Objectives: Rheumatoid arthritis is sometimes misdiagnosed for other diseases, like psoriatic arthritis, erosive OA, viral arthritis, reactive arthritis, IBD arthritis, Lyme’s disease, and palindromic rheumatism. Secondary hyperparathyroidism was not included in the differential diagnosis of RA, though it sometimes presents with joint pains and tenderness, and even arthritis. Fibromyalgia is a psychosomatic disorder characterized by chronic widespread pain and tender areas. Mimicry of some manifestations of these diseases sometimes results in misdiagnosis as RA. Methods: Two hundred patients previously diagnosed as RA from outpatient clinics in Al-Azhar Faculty of Medicine, attended as not responding to medical treatment of RA. All patients were subjected to a re-evaluation of disease activity including HAQ, and DAS 28, CDAI, and SDAI. Also, we measured serum vitamin D3, PTH, total and ionized Calcium, Phosphorus, Uric acid, ACPA, and other routine lab. All patients were exposed to various radiological imaging modalities. Results: Cases not responding to RA treatment were reevaluated and were found to have a syndrome of fibromyalgia associated with vitamin D3 deficiency and secondary hyperparathyroidism. Conclusions: Fibromyalgia/Hyperparathyroidism syndrome is an underdiagnosed disease, which results from chronic vitamin D3 deficiency. SHPT can cause bone erosions, which are mostly shaggy in appearance and distributed in the radiocarpal, radioulnar, metacarpophalangeal and distal interphalangeal joints, in contrast to that which predominate proximal IP joints of rheumatoid arthritis. Radiology of FM/HPT syndrome patients revealed a sign of spur-like excrescences in terminal finger tufts unilaterally or bilaterally, which we think is pathognomonic.
Secondary hyperparathyroidism (SHPT) is the medical condition of excessive secretion of parathyroid hormone (PTH) by the parathyroid glands in response to hypocalcemia, with resultant hyperplasia of these glands. Chronic kidney failure is the most common cause of SHPT due to failure of kidneys to not convert enough vitamin D2 to its active form D3, and hence to not adequately excrete phosphate. When this happens, insoluble calcium phosphate forms in the body and removes calcium from the circulation. Both processes lead to hypocalcemia and hence SHPT [
HPT is usually associated with muscle cramps and bone pain, perioral tingling or paresthesia in fingers or toes, positive Chvostek and Trousseau signs. Arthritis simulating rheumatoid arthritis as the presenting feature of HPT was reported in literatures only rarely [
Rheumatoid arthritis (RA) is a chronic autoimmune disease that primarily affects joints. It typically results in warm, swollen, and painful joints. Most commonly, wrists and hands are involved, with the same joints typically involved bilaterally. It was known that RF is not specific for RA and could be found in other diseases such as Epstein–Barr virus or Parvovirus infections and in 5% to 10% of healthy persons, especially the elderly [
As we know, one of the causes of SHPT is vitamin D3 deficiency which was found to be widespread in Middle East whilst the area is rich in sun rays and consequently UV exposure. One of the most probable causes of vitamin D deficiency in Middle East area is pollution with heavy metals, like cadmium and lead [
Cadmium preferentially selects to settle in kidneys. Renal cadmium deposition induces injury resulted from accumulation of cadmium-metallothionein (CdMT) in the proximal convoluted tubules. CdMT-induced nephrotoxicity might be due, at least in part, to its preferential uptake of CdMT into the S1 and S2 segments of the proximal tubules, which is responsible for converting 25(OH)D3 to 1,25(OH)2D3 [
Vitamin D3 deficiency and HPT are established to be associated with Fibromyalgia syndrome [
This study included 200 female patients attended outpatient clinics of Al-Azhar University Faculty of medicine Hospitals, who had a previous diagnosis of RA and not responding to classic treatment including DMARDs, and had been allocated for biological therapy (
All patients were diagnosed according to old and new criteria for classification of RA [
Patients were reevaluated using old and new criteria for classification of RA. [
