130 Journal of the Royal Society of Medicine Volume 86 March 1993

Rheumatism and the thyroid

D N Golding MA MD FRCPI The Old Forge, Woodside Green, Bishop's Stortford, Herts CM22 7UL

Keywords: thyrotoxicosis; rheumatism; hypothyroidism; Hashimoto's disease

Muscle weakness and are well-known Paradoxically the serum muscle enzymes (such as Presidential features of thyrotoxicosis. It is less well-known that creatine kinase) are more likely to be elevated in the Address muscle weakness, pain and even swelling of small mild myopathy associated with hypothyroidism than given to joints are not uncommon in hypothyroidism. Recently in the clinically more severe thyrotoxic myopathy6. Section of it has become apparent that a seronegative poly- Capsulitis of the is seen in some hypo- & arthritis of small joints may occur in patients with thyroid patients, though is commoner in thyrotoxicosis. Rehabilitation, Hashimoto's disease (even when euthyroid), and that A bilateral case has been described in a myxoedem- 13 May 1992 this condition may be responsible for other rheumatic atous patient with proximal myopathy and an acute features, such as and chest pain. phase response7. In hypothyroidism muscular pain is often associated with marked (the 'after tennis Historical note feeling') and prolonged morning stiffness (thought That rheumatic features can be associated with thyroid to be due to deficiency of alpha-glucosidase in this disorders has been known for some time: for example, condition), which may give a mistaken diagnosis in 1873 Sir William Gull described two cases of 'A of polymyalgia rheumatica. It must however be cretinoidal state supervening in Adult Women', remembered that polymyalgia rheumatica may coexist describing neck stiffness and joint pain; and early with hypothyroidism8- and indeed the prevalence of British reports were described in a recent paper by hypothyroidism in patients with polymyalgia is about in 5%, significantly greater than in controls. In practice Doyle this journal'. In 1883 Coxwell described it is myopathy in a case ofjuvenile myxoedema - a 13-year- worth screening polymyalgia patients, particularly old girl who 'previously could read a chapter out of those who have a normal, or only slightly raised the Bible, but then developed defective memory, her erythrocyte sedimentation rate (ESR), and those who head drooped forward unto her chest, her legs became are not doing so well on steroids, for hypothyroidism. weak and unsteady' 2. Retrospectively, this sounds Apart from muscle weakness, generalized pains and rather like stiffness may occur in hypothyroidism and this has myxoedematous cerebellar degeneration, been said to be a cause of 'fibrositis' (). a rare complication of hypothyroidism. As recently in as 1966 the first full Impairment ofstage IV sleep occurs both conditions Ramsey gave description of and in a recent study of 15 patients fulfilling the thyrotoxic myopathy3. criteria of fibrositis all were found to have either hypothyroidism or psychiatric disturbance8. In a paper Rheumatic features of hypothyroidism presented at Budapest last year 22% cases offibrositis The spectrum ofrheumatic disorders which have been had a blunted thyroid-stimulating hormone (TSH) described in hypothyroidism is depicted in Figure 1. response and 7% had subclinical hypothyroidism9. These vary from muscle weakness to generalized pain Tricyclic antidepressants can be beneficial in treating and stiffness, of small or large joints and some patients with fibrositis associated with latent occasionally a destructive type of arthropathy4. depression, but this is not so in fibrositis associated Unlike thyrotoxicosis, severe myopathy and poly- with hypothyroidism, and indeed antidepressants are rare in hypothyroidism. However, general often seem to aggravate pain in this condition. muscle weakness (often with some degree of pain or Coming to the synovial joints, a small-joint poly- discomfort) is not uncommon5. Histologically the arthritis is sometimes seen in patients with muscle may show deposits ofmucin in the perimysium