Actn l).Ieclicn Scnndinavica. Vol. CSLIS, fnsc. TI, 1064.
`
`Froin the Medical Department of the )>Onze Lieve fTrouwe Gasthuiso, Amsterdam, Holland.
`
`The Effect of Cortisoiie 011 Sjiigren’s Syndroiiic.
`BY
`W. K. GAULHOFER.
`(Submitted for publicstion February 25, 1954.)
`
`I n 1933 Sjogreii (1) described a syndrome, coniprising kerato-conjunctivitis sicca
`with diminished lacrimal secretion, rhinopharyngolaryngitis sicca with decreased
`nasal secretion, recurrent parotitis with diminished secretion of saliva and in some
`cases gastric achylia. Recent investigations, amongst others those of Holm (2)
`and Henderson (3) have shown that mild forms of this syndrome are relatively
`frequent, especially in combination with rheumatoid arthritis. This too was the
`author’s experience in the examination of 456 cases of rheumatoid arthritis in
`the ))Anti-Rheumatic Centre)) in Amsterdam (director: Dr. J. v. Breemen), when
`symptoms of Sjogren’s syndrome were found in 40 instances. It is therefore not
`surprising that various authors have tried to find whether the Sjogren syndrome,
`like rheumatoid arthritis, can be favourably influenced by ACTH or cortisone.
`The results of this treatment are very divergent. Two authors record successes.
`Stephens (4) observed the development of a copious secretion of tears and saliva
`over an unspecified number of days after giving i.m. ACTH injections for 10 days
`t o a 50-year-old woman suffering from Still’s disease and Sjogren’s syndrome.
`Frenkel and co-workers (5) also observed a marked increase of lacrimal and
`salivary secretion during 4 weeks’ treatment with ACTH in a 51-year-old woman
`with a severe non-rheumatic form of Sjogren’s syndrome. Shortly after the sus-
`pension of ACTH-treatment the secretions dropped again to the original level.
`Neither of these authors reports about measurements of the volumes of the secre-
`tions.
`No increase in the amount of secretion in Sjogren’s syndrome, could, on the
`other hand be found by Fitzgerald and co-workers (G), Appelinans and co-workers
`(7), Cadman and Robertson (8) and Sjogren and Eriksen (9) with i.m. administra-
`tion of ACTH, by Appelmans and his co-workers with i.m. administration of corti-
`
`MYLAN - EXHIBIT 1055
`Mylan Pharmaceuticals Inc. et al. v. Allergan, Inc.
`IPR2016-01127, -01128, -01129, -01130, -01131, & -01132
`
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`

`442
`
`W. I<. GAULHOFER.
`
`sone, by Cadman and Robertson, Coste (lo), Offret (11) and Forestier (12) with
`intraconjunctival application of cortisone and by Duke-Elder (13) with subcon-
`junctival injection of cortisone.
`Some of these authors made measurements of the lacrimal secretion but did
`not measure the aniount of salivation.
`As we have developed a semi-quantitative technique for the iiieasurenierit of
`the salivary secretion we have determined in G patients with Sjogren’s syndrome
`the amount of salivation as well as of lacrimal secretion (and the acidity of the
`gastric juice) during and after treatment with cortisone (ACTH respectively).l
`
`Methods.
`lacrimal secretion.
`Measurements of
`The amount of secretion was ascertained by the Schirnier test without previous
`anesthesia of the eye. Strips of pink litmus paper (Johnson’s), 5 nim broad and
`bent 4 mm froin the end, were hooked into the outer corner of the eye behind the
`lower lid and left there for 5 minutes. Three strips were used in every test but not
`as in the original method one immediately after the other but at intervals of about
`9 minutes. This modification was necessary to permit simultaneous measurement
`of salivation. The amount of lacrimation was judged from the length of the litmus
`strip (excluding the folded edge) which had been turned blue by the tears.
`In the following report only the mean of each sct of 3 measurements is given.
`Wetting-lengths of 15 mm or more are generally considered normal; 5-14
`nini
`suggests a slight and 0-4 mni a pronounced reduction of lacrimation.
`
`Measurement of salivation.
`Salivation was measured by the method described by the author in Ned. Tijd-
`schr. v. Geneesk. (14).
`Over a series of 15 (or less) consecutive periods of 3 minutes, one dragbe and 2
`dentist’s cotton wool rolls are placed in the mouth each time - the rolls a t the
`left and right under the tongue, the dragbe on top of the tongue. The draghe must
`not be chewed or sucked. The rolls and the dragbe are weighed before insertion
`and again after removal. Their increase in weight corresponds to the amount of
`saliva secreted during their presence in the mouth. Before insertion of the 4th
`pair of cotton wool rolls, 5 mg pilocarpine hydrochloride is injected subcutaneously
`as a stimulus to salivation. The results are recorded graphically.
`Figure 1 shows a few examples. Curve VI is the highest of those found in 50
`normal subjects. Curve IV is the lowest. Curve V shows the arithmetic mean of all
`50 sets of results.
`It can be shown from this that normal persons produce 3.4 (i 1.3) g saliva
`
`All patients mere treated in the ))Onze Licve Vronwe Gasthuiw in Amsterdwn by a team studying
`problems of cortisone-treatment financed by a grant from the sSetherlantls Kational Health Councils.
`Leader of the team was Dr. Steiner and other members Drs. L. Jansen, Th. Strengers, 0. If. de Vaal
`and the author.
`
`

