|CASE BASED REVIEW
|Ahead of print publication
Gout in premenopausal women and in pregnancy – A case-based review
Lubna Khurshid, Suraj Chaudhari, Sanjiv Kapoor, Anand Narayan Malaviya
Department of Rheumatology, ISIC Superspeciality Hospital, New Delhi, India
ISIC Superspeciality Hospital, Vasant Kunj, New Delhi - 110 070
Source of Support: None, Conflict of Interest: None
Gout is uncommon in reproductive age group. In this report, two women with gout are presented, one of whom became pregnant while under treatment. The causes of gout in premenopausal age and challenges of managing gout flares in pregnancy are discussed.
Keywords: Female, gout, premenopausal, uric acid
| Introduction|| |
Gout is a common chronic crystal arthritis predominantly seen in males >40 years of age. It is much less common in women, especially in premenopausal age. A study from the United Kingdom reported an incidence of gout to be 1/10,000 in a woman younger than 20 years of age. Moreover, since gout is uncommon in premenopausal age group, the occurrence of pregnancy in such patients may pose a challenge in management.
| Case Reports|| |
A 39-year-old woman presented with acute inflammatory arthritis of the right knee. In the past 3 years, she had noted episodes of pain and swelling in the right as well as the left knee usually lasting for 1–2 weeks. She had consulted several physicians and orthopedicians and was treated with short courses of nonsteroidal anti-inflammatory drugs (NSAIDs) and Vitamin D supplementation. On her first visit to our hospital, her right knee was swollen and warm and the left knee was also slightly swollen. The rest of the clinical examination was unremarkable. There was no history of photosensitivity, rash, Raynaud's phenomenon, dryness of eyes or mouth, or parotid swelling. Thyroid was palpable and was of normal size. The investigation reports at the first visit to this hospital were as follows: hemoglobin – 9.8 gm/dL, white blood cell count (WBC) – 15,000/dL, differential count neutrophils – 61%, lymphocytes – 25%, platelets – 385,000/dL, erythrocyte sedimentation rate (ESR) – 109 mm 1st h, serum creatinine – 0.8 mg/dL, and alanine transaminase (ALT) and aspartate aminotransferase (AST) – 15 and 17 units/ml, respectively. Rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs) were negative.
She has a significant history of having episodic paraparesis 20 years ago when she was 19 years of age. She had four such episodes of paraparesis. Initially, she was diagnosed as myositis and given glucocorticoids (GCs) with no relief. Later, she was diagnosed as hypokalemic paralysis by a neurologist and treated with potassium supplements and has been free of symptoms thereafter. Because of this history, a remote possibility of Sjögren's syndrome was considered; however, the antinuclear antibodies (ANAs) by indirect immunofluorescence were negative. Since the patient did not have any symptoms/signs of Sjögren's syndrome and the RF, ANA tests were negative, and she was not investigated any further. Her thyroid function test was normal. She was diagnosed as inflammatory arthritis and prescribed methotrexate (MTX) 15 mg once a week, weekly methylprednisolone of 12 mg dose on the day of MTX, and hydroxychloroquine 300 mg daily. However, she had only minor relief in symptoms.
After 4 weeks, she had a flare of right knee arthritis that was treated with one intra-articular injection of depot triamcinolone injection of 40 mg. The aspirated synovial fluid examination showed the WBC count of 15,000/dL and negatively birefringent MSU crystals under polarised light microscopy [Figure 1]. After a few days, when the joint flare had subsided, the serum uric acid (SUA) level was found to be 9.8 mg/dL, and treatment was changed to allopurinol 100 mg/day and escalated to 200 mg/day in 2 weeks, colchicine 0.5mg twice a day for 1 month, and methylprednisolone 8 mg/day for 1 week. The patient started to improve steadily with no flares over the next 6 months. However, after 6 months of treatment, she became pregnant. Allopurinol was discontinued maintaining her only on colchicine. Within 2 weeks of discontinuing allopurinol, she had a gouty attack in the right knee that was controlled with intra-articular injection of depot triamcinolone injection. She was maintained on colchicine 0.5 mg twice a day and intermittent methylprednisolone between 8 and 16 mg/day and intra-articular injection of depot triamcinolone injection during acute attacks of gout. She had 3 gouty attacks during pregnancy. The pregnancy went successfully, and she delivered a healthy baby by a lower (uterine) segment cesarean section. She is presently not on any treatment and has not had a recent joint flare. Her latest uric acid levels were 9 mg/dL.