hypothyroidism (and indeed in some euthyroid as well as the usual changes ofmyopathy, and electron patients having high titres of thyroid antibodies, as microscopy may show mitochondrial abnormalities. will be mentioned later). However, effusions into large joints, such as the knees, though reported are rarely seen in practice. Bland and Frymoyer first described effusions'0 and found the fluid to be Muceb hyphy synovial highly (re) viscous and to have other non-inflammatory features, suggesting that the effusions are related to hyaluron- tMtuacb,dmes_ - &(PclYm"eeW) (¶lbmdds_ andotffhe ate deposition in the synovium and ligaments. It Myophy has alternatively been proposed that activation of adenylate cyclase in synovial membranes by excess ( (use)~ ~ TSH produces effusions into joints". intfUdWorm Dedwecw Other possible causes ofjoint pain in myxoedema (rem) are secondary gout, hyperuricaemia being common fffob gc in this condition; and pyrophosphate pseudogout, calcium pyrophosphate dihydrate crystals having Figure 1. Spectrum ofrheumatic disorders in hypothyroidism been found in knee effusions, which in fact may be Journal of the Royal Society of Medicine Volume 86 March 1993 131 precipitated by the instigation of thyroid therapy or Rheumatic features of Hashimoto's disease sudden increase in dosage'2. It is ofconsiderable interest that rheumatic features Rarer musculoskeletal disorders in myxoedema may occur in euthyroid patients with auto-immune include a destructive arthropathy ofthe knees, possibly thyroiditis as well as in those with disturbed thyroid resulting from hyaluronate infiltration of bone13 and function. In recent years I have followed up 12 a destructive arthropathy of the small finger-joints such patients (see Table 2) who were euthyroid or has been described. marginally hypothyroid (eg T4 normal, TSH margin- Hypothyroid patients occasionally present at ally raised). These patients have high levels of rheumatology departments with neurological features, circulating thyroid antibodies, in particular thyroid particularly carpal tunnel syndromes. However, while microsomal antibodies - the titres of which may be in it is true that these occur in 7% of patients with the region of 1: 50 000 or higher. Some had a large, myxoedema, there is a mistaken belief that hypo- multinodular goitre, needle biopsy or excision showing thyroidism is a common cause of 'carpal tunnels'. lymphocytic infiltration (especially T-cells), lymphoid In a personal series, 50 patients presenting with follicles and variable destruction of thyroid cells. paraesthesiae ofthe fingers referred for median nerve Many had a raised ESR and altered gamma globulins. conduction tests were screened for hypothyroidism: In my series generalized pains and stiffness 25 had electrical evidence ofmedian nerve compression (especially neck pain) and a benign form of sero- in one or both wrists but only two of these were negative inflammatory polyarthritis resembling hypothyroid. A recent Japanese study confirmed early, mild rheumatoid disease were notable features that hypothyroidism was the cause of carpal tunnel of Hashimoto's syndrome (first described by Leriche syndromes in only 6% of 1215 patients. This contrasts in 198415). Many patients complained of significant with the high prevalence of slowing of median nerve morning stiffness, most had a mild small-joint poly- conduction (possibly 70%) in those with known arthritis, a few had more severe joint changes - these myxoedema, presumably due to an additional intrinsic had positive rheumatoid factor. It seems that these neuropathy'2. patients fall into one of two groups: (a) mild, seronegative, tend to have HLA-DR2 and the joint changes markedly improve with thyroid therapy; Rheumatic features of hyperthyroidism (Table 1) (b) there are more definite rheumatoid-like features Thyrotoxic myopathy is, of course, well-known. It with more severe synovitis, rheumatoid factor is may be due to an auto-antibody developing against present and they have HLA-DR4, the joints are TSH-receptors, so stimulating the thyroid