BRIEF REPORT
`
`WEEKLY INTRAVENOUS METHOTREXATE IN THE TREATMENT
`OF RHEUMATOID ARTHRITIS
`
`ROBERT M. MICHAELS. DAVID J. NASHEL. ANDREA LEONARD. ANTHONY J. Sl..lWlNSK.l. and
`STEPHEN J. DERBES
`
`Patients with rheumatoid arthritis who are unre-
`sponsive to antilnilarninatory drugs and-islo-w—acting
`agents such as gold. hydroxychloroquine. and D-
`penicillaminc. pose a therapeutic challenge. This re-
`port details the effectiveness of weekly intravenous
`methotrexate in 14 such patients resistant to standard
`therapy.
`
`PATIENTS AND METHODS
`
`There were 6 women and 8 men in the study
`group ranging in age from 48 to 66 years. All met the
`American Rheumatism Association criteria for the
`diagnosis of classic rheumatoid arthritis ti). Each
`participant gave informed consent before entering the
`program. All had clinical evidence of active disease
`and had failed to respond to both gold and l1ydro:ty-
`chloroquine. In addition. 6 patients were unresponsive
`to D-peniciilamine. Two had failed to improve with
`
`inimunosuppressivc therapy: I with azathioprine and
`
`From the Divisions of Rheurnatoiogy, The Guthrie Clinic.
`Sayre. Pennsylvania. Veterans Administration Medical Center and
`Georgetown University Medical Center. Washington. DC. and
`Touro Infirmary. New Orleans. Louisiana.
`Supported in part by The Donald Guthrie Foundation for
`Medical Research. Project 79-33 and the Arthritis Foundation.
`Washington. DC.
`Robert M. Michaeis. MD: Chief. Division of Rheumatoi-
`ogy. The Guthrie Clinic: David J. Nashel. MD: Chief. Rheumatoi-
`ogy Section. VA Medical Center; Andrea Leonard. MD: Fellow.
`Division of Rheumatic Diseases. Georgetown University Medical
`Center: Anthony J. Siiwinslti. MD: Acting Chief. Division of
`Rheumatic Diseases. Georgetown University Medical Center: Sie-
`phen J. Derbes. MD: Head. Division of Rheumatoiogy. Touro
`Infirmary.
`Address reprint requests to Dr. Robert M. Mich-aeis. Divi-
`sion of Rheumatoiogy. The Guthrie Clinic. Guthrie Square. Sayre.
`PA I334ll.
`
`Submitted for ptlblicaiiort May 4. i931: accepted in revised
`form August IB, l98l.
`
`..a
`Arthritis and Rheumatism. Vol. 25. No. 3 (March I932)
`
`the other with cyclophosphamidc. Patients were al-
`lowed to continue corticosteroid and any non -steroidal
`antiinfiammatory agents on a stable dosage. Excluded
`from this study were patients with liver disease. renal
`insufiiciency. active infections. known alcohol abuse.
`abnormal white blood cell or platelet count. and wom-
`en with childbearing potential.
`Prior to the study, each patient had a complete
`history. physical examination. and chest roentgeno-
`gram. Joint
`index (sum of the number of swollen.
`tender. and warm joints). grip strength. and an assess-
`ment of morning stiffness were determined initially
`and at monthly intervals. A complete blood count and
`platelet count were performed weekly: Westcrgren
`sedimentation rate, reticuiocyte count. scrum glutam-
`ic-oitaloacetic transaminase (SGOTL serum glutan1ic-
`pyruvic transaminase (SGPT). alkaline phosphatase.
`total hilirubin. crcatininc. albumin. and giobulins were
`determined monthly.
`Methotrexate was administered intravenously
`at weekly intervals. The initial dose was 10 mg. if this
`was wel.l
`tolerated,
`the dosage was increased to a
`maximum of 50 mg. Once a satisfactory response had
`been achieved. the frequency of rnethotrexatc admin-
`istration was reduced to a maintenance schedule of
`one injection every 2 to 4 weeks depending upon
`activity of disease. Before each injection the patients
`were checked for stomatitis. sore throat. skin rash.
