The patients in these series are of different ethnic
the patients in the various series. Hypercalcemia groups and cultures, and live in radically different en-

TABLE VIII Treatment and Mortality

London New York Palls Los Angeles Tokyo

Data No. 9’0 No. % No. % No. “i No. “4

Treatment
Corticosterolds 185 34 103 33 224 68.5 97 65 I93 68
None 352 66 208 67 89 27 53 35 85 32
Mortality
Due to sarcoidosis 25 5 17 5 6 1.8 6 4 1 0.4
Due to other causes 8 1.5 9 3 7 2 2 1.3 1 0.4

December 1974 The American Journal of Medicine Volume 57 851

 SARCOIOOSIS AROUND THE WORLD-SILTZBACH ET AL.

vironments and climates. Nevertheless, there is an composite patient is likely to have a negative or only
extraordinary parallelism of the findings in the five weakly positive skin test reaction, and also possibly
cities. It allows a composite generalization. The pa- abnormal serum globulin levels. The patient may
tient with sarcoidosis is of either sex but under 40 have transient hypercalcemia. If the patient presents
years of age when the disorder is discovered on a with bilateral hilar lymphadenopathy, resolution may
routine chest roentgenogram because of respiratory be expected without steroid therapy, but if pulmonary
symptoms, or skin or ocular lesions. The Kveim-Siltz- infiltrates are also present, resolution is less likely
bath test is positive in four fifths of the patients and even with steroid therapy. Depending on the duration
false-positive reactions have not marred its value in of observation, it seems that the mortality risk due to
this over-all large series spanning the world. The sarcoidosis is 5 per cent.

952 December 1974 The American Journal of Medicine Volume 57