INTRODUCTION:

The most common aetiology of hyperthyroidism, Graves’ disease (GD) is a syndrome first recognized in the 19^th century. It is caused by activation of Thyrotropin-receptor antibodies which induce thyroid hormone overproduction. It comprises of an enlarged and overactive thyroid gland, an accelerated heart rate and visual abnormalities.^1,2

There are three different modes of medical treatment for Grave’s hyperthyroidism: Antithyroid drug (ATD) therapy, radioactive iodine (RAI) therapy and surgical intervention.³Antithyroid drugs are primarily aimed at obstructing the thyroid peroxidase enzyme mediated iodination of tyrosine residues in the thyroglobulin- a crucial step in the synthesis of thyroxine (T4) and triiodothyronine (T3), thereby inhibiting the synthesis of new thyroid hormones. However they do not remove thyroid hormones which are already in the thyroid gland or in the blood stream. In addition, these drugs have significant immunosuppressive and antioxidant actions that help in inducing remission of the disease. The immunosuppressive effects include reduction in serum levels of Thyroid-stimulating hormone receptor antibodies (TRAb), induction of intrathyroidal lymphocyte apoptosis, increasing the count of CD8+ suppressor T cells and decrease in the count of CD4+ helper T cells - facilitating Grave’s disease remission.^4,5

Thionamide drugs are the cornerstone of hyperthyroidism treatment and include Methimazole (MMI), Carbimazole (CMI) and the Thiourea derivative- Propylthiouracil. They are highly efficacious, but some patients may experience serious side effects which contraindicates their further use. In such situations these patients may require Non-thionamide ATD’s like iodine containing compounds for their further management.^2,5Methimazole is recommended over Propylthiouracil for most of the Grave’s disease patients except for pregnant women in the first trimester as per the 2016 American Thyroid Association guidelines due to its longer half-life, longer duration of action, fewer major side effects and faster improvement in T4 and T3 serum concentrations.^4,5,6The suggested starting dose of Methimazole is usually a single dose of 15mg to 30 mg/day while that of Propylthiouracil is 300mg/day in three divided doses. Nonetheless, the condition of many patients can be contained with relatively lower doses of Methimazole like 5mg to 10mg.⁴

ATD treatment is usually associated with the risk of side effects. These include minor side effects like cutaneous reactions, arthralgias and gastrointestinal upset symptoms which are not life threatening and do not require discontinuation of drug. Switching to another Antithyroid drug, dose reduction and use of antihistamines also prove to be useful. Major side effects are potentially life threatening or even lethal like agranulocytosis, vasculitis, hypoglycemia, cholestasis and aplastic anemia which might require immediate discontinuation of Antithyroid drug and hospitalization. ^4.5Arthralgias are a relatively common side effect of ATD treatment. In a review of 500 patients with thyrotoxicosis treated with ATD by Shabtai et al, Polyarthralgias (1.6%) was the second most commonly noticed complication after skin reactions (1.8%).⁷Even though classified as a “minor” reaction the development of arthralgias should elicit drug withdrawal, since this symptom maybe a precursor of a severe transient migratory polyarthritis also called “the antithyroid arthritis syndrome”.⁴

Antithyroid Arthritis Syndrome (AAS) is an uncommon but serious and potentially fatal complication of antithyroid drugs.^8,9It occurs predominantly in females, of any age group, and at any time during the therapy with Propylthiouracil and Methimazole. ^[10]In majority of cases of AAS, the first symptom is arthralgia. It can occur at any time and other symptoms may include myalgia, skin rash and high grade fever which may quickly progress to full-blown polyarthritis involving small, medium and large joints.^8,10

CASE HISTORY:

A 32 year old female presented to outpatient clinic with complaints of palpitations, tremors, easy fatigability and 8kg weight loss of 1 month duration. Her workup showed low levels (0.01mIU/L) of Thyroid-stimulating hormone (TSH), reduced Free-T4 (FT4) of 4.05ng/dL and elevated Free-T3 (FT3) values >20pmol/L. The assay for Anti-Thyroid Peroxidase (Anti-TPO) antibody showed Anti-TPO positivity with an elevated value of 155.5 IU/ml. She was diagnosed with Graves’ Disease based on the clinical and laboratory findings. She was started on Methimazole 10 mg three times a day.