cells to unaffected by thyroid therapy and usually require produce excessive thyroxine and breaking down second-line drug therapy for control. It appears that muscle fibres. As already mentioned, muscle biopsy the first, seronegative group represents a definite, often shows typical myopathic appearances but, non-rheumatoid syndrome ofseronegative polyarthritis unlike hypothyroid myopathy, paradoxically the associated with auto-immune thyroiditis. muscle enzymes are often normal. Occasionally Table 3 gives other possible associations ofrheumatic myasthenia gravis may coincide with severe pro- disorders with Hashimoto's disease, which must be gressive thyrotoxic myopathy. Frozen shoulders, considered as a generalized disorder often overlapping often bilateral, are not uncommon in patients with with systemic connective tissue disorders such as thyrotoxic myopathy and often antithyroid treatment systemic and Sjogren's syndrome (thyroid improves the pain and stiffness14, though will not antibodies are found in 40% patients with Sjogren's afford complete resolution ofthe capsulitis. Sometimes syndrome16). In one series, abnormal thyroid function -hand syndromes occur in association with frozen shoulders - pain and swelling ofthe hands due to reflex sympathetic dystrophy, thought to be Table 2. Personal series of 12 patients with rheumatic dis- brought about by catecholamine-like actions of orders thought to be associated with auto-immune thyroiditis thyroid hormones. Two other conditions, probably auto-immune in Generalized pains/stiffness 5 nature, must be mentioned in connection with Neck pain 3 hypothyroidism. Thyroid acropachy is a rare soft- Carpal tunnel syndromes 3 tissue swelling of the hands and feet with clubbing Polyarthralgia/synovitis 5 of the fingers and periosteal reactions visible along Myopathy 1 the metacarpal bones. Pretibial myxoedema is Thyroid enlargement 3 the name given to mucinous thickening and dis- Thyroid antibodies + + + (esp. microsomal) 12 colouration of the skin of the skin of the legs, Rheumatoid factor 1 sometimes giving an appearance akin to erythema Antinuclear antibody 0 nodosum.

Table 3. Reported associations of auto-immune thyroiditis with connective tissue disorders Table 1. Rheumatic features of hyperthyroidism Systemic connective tissue disorders (eg SLE, Sjogren's) Thyrotoxic myopathy Rheumatoid arthritis +myasthenia gravis Polymyalgia rheumatica/ Capsulitis of shoulders Muscle pain/stiffness/fibromyalgia (including 'chest pain +shoulder-hand syndrome syndrome') Thyroid acropachy Anterior neck pain Pretibial myxoedema Inflammatory/small-joint seronegative polyarthritis 132 Journal of the Royal Society of Medicine Volume 86 March 1993 tests occurred in 53% of 332 patients with SLE'5. (4) In thyrotoxicosis, proximal myopathy is common. Auto-immune cross-reactions are common, high titres Occasionally frozen shoulders and shoulder-hand ofthyroid antibodies often occurring in these conditions. syndromes are seen in this condition, otherwise Blake17 studied thyroid antibodies in the synovial muscle and joint pain are not common features. fluid ofpatients with various types of arthritis, finding (5) Patients with Hashimoto's disease may present microsomal and thyroglobulin activity in 34 of 50 with a mild, seronegative small-joint polyarthritis patients, of which only four had thyroid antibodies in resembling early rheumatoid disease. This is a dis- the serum. This suggested that thyroid antibodies may tinctive non-rheumatoid syndrome, the symptoms be produced locally in the joints and the synovial responding rapidly to thyroid therapy. tissues may contain a repository of antithyroid- (6) Important 'soft-tissue' rheumatic features of antibody-forming cells. Hashimoto's disease include syndromes of A peculiar syndrome of anterior chest pain has been anterior chest pain and anterior neck pain, the described in Hashimoto's syndrome, as illustrated by latter being associated with enlargement of the the following personal case. For years a woman thyroid. suffering from anterior chest pain had been