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Medical Professionals: Articles:
Case Reports:
MULTIPLE AUTOIMMUNE DISEASES
Nattaporn Tesavibul, M.D.
ABSTRACT
Purpose and Methods: Multiple autoimmune disorders occur with increased frequency in
patients with a previous history of another autoimmune disease. We present the patient who
initially presented with ocular cicatricial pemphigoid OU, history of hypothyroidism and
chronic erosive ulcers in the mouth. Continued follow up, careful examination and repeated
biopsies of the mouth ulcers reveal lichen planus of the mouth. Conclusion: This case
highlights the need for awareness of the possibility of multiple autoimmune phenomena
which also indicates the need for continued surveillance for the development of new
autoimmune diseases in predisposed patients.
CLINICAL CASE
This is a case of 71 year old white female who was referred by her primary
ophthalmologist for evaluation and management of probable ocular cicatricial pemphigoid
(OCP) in both eyes. She had had intermittent episodes of blepharitis and conjunctivitis OU
for 6 years which were relieved with Tobrex. Recurrent sores of lips, tongue and under the
nose were noted. She also complained of mild discomfort on swallowing. An esophagoscopy
and esophageal biopsy had been performed in 1993. The results were non diagnostic.
Her past medical history was significant for epilepsy since early childhood and
hypothyroidism diagnosed a few years prior to presentation.
Family history was notable for a sister with multiple sclerosis.
On review of systems, the patient noted occasional pain in her right knee.
At the time of presentation, her medications were:
Dilantin 200 mg per day
Synthroid 0.125 mg
B12 by monthly injection
Tobradex drops bid OU
Examination on first presentation revealed best corrected visual acuity of 20/50 in the
right eye and 20/40 in the left. On slit lamp examination, there was slight meibomian
gland dysfunction and blepharitis bilaterally. There were occluded lacrimal puncta, mild
conjunctival injection, fornix foreshortening and symblepharon bilaterally. The
anterior chambers were deep and quiet . The irides and pupils were unremarkable. Both
lenses showed mild nuclear sclerosis. The vitreous bodies were clear . Fundoscopic exam
was unremarkable in both eyes. Intraocular pressures were normal bilaterally.
These are photographs of the patient at the first presentation.
It should be noted that an antineutrophil cytoplasmic autoantibodies (ANCA) assay done in
April of 1993, which was a year before her first visit, was positive for perinuclear
staining (pANCA) and a positive ELISA confirmed the presence of antibodies to
myeloperoxidase (MPO).
In light of these findings, the impression at this presentation was cicatrizing
conjunctivitis OU
Conjunctival biopsy from the right eye was performed and blood was sent for complete
blood count (CBC), antinuclear antibodies (ANA), glucose 6 phosphate dehydrogenase (G6PD),
liver function test (LFT) and Lyme titers.
The patient returned 2 weeks later (11/08/94) , feeling subjectively the same. The
examination was the same except for slightly increased conjunctival injection.
The lab results were significant for ANA (both rat liver and hep 2 substrate were
positive at 1:640 homogenous pattern). Antibody to double stranded DNA was moderately
positive. ANCA was negative. Slightly elevated Alkaline phosphatase was noted.
Conjunctival biopsy demonstrated C4 deposition at the basement membrane zone (BMZ).
The diagnosis was ocular cicatricial pemphigoid (OCP) stage 3 and Dapsone 25 mg twice
daily was started.
On the next follow up (12/22/94), the patient was subjectively better. Her exam showed
1+ conjunctival injection. Dapsone was increased to 100 mg per day.
Three weeks later (1/12/95), conjunctival injection improved but still active. Her
hematocrit (Hct) slightly dropped and reticulocyte count rose to 2%. At this point, the
decision was made to plan on stopping Dapsone and starting MTX but this change was
withheld pending consultation with her internist.
At the next follow up 6 wks later (3/02/95), the patient reported increased seizure
activity. The exam showed slight conjunctival injection. CBC and reticulocyte count were
normal. Dapsone was maintained and MTX was not initiated.
Two months later (5/09/95), the patient showed evidence of chronic blepharitis
bilaterally and was instructed on lid care. The cicatricial pemphigoid was inactive. She
was on Prednisone taper for polyarthritis.
Three months later (8/08/95), her blepharitis was still active. Doxycycline 100 mg
daily was prescribed.