`fever. shortness of breath. and gastrointestinal symp-
`toms. The rnethoiresate close was reduced or withheld
`if evidence of toxicity developed.
`RESULTS
`
`The findings in all patients while on weekly
`intravenous methotrexate therapy are shown in Table
`
`
`
`
`
`Page 1 of 3
`
`ANTARES Exhibit 1030
`
`

`
`'—— >3?-Eff-—
`Duration
`dose
`AM stiffness.
`of‘
`rnethon
`hours
`Pat-
`therapy.
`trexare,
`
`weeks
`mg
`Start
`ient
`—l
`13
`400
`4
`2
`9
`245
`s
`
`End
`
`D
`
`’
`
`3
`4
`
`5
`6
`7
`El
`9
`to
`
`i
`
`9
`7
`
`I6
`l I
`I0
`l0
`9
`to
`
`M
`
`ll
`I2
`13
`14
`
`
`I4
`9
`ill
`7
`
`360
`260
`
`735
`5 l0
`145
`3H0
`435
`715
`
`560
`385
`2].‘?
`235
`
`3
`2.5
`
`j
`
`l
`I2
`2
`2
`5
`I2
`
`l.5
`I2
`12
`I2
`
`l
`I
`
`I
`0
`D
`0.25
`5
`ii
`
`Cl
`12
`I2
`1
`
`13
`35
`
`51
`48
`40
`70
`st
`41
`
`63
`62
`63
`75
`
`27
`I7
`
`22
`2
`2]
`35
`. as
`3
`
`I5
`50
`ti?
`73
`
`20
`Bi}
`
`457
`82
`M4
`55
`at
`40
`
`95
`65
`till
`40
`
`1. Ten of 14 patients received at least 2 months ol’
`consecutive weekly injections without interruptions
`for toxicity. The data for patients 1-9 are presented in
`Figure 1. Patient ID is not included because he missed
`a scheduled injection.
`The remaining 4 patients required dose modifi-
`cation or withholding of the medication during the first
`2 months of therapy because of either oral ulcerations,
`gastrointestinal symptoms, or liver enzyme abnormali-
`ties. Mcthotrexate was withheld for
`1 week from
`
`decreased from 2 to 0 hours at 2 months; joint index
`was reduced from 50 to 5 at 2 months. Although he had
`failed to respond to cyclophosphamide therapy. this
`patient has continued receiving 40 mg of methotrexate
`every 2 weeks for over 18 months with excellent
`control of his disease. Patients I2 through I4 were
`withdrawn from the study because of toxicity and/or
`failure to improve. After 7 weeks of therapy, patient I4
`developed abdominal pain and diarrhea which re-
`curred with reinstitution of methotrexate.
`Nausea oeeun-ed in B of 14 patients, usually
`
`‘-—‘‘‘‘‘ --
`
`Joint index
`—-—~-
`— -—-J
`Start
`Start
`End
`59’ lo “mi?
`at
`45
`53
`
`.53;'!|
`-«W
`
` I.)AA-'*-;-:.l:—t,;-.-'.'.~.;_-A
`
`
`
`bind
`
`Start
`
`I9‘
`I3
`
`30
`50
`
`35
`38
`79
`33
`45
`42
`
`35
`43
`52
`25
`
`8
`6
`
`Fl
`B
`
`9
`I4
`23
`13
`I4
`IO
`
`12
`it
`3
`I3
`
`Enlil
`
`Toxicity
`I9 Nausea. vomiting
`I8 Mild nausea:
`liver
`30 Liver: oral
`ulcers
`50 Nausea; vomiting
`
`I9 None
`33 Liver: mild
`nausea
`50 Liver
`23 Mild nausea
`ll None
`42 Oral ulcers
`
`-
`
`35 Mild nausea:
`oral ulcers
`43 Nausea: vomiting
`52 Liver: nausea
`oral ulcers
`25 Abdominal pain;
`diarrhea
`
`Concurrent dfitg therapy
`Ibuprofen
`diphenylhydantoin
`Prednisene. enteric coated
`aspirin.
