Patent Application: US-68620396-A

Abstract:
disclosed is a therapeutic regime for treating patients with rheumatoid arthritis supplemental growth hormone is periodically administered to raise insulin - like growth factor 1 levels , and the igf - 1 levels are monitored until they reach optimal levels and ra symptoms subside .

Description:
all patients and controls in this study were female . fibromyalgia (&# 34 ; fm &# 34 ;) was diagnosed according to the diagnostic guidelines of the american college of rheumatology ( acr )( 15 ). fm was the only significant rheumatic diagnosis in 500 patients ( i . e . they had primary fm ). they had no other endocrine disorders apart from treated hypothyroidism in several patients ; all fm patients had a normal thyroid stimulating hormone ( tsh ) level within one year of the study . all the healthy controls ( blood donors ) were reportedly in good health and not taking any medications ( reported previously ( 12 )). ninety - six patients with other rheumatic diseases were also studied ; some of these had concomitant fm . a subset of 90 fm patients were studied in depth with the following tests : complete drug history , maximum oxygen uptake ( vo 2 max ) using a modified balke procedure ( 16 ), an assessment of fm severity using the fm impact questionnaire ( fiq )( 17 ) and quality of life questionnaire ( qol )( 18 ), dsm - iiir psychiatric diagnoses using a computerized diagnostic interview schedule ( 19 ) and beck depression inventory ( 20 ). tender points were examined using the protocol described by wolfe et al . ( 15 ). igf - 1 levels were measured on serum samples that had been acid / ethanol extracted to remove igf - 1 binding proteins prior to radio - immunoassay as previously described ( 12 ). gh levels were measured on serum samples using a sensitive chemiluminescent immunoassay ( nichols institute , san juan capistrano , calif .). this assay utilizes a mouse monoclonal antibody to human gh immobilized on polystyrene beads and a goat polyclonal antibody to human gh labeled with an acridinium ester . intra - assay variability is 4 - 6 % and inter - assay variability is 7 - 10 %, at gh concentrations between 0 . 05 and 20 ng / ml . the sensitivity of the assay is 0 . 02 ng / ml . a subgroup of 50 fm patients with igf - 1 values & lt ; 160 ng / ml were given either gh injections ( nutropin , genentech , calif .) or placebo injections ( saline ) for nine months , according to the following protocol . the initial dose of gh was 0 . 0125 mg / kg per day ; this dose was adjusted monthly ( based on monthly igf - 1 levels ) to try to achieve an igf - 1 level of 250 ng / ml . another sub - group of fm patients underwent a standard protocol for gh stimulation testing using sequential clonidine ( 0 . 25 mg po ) and l . dopa ( 500 mg po )-- blood samples were taken for plasma gh every thirty minutes for two hours following each drug administration . responses were considered normal if any one gh value was & gt ; 5 ng / ml ( 21 , 22 ). analysis of variance ( anova ), students t test or a mann - whitney rank sum test were used for between group comparisons of igf - 1 levels and other variables , as appropriate . a best subsets regression analysis was performed on all variables that might influence the igf - 1 : these were age , years of disease , vo 2 max , weight , total fiq score , pain visual analogue score from fiq , qol score , beck depression score , number of tender points and total myalgic score . igf - 1 levels and ages were available on 500 female fm patients . by way of comparison , igf - 1 levels were available on 152 non - fm control patients , comprising 56 red cross blood donors and 96 patients with various rheumatic diseases -- see table 1 . the mean igf - 1 level in 500 patients with primary fm was 138 ± 56 ng / ml versus 215 ± 186 ng / ml in all controls ( p = 0 . 00000000001 ). anova for all categories , omitting age as a factor , suggested that blood donors , patients with rheumatoid arthritis and patients with polymyalgia rheumatica ( pmr ) were not significantly different from the fm patients . using the mann - whitney rank sum test , the fm patients had significantly lower igf - 1 levels than the female blood donors ( p = 0 . 0001 ). patients with pmr were 18 years older than the fm patents , thus a lower igf - 1 level is expected as igf - 1 levels fall progressively with age the results were plotted as an igf - 1 versus age -- shown as the regression plot with the 99 % confidence limits of the mean ( fig1 ). it is apparent that most of the igf - 1 levels in fm patients fall below the mean for the controls . eighty - five percent of the fm patients had igf - 1 levels below the 50th percentile of the control population and 56 % fell below the 20th percentile . however there was also a considerable overlap of the two populations , as shown in the gaussian distribution curves -- see inset graph to fig1 . patients with a diagnosis of myofascial pain syndrome , a condition differing from fm in that tender points are found only in a regional distribution , had normal igf - 1 levels ( 249 ± 70 , age 42 . 