various types of dermatological manifestations have been reported due to hepatitis c virus ( hcv ) infection and antihcv therapy . some of them have been described during ifn - based therapies .
peg - ifn--2a / rbv combination is used as the international standard of treatment for hcv infection for a long time .
the combination therapy yields an adverse - event profile similar to standard interferon ( ifn ) therapy .
we reported a 43-year - old woman with dystrophic anagen effluvium ( dae ) , rheumatoid arthritis and hashimoto thyroiditis , which were developed under the combination therapy for chronic hcv infection .
although some cases of alopecia areata ( aa ) and telogen effluvium ( te ) were reported in literature , no case of dae associated with peg - inf--2a /rbv combination therapy was reported previously .
peg - ifn--2a / rbv combination therapy is used as the international standard of treatment for hcv infection for a long time .
the combination therapy yields an adverse - event profile similar to the standard interferon ( ifn ) therapy .
these adverse effects include hematological , cardiovascular , endocrinological , rheumatologic , neuropsychiatric , digestive and dermatological manifestations , which are sometimes so severe able to restrain the therapy ( 1 ) .
some adverse effects are also suspected to be an autoimmune character such as alopecia and thyroid disorders ( 1 ) .
hair disorders including reversible hair discoloration , hypertrichosis , straight hair , effluvium ( alopecia ) , diffuse thinning of the hair , hair curling , repigmentation of grizzled hair , trichomegaly of the eyelashes have been described during ifn therapy ( 1 , 2 ) .
a 43-year - old woman was admitted with chronic hcv infection approved by positive anti - hcv antibody and hcv - rna and two - fold increase in maximum transaminase levels for previous six months . according to family and personal history of the patient ,
anti - hcv treatment started in august 2012 with 180 mcg of peg - ifn -2a subcutaneously once a week in combination with rbv 1000 mg / daily for a 48-week course .
she had an early virological response ( evr ) , because hcv rna level was undetectable and the serum aminotransferase levels returned to normal in the second month of therapy . in the seventh month , the patient complained of insomnia and joint - pains on her wrists and ankles . in physical examination , there were mild swellings on the back of the both hands , wrists , metatarsophalangeal ( mtf ) and proximal inter phalangeal ( pif ) joints , and tenderness in the related joints .
ranges of motion were normal . in laboratory tests , anti - cyclic citrullinated peptide ( anti - ccp ) and
c reactive protein ( crp ) levels had positive results ( 59.76 u / ml and 8.54 mg / l ) , but rf had negative finding .
after the treatment with prednisolone 5 mg / day , naproxen 750 mg / day ( 15.04.2013 ) for one month , the symptoms regressed by 50% , and after ceased the inf and rbv treatment the symptoms were alleviated .
treatment with methotrexate 2,5 mg / week , folic acid 5 mg / week and prednisolone 5 mg / day was changed in 22.07.2013 . on the ninth month of therapy ,
v  shaped 16  14 cm on the vertex and occiput and ovoid and 33 cm on the right parieto - occipital region .
on alopecic areas , there were no vellus or miniaturized hairs and no exclamation mark hairs .
no scaling , erythema , scarring , atrophy or induration was seen ( figure 1 a , 1b ) .
fe , ferritine , vitamin e , zn , 25-hydroxy vitamin d3 , 1 - 25-dihydroxy vitamin d3 , igg subtypes , tsh , thyroid function tests , fsh , lh , progesterone , dhea - s , shbg , prolactin , testosterone , parathormone and complement levels ( c3 , c4 ) all had normal findings . rose - bengal , wright agglutination , rf , vdrl , antinuclear , anti - mitochondrial and anti - smooth - muscle antibodies , ena profile and antithyroglobulin antibodies had negative results , but antibodies against thyroid peroxidase ( tpo ) were elevated ( 263.3 iu / ml ) and e2 was low ( 11.8 pg / ml ) .
anti - ccp and crp were still at high levels ( 48.72 u / ml , 6.44 mg / l ) .
ultrasonography showed enlargement of thyroid gland , hypoechoic and heterogeneous appearance and two nodules on the right lobe .
she had been received no therapy for it and decided to get follow - ups . in the trichogram ,
the ratio of anagen , dystrophic anagen , telogen and catagen hairs were 32% , 50% , 14% and 4% , respectively .
histopathological examination of excisional scalp biopsy showed a normal number of catagen - follicles in the dermis .
there were no anagen - hairs on the alopecic patches and no inflammation in the periphery of the follicles ( figure 2 a , 2 b ) . based on clinicopathological and trichological findings
, dae was diagnosed . because of severe alopecic adverse effect and early virological response , the treatment was stopped after getting an informed consent from the patient at 42 week .
although inf therapy was discontinued , anti - ccp level increased and rf became positive ( 145 u / ml , 31.7iu / ml ) , elevated anti - tpo levels remained high ( 239.3 iu / ml ) and virological response persisted for seven months after the termination of therapy .
four months later , she had a sustained virological and biochemical response and hair regrowth was completed ( figure 1 f ) .