|Figure 1: Monosodium urate crystals under polarised light microscopy from synovial fluid aspirated from the knee joint of patient 1|
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The second patient was a 54-year-old postmenopausal woman who presented with 8 days of acute inflammatory arthritis of the hand joints, knees, ankles, right elbow, and low-grade fever for 2 days. She has been having intermittent, asymmetrical arthritis involving peripheral large and small joints for 20 years. She was being managed elsewhere as seronegative rheumatoid arthritis (RA) with GC and NSAIDs with transient relief. On examination, she had cushingoid facies, swollen and tender knees, and ankles. The right elbow had subcutaneous nodules, and there were deformities in several hand joints [Figure 2], with marked quadriceps wasting. Hand radiograph showed damage and deformities that resembled RA [Figure 3] and [Figure 4]. The examination of other systems was unremarkable. Investigations showed ESR – 117 mm 1st h, Hb – 8.9 gm/dL, WBC – 7490/dL, and platelets – 152,000/dL. Serum creatinine was 1.02 mg/dL, ALT/AST – 19/34 units/ml, and SUA – 12.4 mg/dL, and RF and ACPAs were negative. Negatively birefringent MSU crystals were demonstrated in the synovial fluid from the right knee examined under polarized light microscopy.
|Figure 2: Deformed elbow with tophus in the olecranon bursa of patient 2|
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Considering her age at first symptom onset, female gender, involvement of hand joints, deformities of hand joints, and the radiographic findings, the diagnosis of seronegative RA was obvious. She was being treated somewhere by nonrheumatologists with disease-modifying antirheumatic drugs (DMARDs), but details of the drugs she had received were not available. In the recent past, these drugs were discontinued due to anemia that was probably drug induced. At presentation to us, her clinical presentation was that of intermittent episodes of joint flares, mainly in either knee, with quick relief with glucocorticoid tablets taken for a few days that she took without any medical supervision. Because of moderately severe anemia, standard DMARDs could not be initiated, and the patient did not consent for bone marrow examination. Under these circumstances, she was treated just with intra-articular depot triamcinolone injection to which she had good symptomatic relief. To us, this intermittent nature of joint episodes suggested the possibility that the joint disease was predominantly gouty in nature with a strong possibility of overlap with RA. Based on these considerations, she was prescribed colchicine 5 mg and febuxostat 40 mg daily aiming at the SUA level of ~6 mg/dL. At the time of writing this report (end March 2020), she had completed 9 months of follow-up, and during this time, she has had only one flare in a knee joint that was treated with a single intra-articular depot triamcinolone.
Test for the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) and 5-phosphoribosyl-1-pyrophosphate (PRPP) could not be done in both cases because of the nonavailability of the tests in any of the local clinical pathology laboratory.