6 ± 12 ). thirty - seven patients with rheumatoid arthritis had mean igf - 1 level of 157 ± 81 -- on anova this is not significantly different from the fm patients . a subset of 10 ra patients with secondary fm had an igf - 1 level of 88 . 3 ± 34 , this compares to an igf - 1 level of 186 ± 79 in 27 ra patients without fm ( p & lt ; 0 . 001 ). in general the patients with ra plus fm had the lowest igf - 1 levels . however , four patients with rheumatoid arthritis , without concomitant fm , also had low igf - 1 levels ( 111 , 93 , 40 and 81 ng / ml ). these patients had severe long - standing disease . two patients with sle and two patients with polymyalgia rheumatica had concomitant fm ; all four patients had low igf - 1 levels when compared to disease patients without fm . thirty - three fm patients had repeat igf - 1 levels at least once over a period of 12 to 24 months ( mean 14 . 3 months ). the mean value of the initial igf - 1 was 161 ng / ml , on the second testing it had fallen to 118 ng / ml -- an adjusted change of 34 ng / ml per year . this compared to a rate change for the controls of only 2 . 68 ng / ml per year . individual changes are shown in fig2 ; it is seen that only three patients had an increased igf - 1 level . those patients with initially low levels did not change very much over the 12 - 24 months , whereas most patients with normal or elevated levels tended to fall abruptly . these results suggest that the low igf - 1 levels occur during the course of fm and probably represent a secondary phenomenon . it is conceivable that the low igf - 1 levels seen in a subset of fm patients could be due to associations with medications , low levels of aerobic fitness , obesity , level of pain , duration of disease , etc . there was no significant difference in igf - 1 levels in a group of patients taking tricyclics ( users 136 ± 36 . 2 , non - users 127 ± 29 . 6 ) or non - steroidals ( users : 132 ± 40 . 1 , non - users 138 ± 32 . 7 ). patients with major depression had a mean igf - 1 level of 142 ± 45 and patients without depression had a mean level of 139 ± 64 ( p = 0 . 86 ) . eleven continuous variables were analyzed for their contribution to igf - 1 levels by a best subsets linear regression analysis . the best model was a combination of age and vo 2 max and the beck depression score , but this provided only a weak predictive value with an adjusted r 2 of 0 . 0703 ( see table 2 ). the 10 other models contributed even less to predicting an igf - 1 value . hence it does not appear that low igf - 1 levels in fm patients can be attributed to these factors . clonidine and l . dopa stimulation testing were used to assess pituitary secretion of gh . the results of such testing are well standardized ; a maximum stimulated gh response of & lt ; 10 ng / ml is considered suggestive of gh deficiency and a value of & lt ; 5 ng / ml is found in the majority of patients with well - documented gh deficiency . in a series of 25 fm patents so tested , only six reached the 5 ng / ml threshold on one of the tests ( either clonidine or l . dopa ), and in four of these the threshold of 5 ng / ml was only just achieved ( fig3 ) the two fm patents who achieved a maximal gh level of & gt ; 10 ng / ml were probably not gh deficient as their igf - 1 levels were 150 and 190 ng / ml , respectively . there was a positive correlation between the igf - 1 levels in these 25 fm patients and their maximal stimulated pulse of gh ( for clonidine : r = 0 . 6 -- p = 0 . 001 and for l . dopa : r = 0 . 7 -- p = 0 . 0001 ). igf - 1 levels were measured every month for nine months in 50 fm patients having injections of either gh ( nutropin / genentech ) or a placebo . note that these fm patients were selected on the basis of having a low igf - 1 level as part of a gh efficacy study ( to be reported later ). it is seen ( fig . 4 ) that patients taking a placebo had very little variation in their igf - 1 levels over nine months . in contrast , patients taking gh had a sustained 2 - 3 fold rise in igf - 1 levels . the results in the placebo group imply that low igf - 1 levels in fm patents are unlikely to be a result of day - to - day , week - to - week , or even month - to - month fluctuations . the increase in patients having gh injections implies that the low levels found in fm do not result from an igf - 1 receptor defect or some other malfunction of the liver &# 39 ; s ability to secrete igf - 1 in response to gh . there are several conclusions that can be inferred from these results : 1 ) a subset of fm patients have low igf - 1 levels . 2 ) while patients with other rheumatic conditions such as ra , systemic lupus erythemotosus ( sle ) pmr and sjogren &# 39 ; s syndrome usually have normal igf - 1 levels , as do patients with myofascial pain syndromes , some exhibit suboptimal igf - 1 levels . many rheumatic disease patients with concomitant fm had low igf - 1 levels . 