Twenty days into the treatment with Methimazole she was hospitalized at our tertiary care hospital following complaints of multiple joint pains, fever, restriction of movement and difficulty in ambulation of 2 day duration. She had severe pain over multiple joints starting in the right knee, followed by left shoulder, left knee, right hip and right shoulder. These were associated with myalgias in both upper extremities with inability to lift the arms above the shoulders. Three days before presentation, she also had complaints of redness, itching and swelling of both palms and soles that improved with antihistamines. Musculoskeletal examination revealed warm and tender bilateral knees, shoulder joints, left hip joint along with restricted mobility suggestive of inflammatory arthritis. Rest of the examination revealed fine tremors in both hands and mild cervical lymphadenopathy. Methimazole was withheld and patient was started on the anti-inflammatory agent Etoricoxib 60 mg twice daily after which the symptoms resolved. Her labs (Table 1) showed elevated levels for C-Reactive Protein (CRP), Erythrocyte Sedimentation Rate (ESR) and FT4 and lower levels of Neutrophil, Vitamin-D and TSH.

Table 1: Laboratory findings during hospitalization

Lab parameter	Value
Lab parameter	Day 1	Day 3	Day 5
White Blood Cell (WBC)	5.44 K/uL	3.01 K/uL	8.25 K/uL
Neutrophil	51.8 %	2 %	33.7 %
Absolute Neutrophil Count (ANC)	2818 /mm³	60.2 /mm³	2780.25 /mm³
Blood Urea Nitrogen (BUN)	11.0 mg/dL	13.8 mg/dL	-
CRP	19.0 mg/L	72.71 mg/L	-
ESR	33.0 mm/hr	-	-
Alkaline Phosphatase (ALP)	104 IU/L	-	-
Vitamin-D	13.98 ng/ml	-	-
TSH	< 0.005 mIU/L	-	-
FT4	2.77 ng/dL	2.74 ng/dL	-
FT3	6.11 pg/ml	3.75 pg/ml	-
Antinuclear Antibody (ANA)	Weakly +ve	-	-
Perinuclear-Anti Neutrophil Cytoplasmic Antibodies (P-ANCA)	-ve	-	-
Cytoplasmic-Anti Neutrophil Cytoplasmic Antibodies (C-ANCA)	-ve	-	-

Table 2. Adverse Reactions of ATD Therapy^4,7,10,13,14

Severity	Adverse effects	Frequency
Rheumatological
Major	ANCA-positive vasculitis	Rare
	Polyarthritis (Antithyroid arthritis syndrome)	1-2%
	Lupus erythematosus-like syndrome	Rare
	Polyarteritis nodosum	Rare
	Polymyositis	Rare
	Joint Effusions	Rare
	Serum Sickness-like syndrome	Rare
Minor	Arthralgia	1-5%
Gastrointestinal
Major	Immunoallergic Hepatitis	0.1-0.2%
	Cholestasis	Rare
	Pancreatitis	Very rare
Minor	Gastric distress and Nausea	1-5%
	Abnormal sense of taste and smell	Rare
	Sialadenitis	Very rare
Hematological
Major	Agranulocytosis	0.1-0.5%
Major	Thrombocytopenia & Aplastic anemia	Very rare
Cutaneous
Minor	Skin reactions	4-6%
Endocrine
Major	Hypoglycemia (Insulin-autoimmune syndrome or Hirata disease)	Rare

Two days into the admission she was re-challenged with Methimazole at a reduced dose of 10 mg twice daily. After receiving just 2 doses, she had recurrence of inflammatory symptoms and new onset of fever. Repeat labs showed increase in CRP to 72.7mg/L from admission value of 19.0mg/L and decrease in WBC count to 3.01K/uL with agranulocytosis (indicated by the reduction in neutrophil from 51.8% on admission to 2% and an ANC value of 2818 /mm³ on admission to 60 /mm³). Urinalysis findings showed normal results.

Autoimmune workup showed negative Rheumatoid Factor (RF), Anti-dsDNA Antibody, P-ANCA and C-ANCA except for a weakly positive ANA.

Methimazole was promptly withdrawn following which her symptoms considerably improved. Her therapy was changed to a combination of Lithium, Cholestyramine and Propranolol in preparation for Radioactive Iodine treatment which she underwent after 5 days of discharge.

DISCUSSION:

Methimazole is part of the thionamide group of antithyroid drugs commonly used as a first-line agent in the management of hyperthyroidism due to Graves’ disease and toxic nodular goiter.¹¹These group of drugs are actively concentrated against a concentration gradient by the thyroid gland. They mainly inhibit and decrease synthesis of thyroid hormones by interfering in the iodination of tyrosine residues in thyroglobulin. This process is mediated by the thyroid peroxidase enzyme and is an essential step in the synthesis of thyroxine and triiodothyronine. They usually control hyperthyroidism within 4-12 weeks in 90% of patients.^4,12

ATD therapy is also associated with a number of side effects as depicted in Table 2.

Multiple rheumatic complications secondary to antithyroid drugs have been reported as described in Table 2.