told she (7) Subacute thyroiditis (de Quervain's disease) is an had 'intercostalitis'. Extensive cardiac investigations acute form of auto-immune thyroiditis with were normal and notreatment seemedeffective. Thyroid inflammatory features, including a tender thyroid function was normal but she had strongly positive causing neck pain. This condition usually responds thyroid antibodies. It was felt she had Hashimoto's promptly to a short course of systemic steroids. syndrome and the chest pain improved within a few weeks of starting thyroxine. References Anterior neck pain is sometimes a feature of 1 Doyle L. Myxoedema: some early reports and Hashimoto's, particularly where there is a fullness contributions by British authors. J R Soc Med 1991; of the neck due to thyroid enlargement, and this 84:103-6 should always be considered in patients with persistent 2 Coxwell CF. Trans Clin Soc London 1883;16:75 neck pain unrelieved by usual local measures. 3 Ramsey ID. Muscle dysfunction in hyperthyroidism. Lancet 1966;2:931-4 4 Golding DN. Hypothyroidism presenting with musculo- Subacute skeletal symptoms. Ann Rheum Dis 1970;29:10-14 thyroiditis 5 Fesell JW. Myopathy of hypothyroidism. Ann Rheum Subacute thyroiditis (De Quervain's disease) is an Dis 1968;27:590 accentuated form of auto-immune thyroiditis together 6 Griffiths PD. Creatinephosphokinase levels in hypo- with inflammatory features. Neck pain of a more thyroidism. Lancet 1963;i:894 severe variety is a feature ofthis condition, where the 7 Bowman CA, Jeffcoate WJ, Pattrick M, Doherty M. thyroid gland is enlarged, tender and may appear Bilateral adhesive capsulitis, olegoarthritis and inflamed. There may be systemic features such as proximal myopathy as presentation ofhypothyroidism. pyrexia, malaise and a high ESR. This is a rewarding Br J Rheumatol 1988;27:62-4 diagnosis, as there is an impressive response to a 8 Bowness P, Shotliff K, Middlemiss A, Myles AB. course of systemic steroids - the neck pain quickly Prevalence of hypothyroidism in patients with poly- the becomes rheumatica and giant cell arthritis. Br J subsides, thyroid gland progressively Rheumatol 1991;30:349-51 smaller and less tender and the ESR falls to normal 9 Fredricksson E, Nived 0. Does primary fibromyalgia levels. Sometimes minor attacks of de Quervain's exist? Br J Rheumatol 1990;29:368-70 syndrome are seen in patients with Hashimoto's 10 Neeck G, Riedel W. Thyroid function in patients with disease and these rapidly come under control with brief fibromyalgia syndrome. European Meeting, Budapest, courses of steroids. Abstract FP42, 1991:434 11 Bland JH, Frymoyer JW. Rheumatic symptoms of myxoedema. N Engl J Med 1970;282:1171-4 Conclusions 12 Newcombe DS, Ortel RW, Levey GS. Activation of (1) Thyroid disorders may be responsible for soft-tisse human adenylate cyclase by thyroid and joint pains and muscle weakness. stimulating hormone (TSH). Biochem Biophys Res 1972; 48:102-4 (2) Patients with hypothyroidism may complain of 13 Dux S, Pitlif S, Rosenfeld JB. Pseudogouty arthritis in 'fibrositis', muscle weakness and occasionally a hypothyroidism. Arthritis Rheum 1979;22:1416-17 small-joint seronegative polyarthritis resembling 14 Fincham RW, Cape CA. Neuropathy in myxoedema. rheumatoid disease. However, involvement oflarge Arch Neurol 1968;19:464-6 joints and effusions are rare. Another possible 15 Leriche NGH, Bell DA. Hashimoto's thyroiditis and cause ofjoint pain in hypothyroidism is urate or polyarthritis. Ann Rheum Dis 1984;43:594-8 pyrophosphate crystal synovitis. 16 Weiss JJ, Thompson GR, Woodbury D. Hypothyroidism (3) Paraesthesiae ofthe fingers is a common symptom presenting as acute shoulder pain. Mich Med 1973; of myxoedema and may be due to carpal tunnel 72:771-4 syndromes or (less commonly) an intrinsic neuro- 17 Blake DR, McGregor AM, Stansfield E, Rees Smith B. Antithyroid-Antibody activity in the synovial fluid of pathy. However, hypothyroidism is only responsible patients with various arthritides. Lancet 1979;ii:224 for a minority of cases of carpal tunnel syn- drome. (Accepted 13 July 1992)