`diphenylhydantoin
`Aspirin. reserpine
`Fenoprofcn. prednisone.
`furosemide. conjugated
`estrogens
`Fenoprofen
`Prednisone.
`acetaminophen
`Fenuitprofen
`Choline salicylate
`Prednisone. sulihdac ‘
`Hydrosyehloroquine.
`ibuprofen.
`acetaminophen
`Naproxen, prednisone_
`furosemide, aspirin
`Ibuprofen. acetaminophen
`Aspirin. naprotten.
`prednisone. diazepatn
`Enteric coated aspirin.
`isosorbide dinitra
`
`within 24 hours of injection. Only once (patient I2)
`was it severe enough to cause discontinuation of
`treatment. Mild elevations in SGPT (less than two
`times normal) were noted in 4 patients. all receiving 50
`mg of methotrexate each week. This also contributed
`to discontinuation of therapy in patient l3.
`While receiving 25 mg of methotrexate weekly
`and aspirin. patient 2 developed a mild elevation in
`SGPT of 58 U/ml (normal sf. 45 Llfmll. After aspirin
`was discontinued and sulindac substituted. subsequent
`SGPT values were within normal range on continued
`weekly methotrexate therapy. This patient had previ-
`ously been unresponsive to an S-month course of
`azathioprine. Patient 3 had an SGPT increase to 54
`U/ml, but because she was doing well on therapy, the
`dose interval was increased to 2 weeks and her SGPT
`level
`returned to normal. Patient 6 developed an
`increase in SGPT to I64 Ufml. At
`this point
`the
`patient's arthritis was quiescent so methotrexate was
`discontinued. However. his arthritis flared while olil"
`methotrexate, and 10 months later the drug was re-
`sumed at a dose of 15 mg each week. His clinical
`response was excellent and immediate (within 3
`weeks). During the next 8 months of therapy. there
`was no recurrence of liver enzyme elevation. Ho
`
`
`
`Page 2 of 3
`
`

`
`[jam snrmizss
`fl moon JOINTS
`fisweurw JDINTS
`
` $stniMti~ri'Ariciu inns
`
` nessihrs]
`Durallenof‘in:Sliif
` 1
`
`ate therapy.
`
`2
`'
`"ma In Harm“
`Figure1. Changeinparameters ofdiseaseactivityduringl'l1€li'l<'l1rI'.')t-
`patients experienced leul-topenia, ihrombocytopenia.
`increased anemia. or changes in blood urea nitrogen or
`creatinine.
`
`t-'
`
`'
`
`;
`
`treatment of rheuma-
`have suggested year-
`
`tage of producing less toxic
`ity. The intravenous route
`ofadmini-atratlon allows the physician control over the
`amount of drug admlmsmmd and rcdqces concern
`
`al cytosiatic agent
`rheumatoid arthritis.
`that intravenous meth
`
`which has been resist-
`
`DISCUSSION
`
`_
`_
`ment within 2 months of
`therapy. and most did so by l
`month. All patients reported subjective improvement.
`Although this was not a doubie—b-Iind study.
`it
`is
`unlikely that improvement would have occurred spon-
`taneously in Ii'I]"i group of patients with very resistant
`
`disease.
`
`I. Ropes MW. Bennett GA. Cobb .
`-
`-
`-
`
`meihon-exate in rheumaiolri arthnlis JRru.-umainl75m-
`2. Will-tins RF. Watson MA. Paxon CS: Low dose pulse
`505. 1930
`3 Wm“? W5 Cfl‘3t""-“““~ LH 5
`
`Should be Parfmmed TWO reccnt 5md"35 wggcfit that
`oral methotrexate is also effective for
`rheumatoid
`arthritis (2.3) Currently it is not known which route of
`administration I"i
`
`hepatotoxicity in p*oUrld'sl“'.—-CtJmpdrl‘ttJn oi"c.iiH'erent dust.
`5 Dahl MGC Gregory MM. fschcuer PJ: Methntrex.-ite
`,..,5,m,,M 3,. Med J’
`1 5544,-;.5 197;
`
`
`
`Page 3 of 3