AAS caused by thionamides, propylthiouracil was described in 1946 by Williams et al.¹⁵Antithyroid drug-induced arthritis, one of the major adverse effects induced by thionamide therapy can be part of the AAS or ANCA-Associated Vasculitis (AAV). Unfortunately the course can be unpredictable and fatal leading to renal and respiratory failure. Most cases present initially with arthralgia.¹⁶But arthritis in distinction from arthralgias are associated with synovitis, elevated inflammatory markers such as leukocytosis, elevated CRP and ESR.⁸ Development of arthralgias, even though is regarded as one of the minor side effects of ATD therapy should be distinguished from arthritis. Discontinuation of therapy should be considered early as it may lead to a severe transient migratory polyarthritis.¹⁶ Clinicians when suspecting antithyroid drug-induced arthritis should consider autoimmune workup with complement levels, gamma globulins, RF, ANA, Anti-Ds DNA and ANCAs in addition to routine laboratory investigations. However, routine laboratory investigations for ANCA is not indicated in all cases of arthralgias as patients with Graves’ disease show ANCA positivity before onset of ATD therapy. In our patient, the laboratory analysis for ANCA were negative.^7,10,16

An adverse reaction to any drug therapy is based on temporal association, clinical features, final organ impairment, dramatic improvement of symptoms following the withdrawal of the drug (dechallenge) or reappearance of the reaction on repeated exposure (rechallenge).^17,18In our case, the rechallenge of methimazole at a lower dose on re-hospitalization led to fever, agranulocytosis and rheumatic symptoms. Later, in view of these symptoms methimazole was withdrawn which led to a significant improvement in the symptoms.

Patient also had a score of 9 on Naranjo Adverse Drug Reaction (ADR) probability scale, used for assessing adverse drug reactions suggesting high probability of relationship between Methimazole exposure and development of AAS.^23,24

The rheumatic complications may manifest similarly and need to be distinguished from each other. It is also important to rule out autoimmune diseases which can mimic antithyroid arthritis syndrome.⁹In our case we considered the possibility of reactive arthritis, other autoimmune diseases like lupus, AAV and antithyroid drug induced ANCA-Associated Vasculitis. All immunological workup was negative except for ANA. The absence of antibodies and systemic symptoms helps clinicians to distinguish AAS from AAV or lupus erythematosus-like syndrome.⁹We therefore concluded that patient had AAS based on the absence of auto-antibodies especially ANCA and most of the vasculitis symptoms such as nephritis, skin lesions and systemic symptoms.

While there is scant knowledge regarding the exact pathogenesis of AAS, one theory explains that the thiol group in antithyroid drugs bind with macromolecules to form a hapten complex which then induces antibody production or modify proteins involved in the immune response. ^[10]The detection of circulating ANA in cases of AAS could possibly be explained by this theory. This has been reported previously in medical literature and was also observed in our patient. Even so, ANA specificity is low as the prevalence in healthy persons is 10% and an increased prevalence of positive ANA exists in patients with Graves’ disease.¹⁶

Autoimmune diseases like AAV syndrome was ruled out. Antithyroid drug induced AAV and autoimmune forms of collagen vascular diseases like lupus, rheumatoid arthritis, scleroderma and temporal arteritis were also ruled out. Based on the normal urinalysis findings and lack of evidence of any infection, we excluded reactive arthritis.

We compared our case with seven other cases of AAS reported in literature (Table 3).

Table 3: Comparison of our case with other case reports of patients with AAS

Article	Our study	Ploegstra et al.¹⁶	Nihei H et al. ^[19]		Modi et al. ¹⁰	Khaledi et al. ⁹	Takaya et al. ²⁰	Mancuso et al. ⁸
Year of study	2020	2011	2013		2017	2018	2016	2019
Number of cases	1	1	2		1	1	1	1
Age	32	15	15	11	50	31	38	37
Sex (M/F)	F	F	F	F	F	F	F	F
Dose	30mg, re-challenged with 20mg	30mg increased to 90mg	30mg	20mg increased to 50mg 28 days after initiation	60mg	10mg	45mg	30mg
Duration of therapy	1 month	21 days	24 days	40 days	35 days	-	-	44 days
Onset of ADR	20 days	-	-	-	5 days	20 days	3 weeks	38 days
FT3 (2.3-4.1 pg/ml)	6.11 pg/ml	-	32.5 pg/ml	13.74 pg/ml	6.4 pg/ml	650 ng/dL*	> 30 pg/ml	-
FT4 (0.9-2.3 ng/dL)	2.77 ng/dL	4.23 ng/dL	4.29 ng/dL	4.10 ng/dL	3.7 ng/dL	22 mcg/dL**	9.44 ng/dL	-
TSH (0.5-3 mIU/L)	< 0.005 mIU/L	0.005 mIU/L	< 0.05 mIU/L	< 0.03 mIU/L	< 0.01 mIU/L	< 0.005 mIU/L	0.0002 mIU/L	-
ESR (0-29 mm/hr)	33.0 mm/hr	-	-	64 mm/hr	67 mm/hr	45 mm/hr	62 mm/hr	Markedly elevated
CRP (3-10 mg/L)	72.7 mg/L	12.0 mg/L	34.1 mg/L	24.1 mg/L	201.6 mg/L	-	23.3 mg/L	Markedly elevated
P-ANCA	-ve	-ve	-ve	-	-ve	-ve	- ve	-ve
C-ANCA	-ve	-ve	-ve	-	+ve	-ve	- ve	-ve
ANA	Weakly +ve	+ve	-	+ve	-ve	-ve	-ve	-ve
Anti-dsDNA Antibody	-ve	-	-	-ve	-ve	-ve	-ve	-ve
Myeloperoxidase (MPO) Antibody	-	-	-	-ve	-ve	-	-ve	-
WBC (4-11 K/uL)	3.01 K/uL	8.6 K/uL	8.6 K/uL	6.8 K/uL	-	10.3 K/uL	7.2 K/uL	Normal