3 ) low levels of igf - 1 are a result of impaired gh secretion -- since exogenous gh administration increases igf - 1 levels . 4 ) the cause of this gh deficiency cannot be explained by medications or clinical features . 5 ) the defective production of gh is probably secondary to the development of fm -- since initially normal igf - 1 levels tended to fall disproportionately over 1 to 2 years . 6 ) impaired gh secretion on stimulation testing implicates a functional defect at the level of the hypothalamic - pituitary axis . there is no general consensus as to the diagnosis of gh deficiency in adults ( 23 , 24 ). an inappropriately low age - adjusted igf - 1 and an absence of stimulated gh secretion have been considered valid tests by some authors ( 21 , 25 , 26 ). the probable gh deficiency that has been observed in a subset of fm patients has not been resolved by the current study ; but it has provided some clarification and ideas for future research . low igf - 1 levels were not related to medications , pain , duration of illness , depression , obesity , or poor aerobic fitness . furthermore , it is evident that low igf - 1 levels are not an artifact of sampling , as patients that have been tested monthly over nine months continued to have persistently low levels . some patients had an abrupt decline in igf - 1 levels over a period of 12 - 24 months ; this was seen mainly in patients who initially had normal levels of igf - 1 . this suggests that gh deficiency is probably associated with having fm , i . e ., a secondary consequence rather than a primary event . the observation that igf - 1 levels were normalized by daily gh injections proves that the end organ response to gh is intact . the original impetus for measuring igf - 1 in fm patents was based on the hypothesis that the dysfunctional sleep pattern of fm patients would disrupt the circadian secretion of gh ( 13 ); the absence of a gh response to stimulation testing suggests that this hypothesis requires modification . over the past few years a disturbance of the hypothalamic - pituitary - adrenal axis has emerged as being of possible relevance to the etiology of some fibromyalgia symptoms . the principle findings have been : ( 1 ) blunting of the plasma circadian cortisol rhythm with a relative elevation of the usual evening nadir , ( 2 ) absent dexamthasone suppression in up to 30 % of fm patients ( 27 ), ( 3 ) reduced 24 hour urinary excretion of free cortisol ( 27 , 28 ), ( 4 ) accentuated acth response to corticotrophin releasing hormone ( crh ) with an impaired adrenal responsiveness to acth ( 29 ). furthermore , three studies have now reported changes in the gh / igf - 1 axis ( 13 , 14 ). however , the study of griep et al . reported an enhanced gh response to provocation testing with insulin induced hypoglycemia ( 14 ). this is in contradistinction to the findings reported here of impaired pituitary release of gh with l . dopa and clonidine . the reasons for this difference are not readily apparert . both clonidine and l . dopa induce gh release by inhibiting hypothalamic somatostatin secretion via stimulation of α2 adrenergic and dopamine receptors respectively it may be relevant that insulin induced hypoglycemia has a more profound stimulatory effect on the pituitary secretion of several hormones . the hypoglycemic stimulation of gh secretion in fm suggests that defective secretion is not due to a diminished pituitary reserve of gh , but rather an alteration in the stimulatory / inhibitory ratio of critical hypothalamic hormones . the pulsatile secretion of gh is primarily due to the tonic - inhibitory action of two hypothalamic peptides ( 30 )-- namely gh releasing hormone ( ghrh ) and somatotropin release inhibiting hormone ( srih )-- also called somatostatin . the control of gh secretion is quite complex and is influenced by several neurotransmitters as well as some hormones . for instance , α2 nor - adrenaline , adrenaline , dopamine , serotonin , and gaba all stimulate gh secretion . gh release is inhibited in hyperglycemic states and elevated free fatty acids , as well as feedback inhibition by gh itself and igf - 1 ( 31 ) there is impaired gh release in states of hypothyroidism and excessive cortisol secretion . it is possible that alterations in one or more of these hypothalamic and peripheral factors play a role in the gh deficiency observed in fm patients . there is a well - described decline of igf - 1 levels with aging that is related to a progressive decline in the pulsatile secretion in gh . cross - sectional studies of adults indicate that the level of igf - 1 in serum or plasma progressively declines with age in both women and men . rudman et al . reported a progressive decrease in un - extracted serum igf - 1 levels ; 11 % of individuals in the fourth decade and 55 % in the ninth decade had evidence of impaired gh production ( 32 ). there is evidence , from animal studies , that the age - related reduction in gh secretion is mainly due to an increase in somatostatin tone ; but it is not clear whether this mechanism is important in humans ( 33 ). we speculate that the gh deficiency in fm patients is caused by a premature aging response of the hypothalamic - pituitary gh axis -- secondary to having fm . the fm population described here is 33 years older , in terms of their igf - 1 levels , than their chronological age . in the framingham heart study , 533 elderly women ( age 79 ± 5 ) had a mean igf - 1 level of 139 ± 56 ng / ml ( 23 ); this compares to the mean igf - 1 level of 138 ± 56 ng / ml reported here in female fm patients aged 46 . 