`

`THE EFFECT OF CORTISONE ox S J ~ G R E N ’ S SYNDROME.
`
`443
`
`Fig. 1. Curves of salivary secretion. Curves I, II and I1 C are from cascs of Sjogrcn’s syndrome. Curve
`I from R severe CRSC complicatcd by parotitis. Curve 1[ from a case of moderate severity. Curve Ill
`from a mild casc of Sjogren’s syndrome. Curve l\’. The lowcst curve found among 50 normal subjects.
`Curvc V. Curve compiled from the arithrnet,ic mean of 50 normal subjecl;s. Curve 1’1. Highest ciirvc
`obtained from 50 normal subjects. These ciirrcs indicate the secretion of saliva measured in gra.ms
`during 13-15 3-minute periods before and after injection of 5 mg pilocarpine hydrochloride.
`
`in 3 minutes if no strong stimulus is applied. After stimulatioii of salivation with
`pilocarpine a maximum of 7.8 (+ 2.6) g is secreted in 3 minutes.
`Curves 1-111
`are taken from patients with Sjogren’s syndrome. Curves of
`type I are found oiily in the most severe forms of the disease, which are accom-
`g aiid do iiot show
`panied by parotitis. The curves do iiot begin above 0.05-0.2
`any elevation after injection of pilocarpine. Curves of type 111 are found in moder-
`ately severe forms of the disease. They start a t a lower value than normal curves
`aiid do not rise as high as normal curves after iiijectioii of pilocarpine. Curves of
`type I11 show the slightest deviation from normal. They begin, in contradistinc-
`tion to type 11 curves, a t as high values as normal curves, only they do iiot rise
`as high as normal curves after iiij ectioii of pilocarpine.
`These curves are reproducible. If the test is repeated under the same conditions
`1-7
`days later the maximum values do not differ by more than 1 g from the
`value obtained the first time, provided this was not more than 9 g. I n this case
`the difference in a subsequent test may be as much as 3 g.
`
`Case Histories.
`Case A : a 49-year-old housewife who had suffered from rheumatoid arthritis for 12
`years and for the past 3 years had not been able to produce tears on crying. Her
`conjunctivae colourecl strongly with Bengal Rose. Her lacrimal secretion was markedly
`
`