Two weeks later (8/22/95), the patient had arthritis in her knees, right MCP joints and
right wrist. She had fluid aspiration from her left knee and local steroids injection by a
rheumatologist. Persistent significant oral ulcers were noted. Medications were the same.
A month later (9/18/95), oral ulcers still persisted with burning sensation. Imuran was
started at 100 mg daily.
These are pictures of the mouth lesions:
Repeated lab results were significant for:
pANCA
ELISA was positive for anti MPO antibodies.
Raji cell assay was positive
repeated ANA titer was negative and the complements were normal.
Nine weeks later (11/27/95), the patient continued to have oral ulcers which were
biopsied by a dermatologist. The result could not distinguish pemphigoid or lichen planus.
A month later (12/28/95), her rheumatologist had discontinued Imuran as it didn't
appear effective against the oral lesions.
Oral Prednisone was increased to 50 mg daily.
Four weeks later (1/25/96), the patient's oral ulcer worsened and repeat oral biopsy
revealed lichen planus. Her eye condition remained stable.
2% CsA solution swish was prescribed and Prednisone was tapered and discontinued.
Five month later ( 6/19/96), a third oral biopsy confirmed the diagnosis of lichen
planus. Eyes remained stable and Dapsone was discontinued.
Two month later (8/14/96), the oral lesions were less bothersome. The eyes were quiet.
The patient was offered Plaquenil but refused.
The lab results were negative for ANA, ANCA and rheumatoid factor (RF).
These pictures showed the improvement of the mouth lesions:
These are the patient's eyes.
DISCUSSION
This case reveals to us the scenario of multiple autoimmune diseases. The history of
recurrent cicatrizing conjunctivitis along with strongly positive compliment deposition at
the level of conjunctival BMZ make a definite diagnosis of OCP.
However, this patient also presents with the problem of recurrent painful lesions at
the tongue and buccal mucosa. The review of systems doesn't show any dermatologic problem
other than her oral lesions. Oral mucosal biopsy was repeated until the final result
revealed lichen planus. Past medical history revealed hypothyroidism and recurrent
polyarthritis plus +ANA and + pANCA. However, other clinical findings and lab results are
not enough to make a definite diagnosis of SLE, rheumatoid arthritis or other form of ANCA
associated vasculitis.
OCP and lichen planus will be described briefly, just to give you the overview of these
two autoimmune diseases. The association of multiple immune diseases will be discussed
later.
OCULAR CICATRICIAL PEMPHIGOID
INTRODUCTION
Ocular cicatricial pemphigoid is a systemic autoimmune disease with both ocular and
nonocular manifestations. It produces scarring of the affected skin, conjunctiva and other
mucous membrane. Conjunctival involvement may occur as early as 10 years before other
mucosal or skin lesion develop or the disease can be limited to the conjunctiva. This
disease can be fatal when stricture from scarring in the esophagus or trachea developed.
EPIDEMIOLOGY
The estimated prevalence of this disease is 1 in 15,000 (Bittelheim) to 1 in 20,000
(Hardy and Lamb). However, the earliest stage of the disease is usually underrecognized.
This disease has a slight female preponderance with a female to male ratio of 2:1. It has
a worldwide distribution and effects all races. CP is said to be a disease of the elderly
with the average age of 65 but this figure are probably under reported because the cases
are usually not in their earliest stages. However, this disease can begin as early as the
third decade of life as well.
PATHOGENESIS
OCP is an autoimmune disease and is believed to result from a type 2 hypersensitivity
with a genetic predisposition and environmental factors to trigger the onset of the
disease. The susceptibility gene is at or closely linked to the HLA-DQw7 gene. Individuals
carrying this gene have approximately 9.6 relative risk of developing OCP. The
environmental trigger that stimulates the individual to develop OCP may be microbial or
chemical.
Drug induced OCP can be associated with
Practolol Pilocarpine Timolol Echothiophate iodide Epinephrine
HISTOLOGY AND IMMUNOPATHOLOGY
Pemphigoid is characterized by a separation of basal epithelium from underlying
basement membrane, forming a subepithelial bleb that tend to form scar.
The histopathologic finding of the conjunctiva in OCP patients shows: submucosal
scarring, chronic inflammation, perivasculitis, squamous metaplasia of the epithelium with
loss of goblet cells.
Immunohistochemical staining shows predominantly CD4 helper T lymphocytes in the
inflammatory cell population that develops in the substantia propria.