hcv rna level was undetectable during the whole treatment period and the patient had still sustained virological response 14 months after the cessation of therapy ( 21.07.2014 ) . at the time of writing the manuscript , she was still under follow - up and hcv rna level was controlled every six months .
her anti - ccp level and rf still had positive results ( > 300 u / ml , 29 iu / ml ) , therefore she was under control of our rheumatology department ( 21.07.2014 ) . a , b , ninth month of the combine therapy ; c , d , 3 weeks later ; e , 7 weeks later , and f , 4 months later cessation of the therapy .
a , b , histopathological examination of an excisional scalp biopsy showed a slight orthokeratosis in the epidermis and a normal number of catagen follicles in the dermis .
there was no anagen hair on the alopecic patches and no inflammation on the periphery of the catagen follicles .
alopecia is a frequent adverse effect of peg - ifn--2a / rbv combination therapy in 19% of reported patients ( 2 ) .
drug - induced hair loss can be te , dae , dystrophic - telogen effluvium ( dte ) or anagen effluvium ( ae ) according to the degree of toxicity in the hair molecules and the types of affected hair cycles ( 3 , 4 ) .
inf - therapy related alopecia types are te , localized alopecia ( la ) at the injection site , alopecia areata ( aa ) and alopecia universalis ( au ) ( 1 ) .
it usually occurs in some metabolic deficiencies or diseases such as iron , vitamin b12 , folic acid deficiencies , high fever , hypothyroidism and hyperthyroidism ( 3 , 5 ) in approximately 30% of patients treated with ifn ( 1 , 6 ) . hair pull test has negative results .
the percentage of telogen - hairs is abnormally high compared to the percentage of anagen - hairs .
the a / t ratio ( normally is 80 - 85/15 - 20 ) is low .
the percentage of dystrophic - hairs is normal and the percentage of catagens sometimes increases ( 3 , 5 ) .
au is a severe form of aa , which hair loss extends over the whole skin ( 1 ) .
there are published cases of aa during or after treatments with warfarin , cyclosporine , rifampicin , zotepine and zidovudine ( 6 ) .
hair pull test has positive results and exclamation mark hairs are shown at alopecic patches ( 3 , 5 ) .
ae is a prominent adverse effect of antineoplastic agents , which is caused by acute damage of rapidly dividing hair matrix cells .
the best - known drugs are antimetabolites , alkylating agents and mitotic inhibitors such as adriamycin , cyclophosphamide and etoposide ( 7 ) .
ae occurs after any insult to the hair follicle that impairs its mitotic or metabolic activity .
inhibition of cell division in the hair matrix can lead to a weakened segment of hair shaft susceptible to fracture .
the follicles should show no signs of inflammation , dystrophic changes of the inner sheath or traction .
these features allow distinction of ae from aa , androgenetic alopecia and traction alopecia . only actively growing anagen follicles are subject to these processes .
this form of alopecia is more common and severe in combination chemotherapy than monotherapy ( 8) . in ae and dae , the shedding course starts within days or weeks , which is much earlier than te .
the growth of anagen hairs usually ends prematurely due to the absence of mitoses within the matrix .
the distal part of the hair takes on a characteristic pointed , discoloured aspect with no matrix or shaft . the number of dystrophic anagen hairs is normally observed below 2% . in dae ,
the percentage of dystrophic hairs is higher compared to the percentage of normal anagen hairs due to acute alteration of the function of the matrix .
moreover , yun et al . reported that chemotherapy - induced ae could be diffuse or patterned .
they also found no significant differences in hair loss patterns according to age , associated symptoms or combination of chemotherapeutic agents ( 7 ) .
trueb stated that the chemotherapy - induced alopecia presents with different clinical patterns of hair loss . when an arrest of mitotic activity occurs , obviously numerous and interacting factors influence the shedding pattern ( 8) . because hair - shedding of our patient was a patterned alopecia and hair pull test had positive results , we firstly thought that the alopecia could be an aa .
however , due to absence of exclamation mark hairs and perifollicular inflammation and presence of a large number of dystrophic - anagen hairs , this diagnosis was ruled out .
te was excluded , because the clinical presentation of alopecic lesions was not similar to a te , also absence of previously mentioned significant metabolic causes , positivity of hair pull test , normal number of telogen hairs and increased dystrophic - anagen hairs .
ae can be distinguished from te by means of hair pull test ( 5 ) .
the pull test of our patient had positive result ; therefore , we secondly thought that the alopecia could be an ae .
although , hair loss usually occurs within days to weeks of drug administration in ae ( 9 ) , the effluvium of our patient began nine months after beginning inf therapy and this starting time of alopecia was not compatible with an usual ae .
moreover , because the a / t ratio of our patient was significantly decreased , and a normal anagen - to - telogen ratio is characteristic finding of ae ( 5 , 8) the diagnosis of ae was excluded , and lesions were diagnosed as dae .
the prevalence and severity of alopecia usually depend on the drug as well as individual predisposition ( 2 , 9 ) . upon the cessation of drug therapy ; follicles resume their normal activity within a few weeks .