| Discussion|| |
Gout is generally not considered as a differential diagnosis of inflammatory polyarthritis in premenopausal women. Whenever we see inflammatory arthritis in women, the most common considerations are RA, systemic lupus erythematosus, scleroderma, Sjögren's syndrome, etc., All these conditions are distinctly more common in women. Gout is uncommon in premenopausal women, the reason being the protective effect of estrogen against gout through its effect on increasing the efficiency of the renal clearance of uric acid, thereby leading to an inherently low SUA levels in premenopausal women as compared to men and postmenopausal women.,,,
Whenever a premenopausal woman is diagnosed with gout, secondary causes including underlying genetic disorders of purine metabolism as well as acquired causes of hyperuricemia should be investigated [Table 1]. A positive family history of gout is much more often reported in premenopausal than postmenopausal gout. Glycogen storage diseases are a group of inherited disorders characterized by impaired glycogen utilization in the liver or muscle where hyperuricemia and gout are common presentations. Certain glycogen storage disorders may cause gout in young people. There is a case report of gout with infertility where a patient had associated von Gierke disease. Another case report describes a 27-year-old female with tophaceous gout associated with Gitelman syndrome. One more case of pregnancy in a young woman with gout has been described due to pseudo-Bartter syndrome secondary to excessive use of laxatives, who had presented with hypokalemia, metabolic alkalosis, hyperuricemia, and gouty arthritis with tophi. Familial deficiencies of the enzyme HPRT and 5-PRPP are well-studied causes of gout in pediatric age persons as well as in premenopausal women., Our first patient had a history of hypokalemic paralysis. A literature search in PubMed for gout and hypokalemic paralysis did not yield any result. Genetic studies on our first patient would have been of interest, but a facility for the same was not available. Another therapeutic challenge that faced us in the management of the first patient was the pregnancy. Literature search on gout and pregnancy revealed two papers that have reviewed literature on gout and pregnancy., The more recent one by Horta-Baas et al. in 2017 has reported 23 pregnancies in 12 women with gout. Among these 23 pregnancies, 16 (69.5%) resulted in live births, 5 (21.7%) aborted, one patient (4.3%) required medical termination of pregnancy, and one (4.3%) report did not provide the pregnancy outcome. Two neonates died within a few hours of birth. This systematic review did not find any maternal deaths nor congenital malformations. The common pregnancy-related complications included renal injury, preeclampsia, postpartum uremia, and anemia. Thus, the present report adds 1 more patient with pregnancy in gout making of total of 13 reported cases in medical literature. Unfortunately, there are no specific recommendations or guidelines on treatment of such patients. The 2016 British Society for Rheumatology guidelines on prescribing in pregnancy also do not mention about managing gout in pregnancy. Therefore, we followed general guidelines. In our patient, allopurinol was discontinued because allopurinol is a potentially teratogenic drug. A recent review by Simsek et al. on the teratogenic potential of allopurinol states that the available data are insufficient to make a certain judgment. Therefore, they recommend a prospective study to resolve this issue. It was interesting to note that allopurinol use in pregnancy was reported in the systematic review by Horta-Baas et al. Despite older reports of teratogenicity of colchicine in animal experiments, more recent reports based on the use of colchicine in pregnancy in patients with familial Mediterranean fever More Details state that its use throughout pregnancy carries no substantial teratogenic or mutagenic risk when used at recommended doses. Our patient was thus maintained on colchicine; however, she kept on having gouty flares. Therefore, she was treated with repeated intra-articular injection of depot triamcinolone injection and colchicine throughout pregnancy. With this treatment, she was able to carry the pregnancy to full term delivering a healthy baby without any further flare during this time. Febuxostat could have been an option, but data on its safety in pregnancy are still scarce; therefore, the US FDA has not given recommendations for its use in pregnancy yet.
|Table 1: Causes of hyperuricemia that should be considered in individuals with low risk* for gout|
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The second patient has evidence of RA, but earlier, she has not been managed appropriately, and gout went unnoticed. The reason we believe that she has gout is that since the time of follow-up with us, she responded well to colchicine and urate-lowering therapy with febuxostat. Whether gout was present from the onset of arthritis or it developed when after she attained menopause could not be ascertained. Literature review showed that the concomitant presence of gout and RA is uncommon; only 33 cases of concomitant RA and gout reported in the literature from 1964 till 2017. These authors also reported a case series of coexistent RA and gout in their clinic. From 2004 to 2017, they identified 13 patients with both RA and gout, in whom nine were men and four were women. Among these, eight patients were diagnosed with RA who subsequently developed gout, while in five patients, gout was diagnosed first and developed RA subsequently. The mean age at the onset of the first disease was 55.3 years and that of the second disease was 64.4 years (either RA or gout being the first disease). Our second patient is likely to be similar to the eight patients described by these authors who had RA and subsequently developed gouty arthritis. Whether menopause adds to the possibility of developing gout in such female patients remains a possibility.
| Conclusion|| |
We report the occurrence of gout in two women, both in whom the diagnosis was not considered earlier. We suggest that in those patients with inflammatory arthritis/polyarthritis, even among premenopausal women, who do not respond to conventional DMARDs, an alternative diagnosis such as gout must be considered and attempts should be made to obtained synovial fluid for microscopic examination for crystals.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]