9 ± 11 . the consequences of adult gh deficiency have been the subject of several recent reviews ( 25 , 34 - 38 ). the following features of gh deficiency may be relevant to fm symptomatology : ( i ) gh deficient patients have both a reduced mass of skeletal muscle and impaired myocardial contractility ( resulting in a decreased stroke volume ), the effect of these changes is to reduce the capacity for strenuous exercise ; ( ii ) gh has an anti - natriuretic action ; a reduced plasma volume in gh deficient patients may be related to symptoms of cold intolerance and low blood pressure , problems also seen in fm patients ; ( iii ) many patents with gh deficiency have decreased psychological well being in terms of low energy , psychological liability , low - grade depression , suboptimal libido , and increased social isolation . many of these adverse consequences of gh deficiency improve with gh replacement therapy ( 39 - 46 ). thus , gh deficiency in fm patents could contribute to symptoms such as reduced exercise tolerance , impaired vitality , cold intolerance , aversion to over - stimulation , dysthymia , and poor healing of muscle microtrauma -- a hypothesized cause of muscle pain in fm ( 12 , 47 ). the validity of these notions must await the results of gh replacement studies it is evident that a subset of fm patients and rheumatic disease patients constitute a previously unrecognized population of patients with adult onset gh deficiency . table 1______________________________________summary table of igf - i levels in all groups diagnosis number age igf - 1 ( ng / m______________________________________fibromyalgia 500 46 . 9 ± 11 138 ± 56 all controls 152 45 . 1 ± 15 215 ± 86 * blood donors 56 45 . 6 ± 13 175 ± 60 myofascial pain 26 42 . 6 ± 12 249 ± 70 * rheumatoid arthritis 37 47 . 4 ± 17 157 ± 81 systemic lupus 15 42 . 5 ± 17 255 ± 70 * primary sjogren &# 39 ; s 8 44 . 4 ± 10 243 ± 74 * polymyalgia rheumatica 7 64 . 0 ± 12 161 ± 93 scleroderma 3 54 . 0 ± 22 291 ± 79 * ______________________________________ * significantly higher igf1 levels compared to fibromyalgia patients on anova ( p & lt ; 0 . 05 ). table 2______________________________________best subset analysis on 90 fm patients using r . squared as best criterionvariable combination adj . r . sq . ______________________________________a . age b 0 . 023 b . vo . sub . 2 max a , g 0 . 052 c . weight a , b , g 0 . 071 * d . beck depress a , b , g , i 0 . 069 e . total fiq a , b , c , g , i 0 . 064 f . vas pain a , b , c , g , i , k 0 . 068 g . fiq depression a , b , c , g , i , k 0 . 069 h . qol score a , b , c , e , g , h , i , k 0 . 063 i . duration a , b , c , e , g , h , i , j , k 0 . 053 j . no . tender pts . a , b , c , e , f , g , h , i , j , k 0 . 041 k . myalgic score a , b , c , d , e , f , g , h , i , j , k 0 . 029______________________________________ * best fit adj . resqr . = 0 . 071 i . e ., age , vo . sub . 2 max and fiq depr . onl account for 7 % of the effect on igf1 levels . in table 1 , igf - 1 levels and ages are shown for 500 female fm patients . by way of comparison , igf - 1 levels are shown on 152 non - fm control patients , comprising 56 red cross blood donors and 96 patients with various rheumatic diseases . nutropin ® ( somatotropin for injection ) would be supplied by genentech in vials containing sterilized lyophilized powder . each vial would contain five mg of somatotropin . excipients would be mannitol , glycerin , usp for isotonicity , and phosphate for ph balance . the vial contents would be reconstituted only with bacteriostatic water for injection , usp ( benzyl alcohol preserved ). nutropin ® ( somatotropin for injection ) would be given to the patient in an initial dose of 0 . 0125 mg / kg / day by subcutaneous injection for the first month . this relatively low initial dose is designed to minimize the development of side effects . the dose is increased at monthly increments to achieve an igf - 1 level in the range of 275 - 350 ng / ml . if side effects such as edema , arthralgia or increased bp occur , the dose would be reduced to 0 . 0125 mg / kg / day until the problem subsides . for most patients , symptomatic features of a growth hormone deficiency would be expected to subside as the igf - 1 levels reach normal levels for that patient &# 39 ; 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