* Total T3 (Normal Range: 100-200 ng/dL)

** Total T4 (Normal Range: 5-12 mcg/dL)

It was suggested that adverse effects of methimazole are dose dependant meaning- the higher the dose is, more frequent the adverse effects will be.^4,21,22We analyzed each case in Table 3. While cases such as the one reported by Plogestra et al suggested that developing arthritis maybe related to higher doses of methimazole based on the report of a 15 year old girl who had undergone treatment with methimazole 90 mg daily and developed arthritis. Another study by Khaledi et al reported a case of of AAS which occurred at a lower dose of methimazole at 10 mg/day.^9,16These reports indicate that AAS induced by methimazole is non-dose dependant and may occur following any dose of methimazole unlike other adverse effects induced by antithyroid drugs which are dose dependant.

In our case the patient developed AAS following administration of methimazole at a dose of 30mg/day. When re-challenged at a lower dose she developed symptoms of AAS with the same intensity and frequency as the higher dose.

It was also noted that all the cases of AAS discussed in Table 3 were of females indicating a possibility that females may be predisposed to developing it following treatment with the drug. It could also be due to the fact that Graves’ disease is more prevalent among females, who are therefore exposed more to methimazole therapy than males, leading to increased reporting of AAS from females.

CONCLUSION:

Antithyroid arthritis syndrome is a rare complication of antithyroid medications comprising a constellation of symptoms such as myalgia, arthralgia and arthritis along with fever and rash of varying severity and non-specific laboratory findings, making its diagnosis clinically challenging. Following diagnosis, immediate discontinuation of the offending drug is needed for resolution of symptoms as it can rapidly progress to a life-threatening condition. In our case, rechallenge with the medication led to AAS symptoms and severe agranulocytosis. So continuation without proper recognition or rechallenge with even smaller doses can prove to be dangerous. Preventive steps such as increased clinical awareness, patient information handout regarding the medication at the time of starting the medication, counseling by a pharmacist and prompt withdrawal of the antithyroid drug at the onset of symptoms are very important. In conclusion, our case report underlines the importance of differential diagnosis and recognizing of AAS as an adverse effect of antithyroid agents and the need for prompt withdrawal of the medication.

ABBREVIATIONS:

GD: Graves disease

ATD: Antithyroid Drug Therapy

RAI: Radioactive Iodine

T4: Thyroxine

T3: Triiodothyronine

TRAb: Thyroid-stimulating hormone receptor antibodies

MMI: Methimazole

CMI: Carbimazole

AAS: Antithyroid Arthritis Syndrome

TSH: Thyroid-stimulating hormone

FT4: Free-Thyroxine

FT3 : Free-Triiodothyronine

Anti-TPO: Anti-Thyroid Peroxidase

CRP: C-Reactive Protein

ESR: Erythrocyte Sedimentation Rate

WBC: White Blood Cell

ANC: Absolute Neutrophil Count

BUN: Blood Urea Nitrogen

ALP: Alkaline Phosphatase

ANA: Antinuclear Antibody

P-ANCA: Perinuclear-Anti Neutrophil Cytoplasmic Antibodies

C-ANCA: Cytoplasmic-Anti Neutrophil Cytoplasmic Antibodies

RF: Rheumatoid Factor

AAV: ANCA-Associated Vasculitis

ADR: Adverse Drug Reaction

MPO: Myeloperoxidase

CONFLICT OF INTEREST:

The authors declare that there is no conflict of interest.

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Received on 13.08.2020 Modified on 02.10.2020

Research J. Pharm. and Tech 2021; 14(10):5483-5488.

DOI: 10.52711/0974-360X.2021.00957