We reevaluated 70 seronegative and 130 seropositive RA patients. Eighty patients (Group 1) were fulfilling both old and new criteria of fibromyalgia syndrome, and not fulfilling any RA criteria, 65 of them were seronegative and 15
No | % | Age years | Female Sex | Duration years | ||
---|---|---|---|---|---|---|
N | % | |||||
Seropositive | 130 | 65% | 40 ± 13 | 130 | 100% | 6.5 ± 3.2 |
Seronegative | 70 | 35% | 38 ± 16 | 70 | 100% | 5.9 ± 2.8 |
200 | 100% |
were seropositive with low RF titers and negative ACPA. All patients had vitamin D3 deficiency, but it was significantly lower in Group 1. Sixty patients in Group 1 (75%) had abnormally high levels of PTH 99 ± 15 pg/ml, and had no parathyroid gland pathology; hence we called them SHPT group (
RA (Group 2) were fulfilling either or both ACR and EULAR criteria, and not fulfilling any of Fibromyalgia criteria. They yielded moderate to high scores 0f DAS 28 (5.68 ± 1.25), CDAI (30.4 ± 6.4), and SDAI (31.67 ± 15.25) (
No | ESR mm | SUA mg/dl | Ca mg/dl | Ca2+ mg/dl | D3 ng/ml | PTH pg/ml | P mg/dl | |
---|---|---|---|---|---|---|---|---|
Group 1 SHPT | 80 | 45 ± 11 | 7.6 ± 2.3 | 8.8 ± 1.6 | 1.12 ± 0.21 | 12.56 ± 4.76 | 99 ± 15 | 4.9 ± 1.8 |
Group 2 RA | 120 | 78 ± 18 | 5.6 ± 1.3 | 9.5 ± 1.2 | 2.8 ± 1.1 | 14.64 ± 7.87 | 45 ± 14 | 3.8 ± 1.2 |
P | <0.001 | <0.001 | <0.001 | <0.001 | <0.05 | <0.001 | <0.001 |
RA: rheumatoid arthritis, SHPT: secondary hyperparathyroidism, ESR: erythrocyte sedimentation rate, SUA: serum uric acid, Ca: total calcium, Ca2+: ionized calcium, D3: vitamin D3, PTH: parathyroid hormone, P: serum phosphorus.
NO | RN | Dur | CCP | RF | Radiology | TTP | SSS | WPI | |
---|---|---|---|---|---|---|---|---|---|
Group 1 SHPT | 80 | 0 % | 1.22 ± 0.86 | 0% | 18% | 0% | 15.2 ± 2.3 | 9.62 ± 2.11 | 15.32 ± 3.34 |
Group 2 RA | 120 | 35% | 4.6 ± 2.3 | 90% | 70% | 100% | 4.2 ± 1.2 | 3.11 ± 1.13 | 4.31 ± 1.65 |
P | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 |
RA: rheumatoid arthritis, SHPT: secondary hyperparathyroidism, RN: rheumatoid nodules, Dur: duration, CCP: anti-CCP, RF: rheumatoid factor, TTP: tender trigger points, SSS: symptom severity score, WPI: widespread pain index.
DAS 28 | SJC | TJC | MS | VAS | CDAI | SDAI | ||
---|---|---|---|---|---|---|---|---|
Group 1 SHPT | 80 | 1.61 ± 0.71 | 2.01 ± 0.91 | 6.54 ± 2.43 | 0 | 54.77 ± 11.33 | 5.68 ± 1.25 | 1.8 ± 0.3 |
Group 2 RA | 120 | 5.68 ± 1.25 | 7.13 ± 5.02 | 11.55 ± 7.39 | 31.4 ± 29.3 | 63.48 ± 25.43 | 30.4 ± 6.4 | 31.67 ± 15.25 |
P | <0.001 | <0.001 | <0.001 | <0.001 | <0.05 | <0.001 | <0.001 |
RA: rheumatoid arthritis, SHPT: secondary hyperparathyroidism, DAS: disease activity score, SJC: swollen joint count, TJC: tender joint count, MS: morning stiffness, SDAI: simple disease activity index, CDAI: clinicaldisease activity index, VAS: visual analogue scale.
Plain radiographs of RA (Group 2) show identical RA changes of juxta-articular osteoporosis, subchondral cysts, juxta-articular bony erosions, ulnar deviation of the MCP joints, boutonniere and swan neck deformities, hitchhiker’s thumb deformity, and ulnar translocation.
On the other hand, X-rays of SHPT (Group 1) hands showed subperiosteal and subchondral resorption of mainly thumbs, subchondral osteopenia of proximal and middle phalanges, mild subperiosteal resorption along the radial aspect of the middle phalanx and mild tuft erosions, besides changes in the carpus closely resembling those of rheumatoid arthritis, of ulnar styloid resorption, radiocarpal and scapho-trapezoid joint arthritis. Of special interest, the presence of tuft spurs-like excrescences mimicking that of (spade phalanx sign) of acromegaly, but without any other criteria of acromegaly (
Incidence of X-ray findings of subperiosteal resorption, osteolysis of distal phalanges, brown tumors in lumbar spine, rugger jersey appearance of vertebral column, calcaneal spurs, chondrocalcinosis, and tuft spur-like excrescences were described (
Group | N0 | Sr | Odp | Bt | Rj | Cs | ch | Ts |
---|---|---|---|---|---|---|---|---|
Group 1 SHPT | 80 | 58 % | 8.22 ± 0.86 | 23% | 20% | 60% | 5% | 85% |
Group 2 RA | 120 | 35% | 0 | 0 | 0 | 5% | 0 | 0 |
P | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 |
RA: rheumatoid arthritis, SHPT: secondary hyperparathyroidism, Sr: Subperiosteal resorption, Odp: Osteolysis of distal phalanges, Bt: Brown tumours, Rj: Rugger jersey appearance of vertebral column, Cs: Calcaneal spurs, ch: chondrocalcinosis, Ts: Tuft spur-like excrescences.