`

`444
`
`W. K. GAULHOFER.
`
`lowered (1 mm left and right). Her salivation was slightly reduced (type I11 from fig.
`1). Max. gastric acidity 55/72. Diagnosis: rheumatoid arthritis (stage I1 according to
`the classification of the New Pork Rheumatism Association) and a moderately severe
`form of Sjogren’s syndrome.
`The patient was treated for 76 days with cortisone and temporarily with Au or Irgapyrin
`(for dosage see fig. 2). Under this treatment there was a rapid improvement in the joint
`symptoms, which reached a maximum on the 16th day of treatment. After this the con-
`dition deteriorated, slowly at first, and then more rapidly and after the cessation of
`the cortisone treatment was worse than before the treatment was started.
`As can be seen from figure 2 the lacrimal secretion was not improved by cortisone.
`Salivation, however, increased considerably and reached almost double the initial value,
`simultaneously with the maximal improvement in the rheumatic symptoms. Parallel
`with the ensuing deterioration of the articular symptoms, salivation decreased too and
`reached the initial level after treatment. The patient’s gastric acidity did not alter during
`treatment.
`Case B: 42-year-old teacher who had suffered from rheumatoid arthritis for 11 years.
`She could cry with tears and did not complain of a dry mouth. Her lacrimal secretion was
`slightly lowered (8 mm), salivation was slightly reduced (curve 111, fig. 1). Her eyes did
`not stain with Bengal Rose. Gastric acidity max. 32/58. Diagnosis: rheumatoid arthritis
`(stage 11) and a mild form of Sjogren’s syndrome.
`With low doses of cortisone (see fig. 3) an improved mobility of the joints first ap-
`peared on the 19th day of treatment. From the 49th to the 70th day of treatment the
`condition was fair. After this the joint complaints markedly increased. After the sus-
`pension of the cortisone medication a febrile exacerbation developed. Finally there was
`a certain improvement under subsequent treatment with ACTH and Irgapyrin.
`Shortly after the initial improvement in the rheumatic symptoms, on the 21st day of
`treatment, the lacrimal secretion was found to have risen to a normal level. After the
`cessation of cortisone administration the lacrimal secretion fell to a very low level only
`to rise again with Irgapyrin and ACTH.
`The secretion of saliva increased later however than the secretion of tears. In the
`pause in treatment between cortisone and ACTH salivation did not decrease. The gastric
`acidity was not checked in this patient.
`Case C: 50-year-old housewife who had suffered from rheumatoid arthritis for 6 years.
`For the past 3 years when she cried only a few or no tears appeared. She did not complain
`of a dry mouth. On admission rheumatoid arthritis (stage 11) was found, and a moderately
`severe form of Sjogren’s syndrome (marked colouration of cornea and conjunctiva with
`Bengal Rose, markedly reduced lacrimation (2 mm) and a slight decrease in salivation
`(type 111, fig. 1)).
`A histamine-refractory gastric achylia was present.
`Under treatment with cortisone (dosage see fig. 4) the mobility of the joints improved
`until the 34th day, whereafter it decreased again. After cortisone was discontinued
`there developed a febrile exacerbation with violent joint pains which persisted until
`treatment with ACTH was begun. With this a slight and transitory improvement in
`the joint symptoms was achieved.
`From figure 4 it can be seen that the secretion of tears remained more or less un-
`changed throughout the entire treatment, whilst the secretion of saliva rose temporarily
`with cortisone as well as with ACTH. Increase in salivation coincided with the improve-
`ment in the articular symptoms, whilst the decrease in the secretion ran parallel with the
`deterioration of the joint symptoms.
`The achylia remained histamine-refractory throughout the whole treatment.
`Case D: 56-year-old salesman who had suffered from rheumatoid arthritis for 10 years.
`He could cry with tears and did not hare a dry mouth. On examination rheumatoid
`
`