Immunoglobulins and complement components are present in the epithelial basement
membrane zone of the conjunctiva which was used as a definitive diagnosis for OCP. This
can be detected by either Immunofluorescence or Immunoperoxidase method which is much more
sensitive. Circulating autoantibodies to the basement membrane are found in all of these
patients when radioimmunoassay techniques are employed. Circulating antibodies to
conjunctival epithelium have been detected. The idiopathic OCP antigen is definitely
different from those of pemphigoid and drug induced OCP. This antigen is a 205-kd protein
in the lamina lucida of the BMZ.
This is the picture of positive immunofluorescence staining showing a linear deposition of
Ig on the conjunctival BMZ.
The immunopathologic abnormalities are not restricted to the eye. Systemic immunologic
derangements are present as well, including
slightly abnormal proportions of circulating helper T cells
evidence of systemic immunoreactivity with elevated levels of sIL-2R
elevated levels of soluble CD 8 glycoprotein
elevated levels of TNF in the serum.
Circulating autoantibodies against pancreas, thyroid and adrenal gland have been
detected (Yarian). ANA can be found in 67% of OCP patients.
MANIFESTATION
OCULAR:
Ocular manifestation in CP usually begins as a unilateral conjunctivitis which is
chronic in nature. It's usually a bilateral disease but markedly asymmetrical and is not
uncommon to find the disease just only in one eye. Four stages of OCP have been described
as follow:
Stage 1 is characterized by chronic conjunctivitis with mild conjunctival or corneal
epitheliopathy and subepithelial fibrosis of the conjunctiva. The fibrosis is best seen at
the tarsal conjunctiva as fine white striae.
Stage 2 is characterized by cicatrizing process with fornix foreshortening.
Stage 3 is when symblepharon occurred.
Stage 4 which is the end stage, consists of a dry eye with keratinization of the cornea
and ankyloblepharon. This stage is untreatable.
With the appearance of the secondary trichiasis and tear film abnormalities, the
blinding consequences are corneal epitheliopathy, secondary infection and corneal
neovascularization.
EXTRAOCULAR:
The nonocular manifestations include skin, scalp, oral mucosa, nasal mucosa, pharynx,
larynx, trachea, esophagus, vagina, urethra and anus. Scarring of the skin and mucosa is
usual. The desquamative gingivitis presents in nearly all patients. Skin lesions can
manifest as either a recurrent vesicobullous lesions or an erythematous plaques which
evolve into a pruritic blisters.
DIAGNOSIS
Differential diagnosis of cicatrizing conjunctivitis
cicatricial pemphigoid intraepithelial epithelioma
atopic keratoconjunctivitis Stevens-Johnson syndrome
Ocular rosacea Lyell's syndrome
Scleroderma Sarcoidosis
Corynebacterium diphtheriae Trachoma
conjunctivitis Adenovirus conjunctivitis
Chemical burn Trauma
Squamous cell carcinoma Sebaceous cell carcinoma
Epidermolysis bullosa acquisita Sjogren syndrome
Dermatitis herpetiformis Erythoderma ichthyosiform congenita
Porphyria cutanea tarda Pemphigus vulgaris
Many diseases from this differential diagnosis can be excluded on the basis of history
and physical examination. The definitive diagnosis of OCP requires the demonstration of
immunoglobulin or complement component deposition at the epithelial BMZ of the biopsied
conjunctiva.
TREATMENT
OCP is a systemic autoimmune disease and should be treated systemically in
collaboration with the chemotherapist or rheumatologist. Current chemotherapeutic agents
are as shown in the slide. Detail of the treatment will not be discussed here.
Therapy for ocular cicatricial pemphigoid
Agent Initial Dose/ Maximal Dose
Dapsone 25 mg bid /150 mg/day
Methotrexate 7.5 mg once weekly/ 15 mg once weekly
Azathioprine 2 mg/kg/day/ 3 mg/kg/day
Cyclophosphamide 2 mg/kg/day/ 3 mg/kg/day
Prednisone(adjunctive) 1 mg/kg/day /1 mg/kg/day
LICHEN PLANUS
The next disease that will be discussed is lichen planus which is usually a unique
cutaneous entity consisting of an eruption of papules with distinct color and
configuration.
EPIDEMIOLOGY
The incidence of LP appears to vary slightly among geographic area. The disease was
found in 0.44 percent of the dermatologic patients in United State and 0.14 percent in
Palestine. No racial or definite sexual predilection has been noted.