mitotic inhibition apparently stops the reproduction of matrix cells , but it does not permanently destroy the hair follicles .
hair regrowth of our patient began within three weeks of completion of combined therapy and completed four months later .
because peg - ifn--2a / rbv therapy has primarily an immune - modulating effect , we thought that late starting time and comparatively faster regrowing time might be related to less toxic follicular effect of peg - ifn--2a / rbv therapy compared to very toxic chemotherapeutic agents such as antimetabolites , alkylating agents and mitotic inhibitors .
it has been stated that peg - ifn does not increase the incidence of alopecia compared to standard ifn therapy ( 36% vs. 32% ) .
because most of reported au cases were caused by pegylated ifn ( 1 , 10 ) , this alopecic effect might be related to the pegylated form of ifn .
the alopecic effects have been seen in approximately one - third of patients receiving peg - inf / rbv and particularly in cases receiving peg - inf--2b ( 10 ) .
the authors stated that some of them were reversible , while some cases were irreversible .
patients with reversible au received long - term treatments , while irreversible cases received very short - term therapies less than fifteen weeks ( 10 ) .
therefore , we think that the alopecic effects of therapy are unrelated to the cumulative doses or treatment duration .
occurrence of this type of alopecia is considered unpredictable ; however , some factors such as psychiatric , endocrine or metabolic disorders may increase the risk of developing this condition ( 1 , 10 ) . on the other hand , neuropsychiatric side effect
is one of the relative contraindications of inf therapy ( 10 ) ; therefore , from when the patient was diagnosed with psychiatric disorder , we continued therapy closely monitoring her .
the association between alopecia and thyroid disorders or thyroid autoantibodies had been documented previously , especially in aa in a ratio of 8 - 28% ( 1 ) .
our patient exhibited a positivity of anti - tpo antibody associated with initiation of alopecia and the positivity continued to persist after stopping the treatment and even after the patient completely recovered from the alopecia . on the other hand ,
ifn- treatment has been clearly linked to the exacerbation or occurrence of several types of autoantibodies or autoimmune diseases ( thyroid disorders , hematological disorders and insulin - dependent diabetes mellitus ) or diseases involving altered cell - mediated immune functions ( inflammatory dermatological diseases , nephritis , pneumonitis and colitis ) ( 1 ) .
moreover , it has been stated that peg - inf might induce immunological modulation ( shift from a t helper-2 immune - driven response to t helper-1 ) and might stimulate synthesis of th1-cytokines such as il-1 , il-2 and inf - gamma and increased cytotoxic t cell activity ( 1 , 3 ) . furthermore , in all reported cases , alopecic lesions developed after the viral clearance ( 10 ) .
similarly , in our patient , ra and ht developed after the viral clearance . therefore , we think that accompanying disorders might have been caused by peg - inf/ induced - immunological modulation .
additionally , except for our patient , there is no example of peg - ifn  2a/ rbv induced dae and enough information to describe its clinical or histopathological features , and even about its pathogenesis in literature .
however , in the light of previously mentioned immunological effects of peg - ifn--2a / rbv therapy , we think that our patient s dae might have been caused by insult of increased cytotoxic t cells to anagen hair follicles .
peg - inf a-2b /rbv induced alopecic effect is reversible , but regrowth of hair can take one year after completion of treatment ( 1 ) .
we think and speculate that the regrowing time can be related to affected hair - cycle , severity of damaging effect of the therapy within the follicular matrix , the subtypes of peg - ifn and even individual predisposition , similarly to the shedding time .
additionally , in the light of clinicopathological and trichogram findings of our patient , we think that dae cases can be incorrectly assessed as te , dte , androgenetic alopecia or aa according to their clinical appearances .
therefore , the diagnosis of dae must be kept in mind when facing with any alopecic condition , especially in patients receiving antiviral therapy . however ,
further investigations are needed to clarify this issue . in conclusion , alopecia is one of the adverse effects of peg - ifn treatment , independently subtypes . to the best of our knowledge ,
our case was the first reported one in the literature for peg - inf -2a/ rbv induced dae .
 introduction : various types of dermatological manifestations have been reported due to hepatitis c virus ( hcv ) infection and antihcv therapy . some of them have been described during ifn - based therapies . 
 peg - ifn--2a / rbv combination is used as the international standard of treatment for hcv infection for a long time . 
 the combination therapy yields an adverse - event profile similar to standard interferon ( ifn ) therapy . 
 some of these adverse effects are rheumatologic , neuropsychiatric and dermatological manifestations including alopecia.case presentation : we reported a 43-year - old woman with dystrophic anagen effluvium ( dae ) , rheumatoid arthritis and hashimoto thyroiditis , which were developed under the combination therapy for chronic hcv infection.conclusions:although some cases of alopecia areata ( aa ) and telogen effluvium ( te ) were reported in literature , no case of dae associated with peg - inf--2a /rbv combination therapy was reported previously . 
Introduction:
Case Presentation:
Conclusions:
1. Introduction
2. Case Presentation
3. Discussion