`

`T H E EFFECT O F CORTISONE ON SJOGREN’S SYNDROME.
`
`445
`
`arthritis stage 111 and a fairly severe form of Sjogren’s syndioriie were found (lacrinia-
`tion 3 mm, salivation slightly decreased: type 111, figure l). Hengal Rose colouration
`negiitivc.
`During the treatment with cortisone (dosage see figure 6 ) a rapid improvement in the
`articular symptoms was reached, which improvement was entirely lost after the end of
`the treatment. The lacrimation once during the treatment showed a somewhat higher
`value than before or after treatment. The salivation on the 11th day of treatment, when
`the articular manifestations were clearly improved, was found to have risen to 7 g. There-
`after it fell to its initial level. On the 18th day of treatment pains began in the gastric
`region and the gastric acid values (45/22 before treatment) were found to have risen to
`98/95. The gastric pains disappeared with antacids. This hyperacidity continued
`throughout the entire period of treatment.
`
`Case E : 64-year-old housewife who had not been able to cry with tears for 4 years.
`For the same period there had been no secretion from the nose and she could no longer
`swallow dry food. Her tongue and lips burned when they came into contact with spiced
`or salty foods. On three occasions during the prcvious 2 years an inflammation of the
`right parotid gland had arisen. On examination, swelling of both parotids and the left
`submaxillary gland was found. The tongue was red and smooth. The lips displayed rha-
`giides. 130th conjunctivae and corneae coloured strongly with I3engal Bose. A rhinitis
`sicca was present. The secretion of tears was markedly reduced ( 2 mm). Salivation was
`more or less absent (type I from figure 1).
`E. S. R. 41 mni. There were no abnormalities of the joints.
`Under treatment with cocarboxylase (Berolase ’Roche’) and vitamin B-coaiples i.r.
`and i.m. (Becozym ’Roche’) the rhagades disappeared without any increase in secretion.
`W’e did not care to administer cortisone i m . because of the chronic recurrent parotitis.
`In consultation with the ophthalmologist, Dr. Winkelman, and under his supervision,
`cortisoiie eyedrops (1 drop 3 times daily in the left eye) were given over a period of 6
`weeks. From the first day of treatment the pain in both eyes wits less. Lacrimation and
`salivation however, did not increase.
`
`Case F : 43-year-old woniaii, who had suffered from parotitis 6 times in the past 5
`years. She could no longer produce tears when she cried. On examination a marked Bengal
`Rose colouration of both eyes, a markedly decreased lacrimation (0 mm) and a markedly
`decreased salivation (type I from figure 1) were found.
`In this patient too, general treatment with cortisone was not considered desirable and
`cortisone was applied locally as eye drops in the right eye, over a period of 24 days.
`Here too, the patient’s ophthalmic complaints disappeared, whilst the secretion of saliva
`and tears remained unchanged.
`
`Discnssion.
`S i s cases of Sjogren’s syndrome - 4 rheuiiiatic a n d 2 non-rheumatic - were
`treated with cortisone (and ACTH).
`In the two noii-rheumatic cases (E and F), where Sjogren’s syndrome was
`especially severe and associated with recurrent bacterial parotitis systemic treat-
`inelit with cortisone was judged inadvisable in view of the danger of exacerbation
`of infection and the patients were treated with cortisone eye drops.
`This did not lead t o any significant increase in the secretion of tears. Both
`patients, however, were relieved of the disagreeable symptoms in both eyes during
`the period of treatment, although cortisone had been introduced iiito one eye only.
`As anticipated, there was no iiicrease in the secretion of saliva.
`:;3--541167. A c f n inetl. Scctndinctu. I‘ol. C S L I S .
`
`

`

`446
`
`-
`
`TEARS
`mm,
`
`0
`( 0
`0
`
`- -.
`
`W. K. GAULHOFER.
`-
`
`I .
`
`CASE A
`
`mgmc
`
`a 1 1 1
`I I I I
`Fig. 2. Secretion of tears and saliva in Case A. The upright columns represent the maximum 3-minute
`secretion of saliva after injection of pilocarpine. The hanging columns represcnt the lacrimal sccrction
`(Schirmer-value).
`
`0
`
`150 1
`
`Fig. 3. Secrction of tears and saliva in Case B. See figure 2 for key to graph.
`
`In 4 cases the basal disease was rheumatoid arthritis. For 64 to 88 days treat-
`ment was given with i.m. injections of 10-200 mg cortisone per day. In all these
`4 cases a significant improvement followed, both in reduction of articular pain
`and in the general condition. In all 4 cases the improvement disappeared entirely or
`almost entirely when treatment was stopped.
`Two cases were subsequently treated with ACTH and Irgapyrin which also gave
`temporary improvement.
`In all 4 rheumatic patients secretion of saliva increased during treatment with
`cortisone from slightly reduced levels (at the start of treatment) to nornial levels.
`The increase coincided with the improvement in the articular manifestations.
`In three cases the secretion sank to the original level at the end of treatment.
`The decrease also approximately coincided with the increase in articular pain
`and deterioration in general condition.
`In one case the secretion remained high for 20 days after stopping the admin-
`istration of cortisone, after which, treatment with ACTH and later with Irgapyrin
`was continued, which did not result in any further increase in the secretion of saliva.
`A considerable increase in lacrimation (up to 23 mm) appeared in the least severe
`case of Sjogren's syndrome only. This patient did not complain of dry mucous
`membranes. Her eyes did not stain with Bengal Rose and showed only a moderately
`climinished Schirmer value before treatment (8 mm). Three other patients with
`
`