Most of the affected are between the age of 30 and 60. Although no age group is exempt,
the disease is uncommon in the extreme age groups.
ETIOLOGY AND PATHOGENESIS
The cause of lichen planus remains unknown. Chemical agents as listed in the slide can
induce LP in certain persons. A cell-mediated immune reaction may be involved in the
pathogenesis of this disease.
Agents reported to induce cutaneous disorders that resemble typical lichen
planus
Antiarthritic Gold
Antibiotic Streptomycin Tetracycline
Antiluetic Arsenic Mercury Iodides
Antimalarial Chloroquin Quinidine Quinine
Antitubercular Para-aminosalicylic acid
Ataraxis Phenothiazines derivative
Chelator Penicillamine
Color-film developer p-Phenylenediamine salts
2-amino-5-diethylamino-toluene Cl (CD2)
4-amino-n-diethyl-aniline sulfate (TTS)
Antimony trioxide
Diuretic Thiazides
Respiratory stimulant Amiphenazole
MANIFESTATIONS
The physical signs of lichen planus are usually found on the skin and mucous membranes.
There are a wide array of variants but the classic skin lesion is a tiny, violaceous,
flat-topped, polygonal. glistening papule with or without central umbilication. Lesions
are usually symmetrical and on the flexor surfaces of the forearms, neck, thighs, chin and
lower back. Koebner phenomenon can occur. Lichen planus may exhibit numerous variations as
shown here:
Variations of pattern in lichen planus
1. Difference in configuration
Annular
Linear
2. Difference in site
Mucous membrane
Genitalia
Nails
Scalp
3. Difference in morphology
Hypertrophic Actinicus
Follicular Erythematous
Vesicular and bullous Exfoliative
Erosive and ulcerative
Atrophic
Malignant degeneration
only mucous membrane involvement will be described. The area of highest incidence is
the buccal mucosa; lesions are also found on the tongue, lips , gum, palate, pharynx and
throughout the gastrointestinal tract. The vaginal mucosa, bladder, larynx, and
conjunctiva also may be affected. Mucous membrane lesions occur in about two-thirds of all
cases and in15 to 25 percent of cases they may be the only manifestation. There is often a
reticulated or lacelike network of linear, white or gray striae. Lesions are asymptomatic
or may have some burning sensation. However, when chronic erosions are present, the
lesions may become extremely painful as seen in our patient.
HISTOLOGY AND IMMUNOPATHOLOGY
Histology shows degeneration of the basal cell layer and mononuclear cell mostly helper
T cells infiltrate in the upper dermis and dermo-epidermal junction. Hyperkeratosis is
prominent. Eosinophilic bodies called colloid bodies are often found in the lower part of
the rete ridges and at the basement membrane zone. This finding may be an example of
apoptosis.
There are characteristic immunofluorescent findings that are suggestive but not
diagnostic of LP. The subepidermal and intraepidermal colloidal bodies contain IgM and /or
IgA, IgG, C3, and fibrin. Fibrin deposition occurred in a broad band pattern along the BMZ
and at the dermo-epidermal junction of the skin and buccal mucosa. Granular basement
membrane deposits of IgM and IgG have been reported. The conjunctiva showed multilamellar
fragmented BMZ.
DIAGNOSIS
Typical lesion is sufficient to make a clinical diagnosis. Histopathology and
immunofluorescent findings will confirm the diagnosis or establish the diagnosis in an
atypical case. In our case the differential diagnosis for oral lesions are as followed:
Differential diagnosis for mucous membrane lesion
Mucous membrane pemphigoid
Lichen planus
Erythema multiform
Leukoplakia
Candidiasis
Lupus erythematosus
Secondary syphilis
In this case, the presence of chronic , atypical oral ulceration demands repeated
biopsies to make a definitive diagnosis which was very helpful in giving the treatment.
TREATMENT
Numerous regimens have been used: heavy metals (arsenic, mercury, bismuth), antibiotics
(penicillin, broad-spectrum drugs), vaccines, antimalarials, antituberculous, calcium
gluconate, physical therapy (x-ray, UV) and vitamins. There are no well-controlled studies
conforming the effectiveness of the various regimens. The variable course and self-limited
duration of the disease make it difficult to adequately evaluate therapy.