Patients who reevaluated as having Fibromyalgia/SHPT syndrome stopped RA treatment, and were allocated to fibromyalgia regimen of SSRI, muscle relaxants, and vitamin D3 supplementation 5000 - 10,000 iu/day, in addition to sulphasalazine 1 - 2 gm/day to which their inflamed joints responded significantly.
We found many patients with bilateral wrists and hands arthritis who had a constellation of vitamin D3 deficiency, elevated parathyroid hormone, and fibromyalgia. They were misdiagnosed as either seronegative or seropositive rheumatoid arthritis, which resulted in nonresponse to treatment and permanent discomfort. A study by Helliwell showed arthritis in 11% of HPT patients, including two cases of erosive arthritis [
Radiographical features were helpful to differentiate both, in addition to clinical and biochemical features. Other than HPT causes osteoporosis and pathological fractures,it can cause bone erosions, which are mostly shaggy in appearance and distributed in the radiocarpal, radioulnar, metacarpophalangeal and distal interphalangeal joints, in contrast to that which predominate proximal interphalangeal joints of rheumatoid arthritis [
Nowadays, the most common radiologic finding in HPT is osteopenia, which may be generalized or asymmetric. Fine trabeculations are initially lost, with resultant coarse and thickened trabeculae. The disease may progress with further destruction that results in a ground-glass appearance in the trabeculae [
Of special interest, the presence of tuft spurs-like excrescences mimicking that of spade phalanx sign of acromegaly [
Due to lack of typical clinical features, hyperparathyroidism is often undiagnosed or misdiagnosed, especially in unspecialized centers. Hence, rheumatologists should have a high degree of suspicion for differential diagnosis at the beginning and during follow-ups especially when the initial diagnosis is doubtful, or the treatment is not effective.
We have characterized a syndrome of VitaminD3 deficiency/Fibromyalgia/ Hyperparathyroidism mimicking Rheumatoid Arthritis. It is characterized by longstanding vitamin D3 deficiency, associated with hyperparathyroidism and fibromyalgia, predominantly negative Anti CCP, while RF may be low positive. Radiologically is characterized by the presence of finger tuft acro-osteolysis with spur like excrescences which is pathognomonic, besides other features of hyperparathyroidism including subperiosteal and subchondral resorption of mainly thumbs, subchondral osteopenia of proximal and middle phalanges, mild subperiosteal resorption along the radial aspect of the middle phalanx and mild tuft erosions, besides changes in the carpus closely resembling those of rheumatoid arthritis, of ulnar styloid resorption, radiocarpal and scapho-trapezoid joint arthritis. This syndrome responds well to treatment of fibromyalgia regimen of SSRI, muscle relaxants, and vitamin D3 supplementation 5000 - 10,000 iu/day, in addition to sulphasalazine 1 - 2 gm/day to which their inflamed joints responded significantly.
All authors confirm that there are no any potential conflicts of interest of each of them. We confirm hereby that the manuscript has not been submitted or is not simultaneously being submitted elsewhere, is not at the time of submission under consideration by another journal or other publication, and that no portion of the data has been or will be published elsewhere while the manuscript is under review by the journal, unless rejected or withdrawn by the author. Also we confirm that no portion of the data has been or will be published elsewhere while the manuscript is under review by the journal.
We confirm also that there are not any financial support or other benefits from commercial sources for the work reported on in the manuscript, or any other financial interests that any of the authors may have, which could create a potential conflict of interest or the appearance of a conflict of interest with regard to the work.
Elbeialy, A., Bauomi, A., Elnaggar, B. and Elzomor, H. (2021) A Syndrome of Vitamin D3 Deficiency/Fibromyalgia/Hyperparathyroidism Mimicking Rheumatoid Arthritis, a Clinical Prospective Study. Open Journal of Rheumatology and Autoimmune Diseases, 11, 79-88. https://doi.org/10.4236/ojra.2021.112010