`

`TEARS
`I*,
`
`,o
`
`jALiVA
`
`CASE C
`
`Fig. 4. Secretion of tears and saliva in Cnse C. See figure 2 for key to graph.
`
`TEARS
`mmr
`
`,o
`
`rn
`
`I
`
`-
`
`
`
`I
`
`Fig. 5. Secretion of tears mid saliva in Case I>. See figure 2 for kcy to graph.
`
`very low Schirmer values (1 tnni, 3 mm, 2 mtn) two of whom showed marked
`colouration of the conjunctivae with Bengal Rose, demonstrated no increase in
`lacrimation.
`I n the case where an increase in the secretion of tears did arise it coincided with
`the improvement in general condition and a t the end of the treatment it, too,
`receded, as the clinical condition deteriorated to rise again during the after-treat-
`nient with ACTH and Irgapyrin.
`Gastric secretion was investigated in 3 patients. In patient A, in whom initial
`normal acid values were found. the acidity rcmained more or less unchanged
`during the administration of cortisone.
`I II patient D the gastric acidity rose during the administration of cortisone
`froin normal initial acid values to hyperacidic values (98/85) coincident with the
`development of severe gastric pain.
`I n patient B, in whom a histamine-refractory achylia was found, no frec acid
`\\-as produced during the entire treatment. The same was found in a 60-year-old
`man whose history is not recorded in this publication but who suffered from
`rheumatoid arthritis and gastric achylia and a fairly severe form of Sjogren's
`syndrome.
`Thus, it appears that where there is a slight reduction in sulioation, with corti-
`sone treatment this can rise to a normal level. Patients with a marked reduction
`of salivation were not systemically treated with cortisone for fear of a possiblc.
`activation of the accompanying chronic recurrent parotitis.
`
`

`

`448
`
`W. I<. CAULHOFER
`
`111 cases of slight reduction of the lacrimation a rise to a normal level is also
`possible. Where the reduction of lacrimal secretion is pronounced, no increase
`in the secretion of tears can be obtained.
`Gastric achylia, too, remains unaltered by cortisone treatment, whilst the
`normal gastric acid values may rise to hyperacidic values under cortisone.
`Finally an answer must be given to the question whether cortisone is a suitable
`treatment for Sjogren’s syndrome. This answer must be in the negative. Severe
`cases are not influenced and mild cases are oiily temporarily benefitted.
`
`Summary.
`Six cases of Sjogren’s syndrome - 4 accompanying rheumatoid arthritis and
`two noii-rheumatic - are reported.
`The 2 non-rheumatic cases were treated with cortisone in the form of eye drops.
`This led to a temporary improvement in the subjective manifestations, but the
`lacrimal and salivary secretion did not show any increase.
`The 4 rheumatic cases were treated with intraniuscular injections of cortisone.
`A return to normal of the secretions under this treatment was observed only in
`cases in which these had been slightly impaired previous t o the treatment (the
`salivary secretion in 4 cases and lacrimal secretion in one). IVhere the secretions
`were greatly reduced (lacrimal secretion in 3 cases; achylia gastric in one case)
`there was 110 improvement. \\’here improvements were seen, these occurred together
`with improvements in the articular manifestations aiid disappeared usually again
`as the articular manifestations returned after the suspension of cortisone medica-
`tion.
`Cortisoiie cannot be reconiniended for the treatment of Sjogren’s syndrome
`
`References.
`1. Sjogren, H.: Acta O p h t h t h . suppl. 11 (1933), 151. - 2. Holm, S.: Bcta Ophthalni.
`suppl. XXXlll (1949). - 3. Henderson, J . W.: Bin. J. Ophthalm. 33 (1950), 197. -
`4. Stephens. D. J.: Yroc. First Clinical ACTH Conference 313 (1950), The Blakiston
`Company, Philadelphia. - 5. Frenkel, M. et al.: Acta Endocrinologica 6 (1951), 161. -
`6. Fitzgerald, J . R. et al.: Arch. Ophthalm. 45 (1951), 320. - 7. Appelmans, M. et al.:
`Ophthalmologica 122 (1951), 337. - 8. Cadman, E. F. 13. and Robertson, A. J.: Brit.
`Med. J. 1952, I, 68; 11, 446. - 9. Sjogren, H. and Eriksen, A.: Acta Ophthalmologica 30
`(1952), 463. - 10. Coste, F. et al.: Rev. Rhum. 19 (1952), 355. - 11. Offret, G. c. s.:
`Bull. SOC. Ophthalm. Franc. 1950, 759. - 12. Forestier, J.: Rev. Rhuni. 19 (1952), 355.
`- 13. Duke-Elder, W. S.: Brit. J. Ophthalm. 35 (1951), 637. - 14. Gaulhofer, W. K.:
`Ned. Tschr. Geneesk. 96 (1952), 1595.
`
`