Corticosteroids are useful in the treatment of lichen planus. Topical application is
usually effective for typical skin lesions. Systemic administration of a 2 to 6 week
course of oral steroids will relief the symptoms in most cases. Oral lesion may be treated
with topical steroid in Orabase or intralesional injection in the resistant case.
Tretinoin in Orabase, 2% CsA swish and betamethasone in aerosol applied topically has been
found to be effective.
MULTIPLE AUTOIMMUNE DISORDERS
INTRODUCTION
Disorders of autoimmune pathogenesis occur with increased frequency in patients with
previous history of another autoimmune disease. The tendency to develop another disease
occurs in about 25% of these patients. Overlapping sometimes occurs but commonly it is the
time that allow one syndrome to take on the features of another.
DEFINITION
Several efforts have been made to group and label these coexisting autoimmune
disorders. The term Overlap Syndromes has been used to describe the group of patients
exhibit features of more than one established autoimmune disorders. Several combinations
of definite connective tissue diseases have been reported.
Undifferentiated connective tissue disease (UCTS) is used for patients who have
features strongly suggestive of connective tissue disease but not definitely diagnostic of
any one disorder.
Mixed connective tissue disease (MCTD) was initially described by Sharp as a new
syndrome with features of systemic lupus erythematosus (SLE), systemic sclerosis,
polymyositis and rheumatoid arthritis and high titers of circulating antibody to nuclear
ribonucleoprotein (RNP) antigen.
It should be noted that the classification of overlap, UCTS and MCTD is based on
descriptive phenomena. This classification usually has only a loose statistical
relationship with prognosis and outcome and is frequently confusing when applied to the
individual patient.
Multiple autoimmune syndromes (MAS) is the combination of at least three autoimmune
diseases in the same patient. This new classification based on 91 reported cases of morbid
associations concerns the grouping of autoimmune conditions in the same patient.
Classification of MAS
Type 1 Myasthenia gravis
Thymoma
Polymyositis
Giant cell myocarditis
Type 2 Sjðgren's syndrome
Rheumatoid arthritis
Primary biliary cirrhosis
Scleroderma
Autoimmune thyroid disease
Type 3 Autoimmune thyroid disease
Myasthenia gravis and /or thymoma
Sjðgren's syndrome
Pernicious anemia
Idiopathic thrombocytopenic purpura
Addison's disease
Diabetes mellitus
Vitiligo
Autoimmune hemolytic anemia
Lupus erythematosus
Dermatitis herpetiformis
Criteria: at least three conditions must be present in the same patient
Conditions found in various combinations in MAS
Type 1 Pemphigus
Autoimmune thyroid disease
Type 2 Chronic active hepatitis
Lupus erythematosus
Pemphigus
Bullous pemphigoid
Autoimmune hemolytic anemia
Idiopathic thrombocytopenic purpura
Alopecia areata
Addison's disease
Type 3 Acquired primary hypogonadism
Hypophysitis
Rheumatoid arthritis
Primary biliary cirrhosis
Relapsing polychondritis
Multiple sclerosis
Chronic active hepatitis
Ulcerative colitis
Scleroderma
This system of classification is of particular interest. Firstly, it should make
research and analysis of these morbid associations easier. Secondly, it offers the
possibility of foreseeing and detecting a new condition liable to appear in a patient who
has had two previous autoimmune diseases. Finally, it provides a new basis of analysis for
the pathophysiological mechanisms of autoimmunity.
PATHOGENESIS
The pathogenesis of multiple autoimmune disorders is still unknown. Environmental
triggers in a genetically susceptible individual are believed to cause disorders of immune
regulation. As supported by the animal experiment which shows multiple autoantibodies
following CMV infection. Multiple autoantibodies can be found in one patient and some of
the specific mono or polyclonal autoantibodies may be multiple organs reactive.
CLINICAL MANIFESTATION
Clinical manifestations depend on the combination of the autoimmune disorders but are
usually nonspecific.
DIAGNOSIS
When establishing the diagnosis of multiple autoimmune diseases, the diagnosis of each
component disease follows its own independent criteria.
CONCLUSION
The presence of one autoimmune disease should alert the physician to watch for the
second immunologic disorder. Finding inconsistent with one's original diagnosis merit the
search for a second autoimmune condition. The case presented here highlights the need for
awareness of the possibility of multiple autoimmune phenomena. The occurrence of multiple
autoimmune phenomena in this case indicates the need for continued surveillance for the
development of new autoimmune disease in predisposed patients.
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